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Sample records for 10-14 m2 s-1

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

    PubMed Central

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

    2017-01-01

    Introduction. Macrophages are key players in complex biological processes. In response to environmental signals, macrophages undergo polarization towards a proinflammatory (M1) or anti-inflammatory (M2) phenotype. Sphingosine 1-phosphate (S1P) is a bioactive lysophospholipid that acts via 5 G-protein coupled receptors (S1P1–5) in order to influence a broad spectrum of biological processes. This study assesses S1P receptor expression on macrophages before and after M1 and M2 polarization and performs a comparative analysis of S1P signalling in the two activational states of macrophages. Methods. Bone marrow derived macrophages (BMDM) from C57 BL/6 mice were cultured under either M1- or M2-polarizing conditions. S1P-receptor expression was determined by quantitative RT-PCR. Influence of S1P on macrophage activation, migration, phagocytosis, and cytokine secretion was assessed in vitro. Results. All 5 S1P receptor subclasses were expressed in macrophages. Culture under both M1- and M2-polarizing conditions led to significant downregulation of S1P1. In contrast, M1-polarized macrophages significantly downregulated S1P4. The expression of the remaining three S1P receptors did not change. S1P increased expression of iNOS under M2-polarizing conditions. Furthermore, S1P induced chemotaxis in M1 macrophages and changed cytokine production in M2 macrophages. Phagocytosis was not affected by S1P-signalling. Discussion. The expression of different specific S1P receptor profiles may provide a possibility to selectively influence M1- or M2-polarized macrophages. PMID:28367448

  2. Form factors of descendant operators: reduction to perturbed M (2 , 2 s + 1) models

    NASA Astrophysics Data System (ADS)

    Lashkevich, Michael; Pugai, Yaroslav

    2015-04-01

    In the framework of the algebraic approach to form factors in two-dimensional integrable models of quantum field theory we consider the reduction of the sine-Gordon model to the Φ13-perturbation of minimal conformal models of the M (2 , 2 s + 1) series. We find in an algebraic form the condition of compatibility of local operators with the reduction. We propose a construction that make it possible to obtain reduction compatible local operators in terms of screening currents. As an application we obtain exact multiparticle form factors for the compatible with the reduction conserved currents T ±2 k , Θ±(2 k-2), which correspond to the spin ±(2 k - 1) integrals of motion, for any positive integer k. Furthermore, we obtain all form factors of the operators T 2 k T -2 l , which generalize the famous operator. The construction is analytic in the s parameter and, therefore, makes sense in the sine-Gordon theory.

  3. High Frequency of vacA s1m2 Genotypes Among Helicobacter pylori Isolates From Patients With Gastroduodenal Disorders in Kermanshah, Iran

    PubMed Central

    Pajavand, Hamid; Alvandi, Amirhooshang; Mohajeri, Parviz; Bakhtyari, Somaye; Bashiri, Homayoon; Kalali, Behnam; Gerhard, Markus; Najafi, Farid; Abiri, Ramin

    2015-01-01

    Background: 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. Objectives: 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. Patients and Methods: 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. Results: 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). Conclusions: 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). PMID:26862378

  4. Effect of irradiances up to 2000 μE m -2 s -1 on marine Synechococcus WH7803—I. Growth, pigmentation, and cell composition

    NASA Astrophysics Data System (ADS)

    Kana, Todd M.; Glibert, Patricia M.

    1987-04-01

    We grew Synechococcus WH7803 at rates exceeding 1.4 d -1 at irradiances from 200 to 2000 μE m -2 s -1 under continuous light in nutrient replete media with no evidence of photoinhibition. Concentrations of the photosynthetic pigments phycoerythrin, phycocyanin, and chlorophyll a, were inversely related to growth irradiance. Phycoerythrin exhibited the greatest plasticity with the concentration in cells adapted to 30 μE m -2 s -1 being ca. 20 times greater than that in cells adapted to 700 μE m -2 s -1. Changes in the phycoerythrin: phycocyanin ratio as well as their respective concentrations indicate that phycobilisomes underwent changes in size at irradiances which saturated or nearly saturated growth and underwent changes in number at irradiances which limited growth. Phycoerythrin in high light adapted cells contained <3% of the cell nitrogen as opposed to >20% in light limited cells. Results support the notion that nutrient replete Synechococcus have the capacity to grow at maximal growth rates in brightly lit oceanic surface mixed layers.

  5. The diffusion of cesium in the graphitic matrix A3-3 under irradiation by a fast neutron flux of 2 × 10 17 m -2 s -1

    NASA Astrophysics Data System (ADS)

    Hensel, W.; Hoinkis, E.

    1995-09-01

    The 137Cs core release rate of High Temperature Reactors (HTR) is effected by the interactions of cesium with the graphitic material used as a matrix for the coated fuel particles. The migration of 137Cs in the graphitic matrix A3-3 at a fast neutron flux of 2 × 10 17 m -2 s -1 was studied in short-term experiments using the thin-film technique. The penetration profiles did not satisfy Fick's second law. The diffusion/trapping/re-emission model was applied to determine the diffusion coefficient D and the trapping coefficient μ for four profiles produced at 1088 and 1166 K. D, μ and the reemission coefficient b at 1293 K were determined for two profiles. Compared to laboratory conditions no effect of the fast neutron irradiation on the 137Cs migration in matrix A3-3 was observed.

  6. 24 CFR 10.14 - Hearings.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 1 2010-04-01 2010-04-01 false Hearings. 10.14 Section 10.14 Housing and Urban Development Office of the Secretary, Department of Housing and Urban Development RULEMAKING: POLICY AND PROCEDURES Procedures § 10.14 Hearings. (a) The provisions of 5 U.S.C. 556 and...

  7. 24 CFR 10.14 - Hearings.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 24 Housing and Urban Development 1 2011-04-01 2011-04-01 false Hearings. 10.14 Section 10.14... RULEMAKING: POLICY AND PROCEDURES Procedures § 10.14 Hearings. (a) The provisions of 5 U.S.C. 556 and 557, which govern formal hearings in adjudicatory proceedings, do not apply to informal rule making...

  8. 24 CFR 10.14 - Hearings.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 24 Housing and Urban Development 1 2012-04-01 2012-04-01 false Hearings. 10.14 Section 10.14... RULEMAKING: POLICY AND PROCEDURES Procedures § 10.14 Hearings. (a) The provisions of 5 U.S.C. 556 and 557, which govern formal hearings in adjudicatory proceedings, do not apply to informal rule making...

  9. Expansion and Evolution of a Virulent, Extensively Drug-Resistant (Polymyxin B-Resistant), QnrS1-, CTX-M-2-, and KPC-2-Producing Klebsiella pneumoniae ST11 International High-Risk Clone

    PubMed Central

    Vitali, Lúcia; Gaspar, Gilberto Gambero; Bellissimo-Rodrigues, Fernando; Martinez, Roberto; Darini, Ana Lúcia Costa

    2014-01-01

    In this study, we report the early expansion, evolution, and characterization of a multiresistant Klebsiella pneumoniae clone that was isolated with increasing frequency from inpatients in a tertiary-care university hospital in Brazil. Seven carbapenem- and quinolone-resistant and polymyxin B-susceptible or -resistant K. pneumoniae isolates isolated between December 2012 and February 2013 were investigated. Beta-lactamase- and plasmid-mediated quinolone resistance (PMQR)-encoding genes and the genetic environment were investigated using PCR, sequencing, and restriction fragment length polymorphism (RFLP). Clonal relatedness was established using XbaI–pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), and phylogenetic group characterization. Plasmid analyses included PCR-based replicon typing (PBRT) and hybridization of the S1-PFGE product, plasmid MLST, and conjugation experiments. Virulence potential was assessed by PCR by searching for 10 virulence factor-encoding genes (ureA, fimH, kfuBC, uge, wabG, magA, mrkD, allS, rmpA, and cf29a) and by phenotypic tests to analyze the hypermucoviscous phenotype. The genetic context of a multidrug-resistant and extensively drug-resistant K. pneumoniae ST11-KpI clone harboring IncFIIk-Tn4401a-blaKPC-2, qnrS1, and blaCTX-M-2 was found. Moreover, three isolates displayed high resistance to polymyxin B (MICs = 32, 32, and 128 mg/liter) as well as mucous and hypermucoviscous phenotypes. These bacteria also harbored ureA, fimH, uge, wabG, and mrkD, which code for virulence factors associated with binding, biofilm formation, and the ability to colonize and escape from phagocytosis. Our study describes the association of important coresistance and virulence factors in the K. pneumoniae ST11 international high-risk clone, which makes this pathogen successful at infections and points to the quick expansion and evolution of this multiresistant and virulent clone, leading to a pandrug-resistant phenotype and

  10. 15 CFR 10.14 - Appeals.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... PRODUCT STANDARDS § 10.14 Appeals. (a) Any person directly affected by a procedural action taken by NIST..., by NIST or the Standing Committee under § 10.10 regarding the review of a published standard, or... action complained of (NIST, the Standard Review Committee, or the Standing Committee) within 30 days...

  11. An Exploratory Pilot Study of the Strengthening Families Programme 10-14 (UK)

    ERIC Educational Resources Information Center

    Coombes, Lindsey; Allen, Deborah Mary; Foxcroft, David

    2012-01-01

    The Strengthening Families Programme 10-14 (SFP10-14; UK) is a seven-session DVD-based family skills training programme. While the programme has been extensively evaluated in the United States, no randomized controlled trial (RCT) of the SFP10-14 has been conducted in the United Kingdom. This exploratory Phase II study was an evaluation of a…

  12. 46 CFR 30.10-14 - Combination carrier-TB/ALL.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 1 2010-10-01 2010-10-01 false Combination carrier-TB/ALL. 30.10-14 Section 30.10-14 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS GENERAL PROVISIONS Definitions § 30.10-14 Combination carrier—TB/ALL. The term combination carrier means a tank vessel designed to...

  13. 46 CFR 30.10-14 - Combination carrier-TB/ALL.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 1 2011-10-01 2011-10-01 false Combination carrier-TB/ALL. 30.10-14 Section 30.10-14 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS GENERAL PROVISIONS Definitions § 30.10-14 Combination carrier—TB/ALL. The term combination carrier means a tank vessel designed to...

  14. M2-F1 Pilots

    NASA Technical Reports Server (NTRS)

    1963-01-01

    The M2-F1 lifting body aircraft rests on the sun-baked floor of a dry lake bed located out in the Mojave Desert at the Dryden Flight Research Center, California. Pilot Chuck Yeager, seated in the cockpit of the M2- F1, talks with fellow pilots from left to right Milt Thompson, Don Malick and Bruce Peterson. All three flew the lifting body in several flights. The vehicle later suffered a mishap when Peterson was landing it--the oil in the landing gear hydraulics was not suitable for cold temperatures and caused the gear to break and the vehicle to suffer minor damage.

  15. Mitsubishi A6M2

    NASA Technical Reports Server (NTRS)

    1943-01-01

    Captured at Akutan Island, Alaska, in August 1942. This Mitsubishi A6M2 fighter was the first 'Zero' to fall intact into Allied hands during WW II. After limited flying on the West Coast, the 'Zero' arrived at Langley for installation of test equipment prior to in-depth flight testing by the Navy at Patuxent River, Maryland.

  16. M2-F1 cockpit

    NASA Technical Reports Server (NTRS)

    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

  17. Drug Ingestions in Children 10-14 Years Old: An Old Problem Revisited

    ERIC Educational Resources Information Center

    Pomerantz, Wendy; Gittelman, Michael; Farris, Sarah; Frey, Lauren

    2009-01-01

    To determine changes in rates of drug ingestions in 10-14 year old children in our country, a retrospective chart review of 10-14 year olds hospitalized for drug ingestion between 1993-1995 and 2000-2004 was performed. Odds ratios and Chi-square were used for analyses. From 1993-1995 there were 92.8 ingestions/100,000 children/year; from 2000-2004…

  18. Drug Ingestions in Children 10-14 Years Old: An Old Problem Revisited

    ERIC Educational Resources Information Center

    Pomerantz, Wendy; Gittelman, Michael; Farris, Sarah; Frey, Lauren

    2009-01-01

    To determine changes in rates of drug ingestions in 10-14 year old children in our country, a retrospective chart review of 10-14 year olds hospitalized for drug ingestion between 1993-1995 and 2000-2004 was performed. Odds ratios and Chi-square were used for analyses. From 1993-1995 there were 92.8 ingestions/100,000 children/year; from 2000-2004…

  19. Cultural accommodation of the Strengthening Families Programme 10-14: UK Phase I study.

    PubMed

    Allen, Debby; Coombes, Lindsey; Foxcroft, David R

    2007-08-01

    Social and cultural differences between the United States and the United Kingdom mean that positive results from US prevention programmes may not translate to the United Kingdom. The Strengthening Families Programme 10-14 (SFP10-14) has been evaluated in a large Phase III randomized controlled trial in rural Iowa in the United States and shown to be effective for delaying alcohol and drug initiation. This paper reports the first stage of the adaptation and evaluation of the SFP10-14 for the United Kingdom through a process of cultural accommodation of the SFP10-14 materials and format. Themes that emerged in nominal group and focus group research with young people and their parents indicated that changes to the US SFP10-14 materials needed to consider language, narrators, realism, acceptability of exercises/games, perceived religiosity and ethnic representativeness. However, not all changes reflected straightforward cultural differences, as adaptations were also required to improve the quality and to update the material, indicating that cultural accommodation does not necessarily imply cultural diversity.

  20. M2-F3 on lakebed

    NASA Image and Video Library

    1970-06-19

    The M2-F3 Lifting Body is seen here on the lakebed at the NASA Flight Research Center (FRC--later the Dryden Flight Research Center), Edwards, California. After a three-year-long redesign and rebuilding effort, the M2-F3 was ready to fly. The May 1967 crash of the M2-F2 had damaged both the external skin and the internal structure of the lifting body. At first, it seemed that the vehicle had been irreparably damaged, but the original manufacturer, Northrop, did the repair work and returned the redesigned M2-F3 with a center fin for stability to the FRC.

  1. Hofbauer cells of M2a, M2b and M2c polarization may regulate feto-placental angiogenesis.

    PubMed

    Loegl, J; Hiden, U; Nussbaumer, E; Schliefsteiner, C; Cvitic, S; Lang, I; Wadsack, C; Huppertz, B; Desoye, G

    2016-11-01

    The human placenta comprises a special type of tissue macrophages, the Hofbauer cells (HBC), which exhibit M2 macrophage phenotype. Several subtypes of M2-polarized macrophages (M2a, M2b and M2c) exist in almost all tissues. Macrophage polarization depends on the way of macrophage activation and leads to the expression of specific cell surface markers and the acquisition of specific functions, including tissue remodeling and the promotion of angiogenesis. The placenta is a highly vascularized and rapidly growing organ, suggesting a role of HBC in feto-placental angiogenesis. We here aimed to characterize the specific polarization and phenotype of HBC and investigated the role of HBC in feto-placental angiogenesis. Therefore, HBC were isolated from third trimester placentas and their phenotype was determined by the presence of cell surface markers (FACS analysis) and secretion of cytokines (ELISA). HBC conditioned medium (CM) was analyzed for pro-angiogenic factors, and the effect of HBC CM on angiogenesis, proliferation and chemoattraction of isolated primary feto-placental endothelial cells (fpEC) was determined in vitro Our results revealed that isolated HBC possess an M2 polarization, with M2a, M2b and M2c characteristics. HBC secreted the pro-angiogenic molecules VEGF and FGF2. Furthermore, HBC CM stimulated the in vitro angiogenesis of fpEC. However, compared with control medium, chemoattraction of fpEC toward HBC CM was reduced. Proliferation of fpEC was not affected by HBC CM. These findings demonstrate a paracrine regulation of feto-placental angiogenesis by HBC in vitro Based on our collective results, we propose that the changes in HBC number or phenotype may affect feto-placental angiogenesis. © 2016 Society for Reproduction and Fertility.

  2. Assigning error to an M2 measurement

    NASA Astrophysics Data System (ADS)

    Ross, T. Sean

    2006-02-01

    The ISO 11146:1999 standard has been published for 6 years and set forth the proper way to measure the M2 parameter. In spite of the strong experimental guidance given by this standard and the many commercial devices based upon ISO 11146, it is still the custom to quote M2 measurements without any reference to significant figures or error estimation. To the author's knowledge, no commercial M2 measurement device includes error estimation. There exists, perhaps, a false belief that M2 numbers are high precision and of insignificant error. This paradigm causes program managers and purchasers to over-specify a beam quality parameter and researchers not to question the accuracy and precision of their M2 measurements. This paper will examine the experimental sources of error in an M2 measurement including discretization error, CCD noise, discrete filter sets, noise equivalent aperture estimation, laser fluctuation and curve fitting error. These sources of error will be explained in their experimental context and convenient formula given to properly estimate error in a given M2 measurement. This work is the result of the author's inability to find error estimation and disclosure of methods in commercial beam quality measurement devices and building an ISO 11146 compliant, computer- automated M2 measurement device and the resulting lessons learned and concepts developed.

  3. Present and Future of M2M

    NASA Astrophysics Data System (ADS)

    Ono, Satoru; Watanabe, Takashi

    In recent years, the rapid progress in the development of hardware and software technologies enables tiny and low cost information devices hereinafter referred to as Machine to be widely available. M2M (Machine to Machine) has been of much attention where many tiny machines are connected to each other through networks with minimal human intervention to provide smooth and intelligent management. M2M is a promising core technology providing timely, flexible, efficient and comprehensive service at low cost. M2M has wide variety of applications including energy management system, environmental monitoring system, intelligent transport system, industrial automation system and other applications. M2M consists of terminals and networks that connect them. In this paper, we mainly focus on M2M networking and mention the future direction of the technology.

  4. Understanding Laser Beam Quality Beyond M2

    NASA Astrophysics Data System (ADS)

    Soskind, Y. G.; Soskind, M. G.

    2016-09-01

    The laser beam M2 quality parameter is based on the second moments' theory, as defined by ISO standards, and provides a common approach for defining the propagation characteristics of laser beams as a whole. At the same time, the M2 parameter fails to quantitatively distinguish the quality of laser beams with different spatial characteristics. For example, several laser beams with very different spatial profiles may have the same M2 value. To overcome this ambiguity, a different beam quality criterion is introduced, allowing for a quantitative definition of both the structured laser beam shape and its propagation characteristics. This criterion, called the encircled power M2 (EPM2), bridges the gap between the M2 quality parameter and the structured laser beam shape. Based on several examples we demonstrate the utility of EPM2 as applied to characterization of several structured laser beam types.

  5. Role of Osteogenic Growth Peptide (OGP) and OGP(10-14) in Bone Regeneration: A Review.

    PubMed

    Pigossi, Suzane C; Medeiros, Marcell C; Saska, Sybele; Cirelli, Joni A; Scarel-Caminaga, Raquel M

    2016-11-22

    Bone regeneration is a process that involves several molecular mediators, such as growth factors, which directly affect the proliferation, migration and differentiation of bone-related cells. The osteogenic growth peptide (OGP) and its C-terminal pentapeptide OGP(10-14) have been shown to stimulate the proliferation, differentiation, alkaline phosphatase activity and matrix mineralization of osteoblastic lineage cells. However, the exact molecular mechanisms that promote osteoblastic proliferation and differentiation are not completely understood. This review presents the main chemical characteristics of OGP and/or OGP(10-14), and also discusses the potential molecular pathways induced by these growth factors to promote proliferation and differentiation of osteoblasts. Furthermore, since these peptides have been extensively investigated for bone tissue engineering, the clinical applications of these peptides for bone regeneration are discussed.

  6. Moving M2 mirror without pointing offset.

    NASA Astrophysics Data System (ADS)

    Ragazzoni, R.; Bortoletto, F.

    1991-09-01

    Moving the secondary mirror M2 to introduce an amount of decentering coma is one of the tasks of active optics. The authors show that this target is accomplished with high accuracy rotating the mirror around a point located near, but not exactly at the center of curvature of M2. Ray tracing results are compared to analytical ones in the case of the Italian Galileo telescope, that will be equipped with an high precision M2 driving device; the close matching with the analytical calculations is demonstrated.

  7. Serum Stability and Affinity Optimization of an M2 Macrophage-Targeting Peptide (M2pep)

    PubMed Central

    Ngambenjawong, Chayanon; Gustafson, Heather H.; Pineda, Julio M.; Kacherovsky, Nataly A.; Cieslewicz, Maryelise; Pun, Suzie H.

    2016-01-01

    Tumor associated macrophages (TAMs) are a major stromal component of the tumor microenvironment in several cancers. TAMs are a potential target for adjuvant cancer therapies due to their established roles in promoting proliferation of cancer cells, angiogenesis, and metastasis. We previously discovered an M2 macrophage-targeting peptide (M2pep) which was successfully used to target and deliver a pro-apoptotic KLA peptide to M2-like TAMs in a CT-26 colon carcinoma model. However, the effectiveness of in vivo TAM-targeting using M2pep is limited by its poor serum stability and low binding affinity. In this study, we synthesized M2pep derivatives with the goals of increasing serum stability and binding affinity. Serum stability evaluation of M2pepBiotin confirmed its rapid degradation attributed to exolytic cleavage from the N-terminus and endolytic cleavages at the W10/W11 and S16/K17 sites. N-terminal acetylation of M2pepBiotin protected the peptide against the exolytic degradation while W10w and K(17,18,19)k substitutions were able to effectively protect endolytic degradation at their respective cleavage sites. However, no tested amino acid changes at the W10 position resulted in both protease resistance at that site and retention of binding activity. Therefore, cyclization of M2pep was investigated. Cyclized M2pep better resisted serum degradation without compromising binding activity to M2 macrophages. During the serum stability optimization process, we also discovered that K9R and W10Y substitutions significantly enhanced binding affinity of M2pep. In an in vitro binding study of different M2pep analogs pre-incubated in mouse serum, cyclic M2pep with K9R and W10Y modifications (cyclic M2pep(RY)) retained the highest binding activity to M2 macrophages over time due to its improved serum stability. Finally, we evaluated the in vivo accumulation of sulfo-Cy5-labeled M2pep and cyclic M2pep(RY) in both the CT-26 and 4T1 breast carcinoma models. Cyclic M2pep

  8. Mitsubishi A6M2 'Zero'

    NASA Technical Reports Server (NTRS)

    1943-01-01

    Mitsubishi A6M2 'Zero': Captured at Akutan Island, Alaska, in August 1942, this Mitsubishi A6M2 fighter was the first 'Zero' to fall intact into Allied hands during WW II. After limited flying on the West Coast, the 'Zero' arrived at Langley for installation of test equipment prior to in-depth flight testing by the Navy at Patuxent River, Maryland.

  9. M2-F2 on ramp

    NASA Image and Video Library

    1966-02-24

    The M2-F2 Lifting Body is seen here on the ramp at the NASA Dryden Flight Research Center. The success of Dryden's M2-F1 program led to NASA's development and construction of two heavyweight lifting bodies based on studies at NASA's Ames and Langley research centers -- 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" and 10 is for the tenth lifting body model to be investigated by Langley. The first flight of the M2-F2 -- which looked much like the "F1" -- was on July 12, 1966. Milt Thompson was the pilot. By then, the same B-52 used to air launch the famed X-15 rocket research aircraft was modified to also carry the lifting bodies. Thompson was dropped from the B-52's wing pylon mount at an altitude of 45,000 feet on that maiden glide flight. The M2-F2 weighed 4,620 pounds, was 22 feet long, and had a width of about 10 feet. On May 10, 1967, during the sixteenth glide flight leading up to powered flight, a landing accident severely damaged the vehicle and seriously injured the NASA pilot, Bruce Peterson. NASA pilots and researchers realized the M2-F2 had lateral control problems, even though it had a stability augmentation control system. When the M2-F2 was rebuilt at Dryden and redesignated the M2-F3, it was modified with an additional third vertical fin -- centered between the tip fins -- to improve control characteristics. The M2-F2/F3 was the first of the heavy-weight, entry-configuration lifting bodies. Its successful development as a research test vehicle answered many of the generic questions about these vehicles. 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 at Dryden from 1965 to 1969.

  10. M2-F2 cockpit instrument panels

    NASA Image and Video Library

    1966-03-27

    This photo shows the right side cockpit instrumentation panel of the M2-F2 Lifting Body. The success of Dryden's M2-F1 program led to NASA's development and construction of two heavyweight lifting bodies based on studies at NASA's Ames and Langley research centers -- 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" and 10 is for the tenth lifting body model to be investigated by Langley. The first flight of the M2-F2 -- which looked much like the "F1" -- was on July 12, 1966. Milt Thompson was the pilot. By then, the same B-52 used to air launch the famed X-15 rocket research aircraft was modified to also carry the lifting bodies. Thompson was dropped from the B-52's wing pylon mount at an altitude of 45,000 feet on that maiden glide flight. The M2-F2 weighed 4,620 pounds, was 22 feet long, and had a width of about 10 feet. On May 10, 1967, during the sixteenth glide flight leading up to powered flight, a landing accident severely damaged the vehicle and seriously injured the NASA pilot, Bruce Peterson. NASA pilots and researchers realized the M2-F2 had lateral control problems, even though it had a stability augmentation control system. When the M2-F2 was rebuilt at Dryden and redesignated the M2-F3, it was modified with an additional third vertical fin -- centered between the tip fins -- to improve control characteristics. The M2-F2/F3 was the first of the heavy-weight, entry-configuration lifting bodies. Its successful development as a research test vehicle answered many of the generic questions about these vehicles. 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 at Dryden from 1965 to 1969.

  11. M2-F2 cockpit instrument panels

    NASA Image and Video Library

    1966-03-27

    This photo shows the left side cockpit instrumentation panel of the M2-F2 Lifting Body. The success of Dryden's M2-F1 program led to NASA's development and construction of two heavyweight lifting bodies based on studies at NASA's Ames and Langley research centers -- 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" and 10 is for the tenth lifting body model to be investigated by Langley. The first flight of the M2-F2 -- which looked much like the "F1" -- was on July 12, 1966. Milt Thompson was the pilot. By then, the same B-52 used to air launch the famed X-15 rocket research aircraft was modified to also carry the lifting bodies. Thompson was dropped from the B-52's wing pylon mount at an altitude of 45,000 feet on that maiden glide flight. The M2-F2 weighed 4,620 pounds, was 22 feet long, and had a width of about 10 feet. On May 10, 1967, during the sixteenth glide flight leading up to powered flight, a landing accident severely damaged the vehicle and seriously injured the NASA pilot, Bruce Peterson. NASA pilots and researchers realized the M2-F2 had lateral control problems, even though it had a stability augmentation control system. When the M2-F2 was rebuilt at Dryden and redesignated the M2-F3, it was modified with an additional third vertical fin -- centered between the tip fins -- to improve control characteristics. The M2-F2/F3 was the first of the heavy-weight, entry-configuration lifting bodies. Its successful development as a research test vehicle answered many of the generic questions about these vehicles. 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 at Dryden from 1965 to 1969.

  12. M2-F3 on lakebed

    NASA Image and Video Library

    1970-06-20

    The M2-F3 Lifting Body is seen here on the lakebed next to the NASA Flight Research Center (FRC--later Dryden Flight Research Center), Edwards, California. The May 1967 crash of the M2-F2 had torn off the left fin and landing gear. It had also damaged the external skin and internal structure. Flight Research Center engineers worked with Ames Research Center and the Air Force in redesigning the vehicle with a center fin to provide greater stability. Then Northrop Corporation cooperated with the FRC in rebuilding the vehicle. The entire process took three years.

  13. M2-F1 in flight

    NASA Technical Reports Server (NTRS)

    1965-01-01

    The M2-F1 Lifting Body is seen here under tow, high above Rogers Dry Lake near the Flight Research Center (later redesignated the Dryden Flight Research Center), Edwards, California. R. Dale Reed effectively advocated the project with the support of NASA research pilot Milt Thompson. Together, they gained the support of Flight Research Center Director Paul Bikle. After a six-month feasibility study, Bikle gave approval in the fall of 1962 for the M2-F1 to be built. 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, Flight Research Center 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. These initial tests produced enough flight data about the M2-F1 to proceed with flights behind a NASA C-47 tow plane at greater altitudes. The C-47 took the craft to an altitude of 12,000 where free flights back to Rogers Dry Lake began. Pilot for the first series of flights of the M2-F1 was NASA research pilot Milt Thompson. Typical glide flights with the M2-F1 lasted about two minutes and reached speeds of 110 to l20 mph. More than 400 ground tows and 77 aircraft tow flights were carried out with the M2-F1. The success of Dryden's M2-F1 program led to NASA's development and construction of two heavyweight lifting bodies based on studies at NASA's Ames and Langley research centers--the M2-F2 and the HL

  14. Suicide rates in children aged 10-14 years worldwide: changes in the past two decades.

    PubMed

    Kõlves, Kairi; De Leo, Diego

    2014-10-01

    Limited research is focused on suicides in children aged below 15 years. To analyse worldwide suicide rates in children aged 10-14 years in two decades: 1990-1999 and 2000-2009. Suicide data for 81 countries or territories were retrieved from the World Health Organization Mortality Database, and population data from the World Bank data-set. In the past two decades the suicide rate per 100 000 in boys aged 10-14 years in 81 countries has shown a minor decline (from 1.61 to 1.52) whereas in girls it has shown a slight increase (from 0.85 to 0.94). Although the average rate has not changed significantly, rates have decreased in Europe and increased in South America. The suicide rates remain critical for boys in some former USSR republics. The changes may be related to economic recession and its impact on children from diverse cultural backgrounds, but may also be due to improvements in mortality registration in South America. Royal College of Psychiatrists.

  15. Anti-influenza M2e antibody

    DOEpatents

    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.

  16. Anti-influenza M2e antibody

    DOEpatents

    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.

  17. M2-F1 simulator cockpit

    NASA Technical Reports Server (NTRS)

    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

  18. M2-F1 in flight

    NASA Technical Reports Server (NTRS)

    1964-01-01

    The M2-F1 Lifting Body is seen here under tow by an unseen C-47 at the NASA Flight Research Center (later redesignated the Dryden Flight Research Center), Edwards, California. The low-cost vehicle was the first piloted lifting body to be test flown. The lifting-body concept originated in the mid-1950s at the National Advisory Committee for Aeronautics' Ames Aeronautical Laboratory, Mountain View California. By February 1962, a series of possible shapes had been developed, and R. Dale Reed was working to gain support for a research vehicle. 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. These initial tests produced enough flight data about the M2-F1 to proceed with flights behind a NASA C-47 tow plane at greater altitudes. The C-47 took the craft to an altitude of 12,000 where free flights back to Rogers Dry Lake began. Pilot for the first series of flights of the M2-F1 was NASA research pilot Milt Thompson. Typical glide flights with the M2-F1 lasted about two minutes and reached speeds of 110 to l20 mph. More than 400 ground tows and 77 aircraft tow flights were carried out with the M2-F1. The success of Dryden's M2-F1 program led to NASA's development and construction of two heavyweight lifting bodies based on studies at

  19. E 3 and M 2 transition strengths in Bi20983

    NASA Astrophysics Data System (ADS)

    Roberts, O. J.; NiÅ£ǎ, C. R.; Bruce, A. M.; Mǎrginean, N.; Bucurescu, D.; Deleanu, D.; Filipescu, D.; Florea, N. M.; Gheorghe, I.; GhiÅ£ǎ, D.; Glodariu, T.; Lica, R.; Mǎrginean, R.; Mihai, C.; Negret, A.; Sava, T.; Stroe, L.; Şuvǎilǎ, R.; Toma, S.; Alharbi, T.; Alexander, T.; Aydin, S.; Brown, B. A.; Browne, F.; Carroll, R. J.; Mulholland, K.; Podolyák, Zs.; Regan, P. H.; Smith, J. F.; Smolen, M.; Townsley, C. M.

    2016-01-01

    The 1 i13/2→1 h9/2 (M 2 ) and 3 s1/2→2 f7/2 (E 3 ) reduced proton transition probabilities in Bi20983 have been determined from the direct half-life measurements of the 13/21+ and 1/21+ states using the Romanian array for γ -ray SPectroscopy in HEavy ion REactions (RoSPHERE). The 13/21+ and 1/21+ states were found to have T1/2=0.120 (15 ) ns and T1/2=9.02 (24 ) ns respectively. Angular distribution measurements were used to determine an E 3 /M 2 mixing ratio of δ =-0.184 (13 ) for the 1609 keV γ -ray transition deexciting the 13/21+ state. This value for δ was combined with the measured half-life to give reduced transition probabilities of B (E 3 ,13/21+→9/21-) =12 (2 ) ×103 e2fm6 and B (M 2 ,13/21+→9/21-) =38 (5 ) μN2fm2 . These values are in good agreement with calculations within the finite Fermi system. The extracted value of B (E 3 ,1/21+→7/21-) =6.3 (2 ) ×103 e2fm6 can be explained by a small (˜6 % ) admixture in the wave function of the 1/21+ state.

  20. What is $$\\Delta m^2_{ee}$$ ?

    DOE PAGES

    Parke, Stephen

    2016-03-09

    Here, the current short baseline reactor experiments, Daya Bay and RENO (Double Chooz) have measured (or are capable of measuring) an effective Δm2 associated with the atmospheric oscillation scale of 0.5 km/MeV in electron antineutrino disappearance. In this paper, I compare and contrast the different definitions of such an effective Δm2 and argue that the simple, L/E independent definition given by Δmee2≡cos2θ12Δm312+sin2θ12Δm322, i.e. “the νe weighted average of Δm312 and Δm322,” is superior to all other definitions and is useful for both short baseline experiments mentioned above and for the future medium baseline experiments JUNO and RENO-50.

  1. M2-F1 in flight

    NASA Technical Reports Server (NTRS)

    1963-01-01

    This 25-second clip shows Milt Thompson being towed in the M2-F1 behind a C-47 aircraft. 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 Shuttles, the X-33 Advanced Technology Demonstrator for the next century's Reusable Launch Vehicle, and the X-38 Technology Demonstrator for crew return from the International Space Station. 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, California, in the mid-1950's, the M2-F1 was built in 1962-63 over a four-month period for a cost of only about $30,000, plus an additional $8,000-$10,000 for an ejection seat. 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 by a souped-up Pontiac convertible until it was airborne. Later a C-47 took over the towing duties. Flown by such famous research pilots as Milt Thompson, Bruce Peterson, Chuck Yeager, and Bill Dana, the lightweight flying bathtub demonstrated that a wingless vehicle shaped for reentry into the Earth's atmosphere from space could be flown and landed safely. Flown from 1963 to 1966, the lightweight M2-F1 paved the way for the heavyweight M2-F2, M2-F3, HL-10, X-24A, and X-24B lifting bodies that flew under rocket power after launch from a B-52 mothership. The heavyweights flew from 1966 to 1975, demonstrating the viability and versatility of the wingless configuration and the ability of a vehicle with low lift-over-drag characteristics to fly to high altitudes and then to land precisely with their rocket

  2. Newly Installed S-1 Truss

    NASA Technical Reports Server (NTRS)

    2002-01-01

    Launched October 7, 2002 aboard the Space Shuttle Orbiter Atlantis, the STS-112 mission lasted 11 days and performed three sessions of Extra Vehicular Activity (EVA). Its primary mission was to install the Starboard (S1) Integrated Truss Structure and Equipment Translation Aid (CETA) Cart to the International Space Station (ISS). The S1 truss provides structural support for the orbiting research facility's radiator panels, which use ammonia to cool the Station's complex power system. The S1 truss, attached to the S0 (S Zero) truss installed by the previous STS-110 mission, flows 637 pounds of anhydrous ammonia through three heat rejection radiators. The truss is 45-feet long, 15-feet wide, 10-feet tall, and weighs approximately 32,000 pounds. The CETA is the first of two human-powered carts that will ride along the International Space Station's railway providing a mobile work platform for future extravehicular activities by astronauts. This is a view of the newly installed S1 Truss as photographed during the mission's first scheduled EVA. The Station's Canadarm2 is in the foreground. Visible are astronauts Piers J. Sellers (lower left) and David A. Wolf (upper right), both STS-112 mission specialists.

  3. Newly Installed S-1 Truss

    NASA Technical Reports Server (NTRS)

    2002-01-01

    Launched October 7, 2002 aboard the Space Shuttle Orbiter Atlantis, the STS-112 mission lasted 11 days and performed three sessions of Extra Vehicular Activity (EVA). Its primary mission was to install the Starboard (S1) Integrated Truss Structure and Equipment Translation Aid (CETA) Cart to the International Space Station (ISS). The S1 truss provides structural support for the orbiting research facility's radiator panels, which use ammonia to cool the Station's complex power system. The S1 truss, attached to the S0 (S Zero) truss installed by the previous STS-110 mission, flows 637 pounds of anhydrous ammonia through three heat rejection radiators. The truss is 45-feet long, 15-feet wide, 10-feet tall, and weighs approximately 32,000 pounds. The CETA is the first of two human-powered carts that will ride along the International Space Station's railway providing a mobile work platform for future extravehicular activities by astronauts. This is a view of the newly installed S1 Truss as photographed during the mission's first scheduled EVA. The Station's Canadarm2 is in the foreground. Visible are astronauts Piers J. Sellers (lower left) and David A. Wolf (upper right), both STS-112 mission specialists.

  4. Eighteenth nuclear accident dosimetry intercomparison study: August 10-14, 1981

    SciTech Connect

    Swaja, R.E.; Sims, C.S.; Greene, R.T.

    1982-11-01

    The Eighteenth Nuclear Accident Dosimetry Intercomparison Study was conducted August 10-14, 1981, at the Oak Ridge National Laboratory. Nuclear criticality accidents with three different neutron and gamma ray energy spectra were simulated by operating the Health Physics Research Reactor in the pulse mode. Participants from 13 organizations exposed dosimeters set up as area monitors and mounted on phantoms for personnel monitoring. Analysis of experimental results showed that about 56% of the reported neutron doses measured using foil activation, thermoluminescent, or sodium activation methods and about 53% of the gamma doses measured using thermoluminescent methods met nuclear accident dosimetry guidelines which suggest accuracies of +- 25% for neutron dose and +- 20% for gamma dose. The greatest difficulties in measuring accident doses occurred in radiation fields with large fractions of low energy neutrons and a high gamma component (> 40%). Results of this study indicate that continued accident dosimetry intercomparisons are necessary to test dosimetry systems and training programs are needed to improve the technical competence of evaluating personnel.

  5. The Strengthening Families Program 10-14: influence on parent and youth problem-solving skill.

    PubMed

    Semeniuk, Y; Brown, R L; Riesch, S K; Zywicki, M; Hopper, J; Henriques, J B

    2010-06-01

    The aim of this paper is to report the results of a preliminary examination of the efficacy of the Strengthening Families Program (SFP) 10-14 in improving parent and youth problem-solving skill. The Hypotheses in this paper include: (1) youth and parents who participated in SFP would have lower mean scores immediately (T2) and 6 months (T3) post intervention on indicators of hostile and negative problem-solving strategies; (2) higher mean scores on positive problem-solving strategies; and (3) youth who participated in SFP would have higher mean scores at T2 and at T3 on indicators of individual problem solving and problem-solving efficacy than youth in the comparison group. The dyads were recruited from elementary schools that had been stratified for race and assigned randomly to intervention or comparison conditions. Mean age of youth was 11 years (SD = 1.04). Fifty-seven dyads (34-intervention&23-control) were videotaped discussing a frequently occurring problem. The videotapes were analysed using the Iowa Family Interaction Rating Scale (IFIRS) and data were analysed using Dyadic Assessment Intervention Model. Most mean scores on the IFIRS did not change. One score changed as predicted: youth hostility decreased at T3. Two scores changed contrary to prediction: parent hostility increased T3 and parent positive problem solving decreased at T2. SFP demonstrated questionable efficacy for problem-solving skill in this study.

  6. American Fisheries Society 136th Annual Meeting Lake Placid, NY 10-14 September, 2006

    USGS Publications Warehouse

    Einhouse, D.; Walsh, M.G.; Keeler, S.; Long, J.M.

    2005-01-01

    The New York Chapter of the American Fisheries Society and the New York State Department of Environmental Conservation invite you to experience the beauty of New York's famous Adirondack Park as the American Fisheries Society (AFS) convenes its 136th Annual Meeting in the legendary Olympic Village of Lake Placid, NY, 10-14 September 2006. Our meeting theme "Fish in the Balance" will explore the interrelation between fish, aquatic habitats, and man, highlighting the challenges facing aquatic resource professionals and the methods that have been employed to resolve conflicts between those that use or have an interest in our aquatic resources. As fragile as it is beautiful, the Adirondack Region is the perfect location to explore this theme. Bordered by Mirror Lake and its namesake, Lake Placid, the Village of Lake Placid has small town charm, but all of the conveniences that a big city would provide. Whether its reliving the magic of the 1980 hockey team's "Miracle on Ice" at the Lake Placid Olympic Center, getting a panoramic view of the Adirondack high peaks from the top of the 90 meter ski jumps, fishing or kayaking in adjacent Mirror Lake, hiking a mountain trail, or enjoying a quiet dinner or shopping excursion in the various shops and restaurants that line Main Street, Lake Placid has something for everyone.

  7. LOSA-M2 aerosol Raman lidar

    SciTech Connect

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

    2011-10-31

    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.

  8. LOSA-M2 aerosol Raman lidar

    NASA Astrophysics Data System (ADS)

    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.

  9. The (178m2)Hf Controversy

    SciTech Connect

    Becker, J A; Gemmell, D S; Schiffer, J P; Wilhelmy, J B

    2003-07-24

    Since its discovery in the 1960's the {sup 178m2}Hf isomer has garnered high attention from both the basic and applied communities in nuclear science. It's combination of high spin (16+), long half life (31 yrs), and high excitation energy (2.446 MeV) offer unique possibilities as an energy storage medium. Interest in the isomer was rekindled beginning in 1999 when a series of publications began to appear from a group (referred to here as the ''Texas collaboration'') primarily based at the University of Texas, Dallas [1]. They reported observations that some of the stored energy could be released (''triggered'') when the isomer was exposed to a fluence of photons in the energy range {approx}10 to {approx}60 keV. The implications of this observation are profound. Even though the claimed cross section for the process was {approx}7 orders of magnitude greater than would be predicted from the known systematics of photon absorption by nuclei in this mass range [2], such a highly efficient method for triggering the isomeric deexcitation immediately suggested applications utilizing the explosive or the controlled gradual energy release from a very compact source. The prospect of such applications has focused considerable interest on realizing the promise that is implicit in the reported observations. However, two experiments performed by a group from ANL/LANL/LLNL at the Advanced Photon Source at Argonne (the ''APS collaboration'') reported negative results for the observation of any photon-triggered deexcitation of the {sup 178m2}Hf isomer [3]. This has led to a continued controversy, where both sides have adamantly defended their observations. At this point an outsider has difficulty determining whether there is indeed a triggering effect that should be pursued energetically with substantial resources, or whether the phenomenon consists of overly optimistic interpretation of data.

  10. Reference values for ductus venosus Doppler flow measurements at 10-14 weeks of gestation.

    PubMed

    Prefumo, F; Risso, D; Venturini, P L; De Biasio, P

    2002-07-01

    To calculate reference ranges for ductus venosus Doppler measurements obtained transabdominally at 10-14 weeks of gestation. Two hundred and one normal fetuses with a crown-rump length (CRL) ranging from 38 to 88 mm were examined in a cross-sectional study. The pulsatility index for veins (PIV), peak velocity during ventricular systole (S-wave), lowest forward velocity during atrial contraction (A-wave) and time-averaged maximum velocity (TAMXV) were recorded from the ductus venosus. Flow velocity waveforms were also classified as normal or abnormal according to the presence (normal) or absence or reversal (abnormal) of frequencies during atrial contraction. Three of 201 fetuses showed an abnormal flow pattern (1.5%; 95% exact confidence interval, 0.3-4.3%). In the 198 fetuses with a normal flow pattern, the mean PIV ranged from 1.07 at a CRL of 38 mm to 1.00 at a CRL of 88 mm (r = -0.093; P = 0.19). A significant increase in mean blood flow velocity with increasing CRL was noted for the S-wave (27.0 cm/s to 33.6 cm/s; r = 0.17; P = 0.02), the A-wave (5.9 cm/s to 7.8 cm/s; r = 0.14; P = 0.04) and the TAMXV (19.4 cm/s to 25.3 cm/s; r = 0.19; P < 0.01). Crown-rump length-specific reference ranges for each parameter were calculated using the method of scaled absolute residuals. Abnormal ductus venosus flow patterns could be observed in normal fetuses, even if they ocurred with a low prevalence. Reference values for Doppler measurements were established in fetuses with normal patterns of flow.

  11. Evidence of paired M2 muscarinic receptors

    SciTech Connect

    Potter, L.T.; Ballesteros, L.A.; Bichajian, L.H.; Ferrendelli, C.A.; Fisher, A.; Hanchett, H.E.; Zhang, R. )

    1991-02-01

    Binding assays involving various antagonists, including N-(3H) methylscopolamine, (3H)quinuclidinyl benzilate, AFDX-116, pirenzepine, and propylbenzilylcholine mustard, disclosed only a single population of M2 muscarinic receptors in membranes from the rat brainstem (medulla, pons, and colliculi). However, competition curves between N-(3H)methylscopolamine and various agonists, including oxotremorine, cis-dioxolane, and acetylethylcholine mustard, showed approximately equal numbers of guanine nucleotide-sensitive high affinity (H) sites and guanine nucleotide-insensitive low affinity (L) sites. This 50% H phenomenon persisted in different buffers, at different temperatures, after the number of receptors was halved (and, thus, the remaining receptor to guanine nucleotide-binding protein ratio was doubled), after membrane solubilization with digitonin, and when rabbit cardiac membranes were used instead of rat brainstem membranes. Preferential occupation of H sites with acetylethylcholine mustard, and of L sites with quinuclidinyl benzilate or either mustard, yielded residual free receptor populations showing predominantly L and H sites, respectively. Low concentrations of (3H)-oxotremorine-M labeled only H sites, and the Bmax for these sites was 49% of the Bmax found with (3H)quinuclidinyl benzilate plus guanine nucleotide. These and other results are most consistent with the idea that H and L receptor sites exist on separate but dimeric receptor molecules and with the hypothesis that only the H receptors cycle between high and low affinity, depending upon interactions between this receptor molecule and a guanine nucleotide-binding protein.

  12. Spectropolarimetry of the Bipolar Planetary Nebula M2-9

    NASA Astrophysics Data System (ADS)

    Trammell, Susan R.; Goodrich, Robert W.; Dinerstein, Harriet L.

    1995-11-01

    We present optical spectropolarimetry of the young bipolar planetary nebula M2-9. The goal of these observations is to determined the origin of the knots or brightness enhancements seen in the lobes of M2-9. The line spectra of the lobes of M2-9 are composed of two components, one that is produced locally in the lobes and one that is scattered from deep in the nebula. The presence of this scattered radiation means that the total flux line ratios do not accurately describe the local conditions in the lobes. We have obtained spectropolarimetric data of the N2 and S2 knots and the adjacent nebula, and we use our data to separate the scattered and unscattered emission-line components. The spectrum of the core of M2-9 exhibits broad Hα emission lines. In our high-resolution spectra we observe a broad wing on the scattered Hα line profile at all of the positions in the north lobe. This confirms that the scattered line emission originates in the core. In addition, we calculate the outflow velocity of the scatterers, ≍15 km s-1, based on the observed wavelength shift between the Hα peak in scattered and unscattered flux. Using the unscattered spectra, we derive the local line ratios as a function of position in the north and south lobes. The degree of ionization of the spectra decreases in the off-knot regions. We measure the gas temperature as a function of position and find that it is approximately constant across the lobes. This result rules out the simple recombination tail model proposed by Goodrich for the origin of the knots. We suggest instead that the off-knot positions are ionized by a UV spectrum that is attenuated by material between the off-knot positions and the central UV source. We have used the photoionization code CLOUDY to test this idea and find that attenuation effects alone cannot accurately reproduce the observed unscattered line ratios. To accurately model the observed line ratios in the knots, we require the presence of both high (≥ 105 cm-3

  13. Asymmetric 1,8/13,2,x-M2C2B10 14-vertex metallacarboranes by direct electrophilic insertion reactions; the VCD and BHD methods in critical analysis of cage C atom positions.

    PubMed

    McAnaw, Amelia; Lopez, Maria Elena; Ellis, David; Rosair, Georgina M; Welch, Alan J

    2014-04-07

    The isolation of six isomeric, low-symmetry, dicobaltacarboranes with bicapped hexagonal antiprismatic cage structures, always in low yield, is described from reactions in which 13-vertex cobaltacarborane anions and sources of cobalt-containing cations were present. The vertex-to-centroid distance (VCD) and boron-H distance (BHD) methods are used to locate the correct C atom positions in the cages, thus allowing the compounds to be identified as 1,13-Cp2-1,13,2,10-closo-Co2C2B10H12 (1), 1,8-Cp2-3-OEt-1,8,2,10-closo-Co2C2B10H11 (2), 1,13-Cp2-1,13,2,9-closo-Co2C2B10H12 (3), 1,8-Cp2-1,8,2,4-closo-Co2C2B10H12 (4), 1,13-Cp2-1,13,2,4-closo-Co2C2B10H12 (5) and 1,8-Cp2-1,8,2,5-closo-Co2C2B10H12 (6). It is shown that a common alternative method of cage C atom identification, using refined (as B) U(eq) values, does not work well, at least in these cases. Having identified the correct isomeric forms of the six dicobaltacarboranes, their syntheses are tentatively rationalised in terms of the direct electrophilic insertion of a {CpCo(+)} fragment into [CpCoC2B10](-) anions and it is demonstrated that compounds 1, 4, 5 and 6 can be successfully prepared by deliberately performing such reactions.

  14. IUTAM Symposium on Vortex Dynamics: Formation, Structure and Function, 10-14 March 2013, Fukuoka, Japan

    NASA Astrophysics Data System (ADS)

    Fukumoto, Yasuhide

    2014-06-01

    This special issue of Fluid Dynamics Research contains the first of a two-part publication of the papers presented at the IUTAM Symposium on Vortex Dynamics: Formation, Structure and Function, held at the Centennial Hall, Kyushu University School of Medicine, Fukuoka, Japan, during the week of 10-14 March 2013. Vortices are ubiquitous structures in fluid mechanics spanning the range of scales from nanofluidics and microfluidics to geophysical and astrophysical flows. Vortices are the key to understanding many different phenomena. As a result, the subject of vortex dynamics continues to evolve and to constantly find new applications in biology, biotechnology, industrial and environmental problems. Vortices can be created by the separation of a flow from the surface of a body or at a density interface, and evolve into coherent structures. Once formed, a vortex acquires a function, depending on its individual structure. In this way, for example, insects gain lift and fish gain thrust. Surprisingly, despite the long history of vortex dynamics, only recently has knowledge about formation, structure and function of vortices been combined to yield new perspectives in the subject, thereby helping to solve outstanding problems brought about by modern advances in computer technology and improved experimental techniques. This symposium is a continuation, five years on, of the IUTAM Symposium '50 Years of Vortex Dynamics', Lyngby, Denmark that took place between 12-16 October 2008, organized by the late Professor Hassan Aref. Originally, Professor Aref was a member of the International Scientific Committee of this symposium and offered his enthusiasm and great expertise, to support its organization. To our shock, he suddenly passed away on 9 September 2011. Furthermore, Professor Slava Meleshko, a leading scientist of fluid and solid mechanics and an intimate friend of Professor Aref, was expected to make an eminent contribution to the symposium. Soon after this sad loss

  15. Motion-to-Energy (M2E) Power Generation Technology

    ScienceCinema

    INL

    2016-07-12

    INL researchers developed M2E, a new technology that converts motion to energy. M2E uses an innovative, optimized microgenerator with power management circuitry that kinetically charges mobile batteries from natural motion such as walking.

  16. Motion-to-Energy (M2E) Power Generation Technology

    SciTech Connect

    INL

    2008-05-30

    INL researchers developed M2E, a new technology that converts motion to energy. M2E uses an innovative, optimized microgenerator with power management circuitry that kinetically charges mobile batteries from natural motion such as walking.

  17. Cosmic ray chemical composition estimated between 2 × 10 14 eV and 2 × 10 16 eV using muon size fluctuations

    NASA Astrophysics Data System (ADS)

    Mitsui, K.; Aoki, T.; Ohashi, Y.; Okada, A.; Muraki, Y.; Maehara, O.; Kojima, H.; Shibata, S.; Takahashi, T.; Kobayakawa, K.; Capdevielle, J. N.

    1995-03-01

    Accurate measurement of the total number of muons in an air shower is important for estimating the cosmic ray chemical composition. In order to translate this view into action, we have constructed an air shower array at Ohya. Many large muon detectors have been deployed in the stone mine and the total area amounts to about 400 m 2. At the ground surface, scintillation counters have been deployed for determining the shower size and arrival direction of an air shower. From the data obtained, we estimated the cosmic ray chemical composition between 2 × 10 14 eV and 2 × 10 16 eV, which includes the well known spectrum's "knee". As a method of estimation, we took the muon size fluctuation. The estimated rate of protons becomes relatively low, and that of helium nuclei increases, above an energy of 2 × 10 15 eV. Also, the fraction of very heavy nuclei such as iron increases above this energy.

  18. S1P control of endothelial integrity.

    PubMed

    Xiong, Yuquan; Hla, Timothy

    2014-01-01

    Sphingosine 1-phosphate (S1P), a lipid mediator produced by sphingolipid metabolism, promotes endothelial cell spreading, vascular maturation/stabilization, and barrier function. S1P is present at high concentrations in the circulatory system, whereas in tissues its levels are low. This so-called vascular S1P gradient is essential for S1P to regulate much physiological and pathophysiological progress such as the modulation of vascular permeability. Cellular sources of S1P in blood has only recently begun to be identified. In this review, we summarize the current understanding of S1P in regulating vascular integrity. In particular, we discuss the recent discovery of the endothelium-protective functions of HDL-bound S1P which is chaperoned by apolipoprotein M.

  19. ABJ(M) and fractional M2's with fractional M2 charge

    NASA Astrophysics Data System (ADS)

    Evslin, Jarah; Kuperstein, Stanislav

    2009-12-01

    Recently Aharony, Bergman and Jafferis (ABJ) have argued that a 3d U(N+M)k × U(N)-k Chern-Simons gauge theory may have a vacuum with Script N = 6 supersymmetry only if M<=k and if a certain period of the B-field in a IIA background is quantized. We use a braneology argument to argue that Script N = 3 supersymmetry may be preserved under the weaker condition that 2Nk>=M(M-k) with no restriction on the B-field. IIB brane cartoons and 11d supergravity solutions corresponding to Script N = 3 vacua that do not preserve Script N = 6 supersymmetry are argued to represent cascading gauge theories, generalizing the Script N = 2 Seiberg duality conjectured by Giveon and Kutasov. While as usual the M2-brane charge runs as a result of the twisted Bianchi identity for *G4, the M5-brane charge running relies on the fact that it wraps a torsion homology cycle.

  20. Implementing and evaluating the German adaptation of the "Strengthening Families Program 10 - 14"- a randomized-controlled multicentre study.

    PubMed

    Bröning, Sonja; Sack, Peter-Michael; Thomsen, Monika; Stolle, Martin; Wendell, Astrid; Stappenbeck, Julian; Thomasius, Rainer

    2014-01-27

    Substance use problems in childhood and adolescence can severely impact youth's physical and mental well-being. When substance use is initiated early, the risk for moving from hazardous substance use to substance use disorders (SUD) is particularly high to developmentally induced biological and psychological vulnerability towards chronic trajectories in youth. Thus, risk factors for developing SUD should be addressed early in life by adequate preventive measures reaching out to children, adolescents, and their families. The study described in this protocol will test the effectiveness of the German adaptation of the Strengthening Families Program for Parents and Youth 10-14 (SFP 10-14) aimed at ten to 14 year old adolescents and their caregivers. The study is conducted in four large German cities by counselling centres in the areas of youth welfare, social work and addiction aid. The effectiveness of the manualised group programme "Familien Stärken" consisting of seven sessions and four booster-sessions is tested among N = 288 children and participating parents in a multicentre randomised controlled trial with standardised assessment instruments. The control condition receives a minimal 2-hour intervention on parenting delivered in a school setting. Data are collected shortly before and after as well as six and 18 months after the intervention. We expect to replicate the favourable effects of the SFP 10-14 programme in the United States in the area of substance use initiation, family functioning and individual psychosocial adjustment. The trial is expected to contribute to the growing literature on family-based preventive interventions, their effectiveness and feasibility. It is in line with several other current European efforts aimed at strengthening families against the detrimental effects of substance abuse in youth. The results of these trials will expand our knowledge on adapting evidence-based interventions and delivering them in diverse cultures and

  1. 26 CFR 1.401(m)-2 - ACP test.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 5 2011-04-01 2011-04-01 false ACP test. 1.401(m)-2 Section 1.401(m)-2 Internal... TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(m)-2 ACP test. (a) Actual... under paragraph (a)(1) of this section either— (A) Pursuant to section 401(m)(5)(C), the ACP test...

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

    Code of Federal Regulations, 2010 CFR

    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...

  3. 26 CFR 1.401(m)-2 - ACP test.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 5 2013-04-01 2013-04-01 false ACP test. 1.401(m)-2 Section 1.401(m)-2 Internal... TAXES (CONTINUED) 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...

  4. CYP2S1: A short review

    SciTech Connect

    Saarikoski, Sirkku T. . E-mail: sirkku.saarikoski@ktl.fi; Rivera, Steven P.; Hankinson, Oliver; Husgafvel-Pursiainen, Kirsti

    2005-09-01

    A new member of the cytochrome P450 superfamily, CYP2S1, has recently been identified in human and mouse. In this paper, we review the data currently available for CYP2S1. The human CYP2S1 gene is located in chromosome 19q13.2 within a cluster including CYP2 family members CYP2A6, CYP2A13, CYP2B6, and CYP2F1. These genes also show the highest homology to the human CYP2S1. The gene has recently been found to harbor genetic polymorphism. CYP2S1 is inducible by dioxin, the induction being mediated by the Aryl Hydrocarbon Receptor (AHR) and Aryl Hydrocarbon Nuclear Translocator (ARNT) in a manner typical for CYP1 family members. In line with this, CYP2S1 has been shown to be inducible by coal tar, an abundant source of PAHs, and it was recently reported to metabolize naphthalene. This points to the involvement of CYP2S1 in the metabolism of toxic and carcinogenic compounds, similar to other dioxin-inducible CYPs. CYP2S1 is expressed in epithelial cells of a wide variety of extrahepatic tissues. The highest expression levels have been observed in the epithelial tissues frequently exposed to xenobiotics, e.g., the respiratory, gastrointestinal, and urinary tracts, and in the skin. The observed ubiquitous tissue distribution, as well as the expression of CYP2S1 throughout embryogenesis suggest that CYP2S1 is likely to metabolize important endogenous substrates; thus far, retinoic acid has been identified. In conclusion, CYP2S1 exhibits many features of interest for human health and thus warrants further investigation.

  5. Safety assessment for the S-1 Spheromak

    SciTech Connect

    Ellis, R. Jr.; Stencel, J.R.

    1984-02-01

    The S-1 machine is part of the Magnetic Fusion Program. The goal of the Magnetic Fusion Program is to develop and demonstrate the practical application of fusion. S-1 is an experimental device which will provide an essential link in the research effort aiming at the realization of fusion power.

  6. Helicobacter pylori vacA s1a and s1b alleles from clinical isolates from different regions of Chile show a distinct geographic distribution

    PubMed Central

    Díaz, MI; Valdivia, A; Martínez, P; Palacios, JL; Harris, P; Novales, J; Garrido, E; Valderrama, D; Shilling, C; Kirberg, A; Hebel, E; Fierro, J; Bravo, R; Siegel, F; Leon, G; Klapp, G; Venegas, A

    2005-01-01

    AIM: To establish the most common vacA alleles in Helicobacter pylori (H pylori) strains isolated from Chilean patients and its relationship with gastritis and gastroduodenal ulcers. METHODS: Two hundred and forty five H pylori clinical isolates were obtained from 79 biopsies from Chilean infected patients suffering from gastrointestinal diseases. An average of 2-3 strains per patient was isolated and the vacA genotype was analyzed by PCR and 3% agarose electrophoresis. Some genotypes were checked by DNA sequencing. RESULTS: The most prevalent vacA genotype in Chilean patients was s1b m1 (76%), followed by s1a m1 (21%). In contrast, the s2 m2 genotype was scarcely represented (3%). The s1b m1 genotype was found most frequently linked to gastropathies (P<0.05) rather than ulcers. Ulcers were found more commonly in male and older patients. Curiously, patients living in cities located North and far South of Santiago, the capital and largest Chilean city, carried almost exclusively strains with the s1b m1 genotype. In contrast, patients from Santiago and cities located South of Santiago carried strains with either one or both s1a m1 and s1b m1 genotypes. Regarding the s2 m2 genotype, comparison with GenBank sequences revealed that Chilean s2 sequence was identical to those of Australian, American, and Colombian strains but quite different from those of Alaska and India. CONCLUSION: Differences in geographic distribution of the s and m vacA alleles in Chile and a relationship of s1b m1 genotype with gastritis were found. Sequence data in part support a hispanic origin for the vacA genotype. Asymmetric distribution of genotypes s1b m1 and s2 m2 recedes H Pylori strain distribution in Spain and Portugal. PMID:16419167

  7. Wackenhut Services, Incorporated: Report from the DOE Voluntary Protection Program onsite review, August 10--14, 1998

    SciTech Connect

    1999-05-01

    This report summarizes the Department of Energy Voluntary Protection Program (DOE-VPP) Review Team`s findings from the five-day onsite evaluation of Wackenhut Services, Inc. (WSI) at Savannah River Site (SRS), conducted August 10-14, 1998. The site was evaluated against the program requirements contained in US Department of Energy Voluntary Protection Program, Part 1: Program Elements to determine its success in implementing the five DOE-VPP tenets. The Team determined that WSI has met in varying degrees, all the tenets of the DOE-VPP. In every case, WSI programs and procedures exceed the level or degree necessary for compliance with existing standards, DOE Orders, and guidelines. In addition, WSI has systematically integrated their occupational safety and health (OSH) program into management and work practices at all levels. WSI`s efforts toward implementing the five major DOE-VPP tenets are summarized.

  8. The M2 protein of influenza A virus is acylated.

    PubMed

    Veit, M; Klenk, H D; Kendal, A; Rott, R

    1991-06-01

    The M2 protein of influenza A virus, a 97 amino acid integral membrane protein expressed on the surface of infected cells, is covalently modified with long chain fatty acids. The fatty acid bond is sensitive to treatment with neutral hydroxylamine and mercaptoethanol, which indicates a labile thioester type linkage. Thin-layer chromatographic fatty acid analysis of [3H]myristic and [3H]palmitic acid-labelled M2 protein shows that palmitic acid is the predominant fatty acid linked to this polypeptide. Palmitoylation of M2 occurs post-translationally and causes an upward shift in the SDS-PAGE mobility of the protein.

  9. The small peptide OGP(10-14) reduces proliferation and induces differentiation of TPO-primed M07-e cells through RhoA/TGFβ1/SFK pathway

    PubMed Central

    Battolla, Barbara; Bernardini, Nunzia; Petrini, Mario; Mattii, Letizia

    2011-01-01

    Summary Background Osteogenic growth peptide (OGP) is a 14-mer peptide found in relevant concentration in blood, and its carboxy-terminal fragment [OGP(10-14)] represents the active portion of the full-length peptide. In addition to stimulating bone formation, OGP(10-14) shows hematological activity. In fact, it highly enhances hematopoiesis-affecting stem progenitors. Moreover, OGP(10-14) reduces the growth and induces the differentiation of the hematological tumour cell line trombophoietin(TPO)-primed M07-e by interfering with RhoA and Src kinase pathways. In the present report, we went deeper into this mechanism and evaluated the possible interference of the OGP(10-14) signal pathway with TGFβ1 and TPO receptor Mpl. Material/Methods In OGP(10-14)-treated M07-e cells cultured with or without RhoA and Src kinases inhibitors (C3 and PP2), expression of TGFβ1, Mpl, and Src kinases was analyzed by immunoperoxidase technique. Activated RhoA expression was studied using the G-LISA™ quantitative test. Results In M07-e cells, both OGP(10-14) and PP2 activate RhoA, inhibit Src kinases, reduce Mpl expression and increase TGFβ1 expression. OGP(10-14) and PP2 show the same behavior, causing an additive effect when associated. Conclusions OGP(10-14) induces TPO-primed M07-e cells differentiation through RhoA/TGFβ1/SFKs signalling pathway. In particular OGP(10-14) acts as a Src inhibitor, showing the same effects of PP2. PMID:21169922

  10. TNF Counterbalances the Emergence of M2 Tumor Macrophages.

    PubMed

    Kratochvill, Franz; Neale, Geoffrey; Haverkamp, Jessica M; Van de Velde, Lee-Ann; Smith, Amber M; Kawauchi, Daisuke; McEvoy, Justina; Roussel, Martine F; Dyer, Michael A; Qualls, Joseph E; Murray, Peter J

    2015-09-22

    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. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  11. Theoretical Assessment of 178m2Hf De-Excitation

    SciTech Connect

    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.

  12. A model of the human M2 muscarinic acetylcholine receptor

    NASA Astrophysics Data System (ADS)

    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.

  13. Secure Data Aggregation Protocol for M2M Communications

    DTIC Science & Technology

    2015-03-24

    surveillance, smart metering , environmental monitoring, industrial automation and military scenarios [1][2]. Despite various M2M applications, the basic M2M...similar works. Thanks to this novel constraint, DPAFT can support fault tolerance of malfunctioning smart meters efficiently and flexibly. DPAFT is...solution for fault tolerance for smart metering . Unlike all of the existing similar works, which depend on the restricted relation of ∑ , an

  14. Revisiting the endocytosis of the m2 muscarinic acetylcholine receptor.

    PubMed

    Ockenga, Wymke; Tikkanen, Ritva

    2015-05-12

    The agonist-induced endocytosis of the muscarinic acetylcholine receptor M2 is different from that of the other members of the muscarinic receptor family. The uptake of the M2 receptor involves the adapter proteins of the β-arrestin family and the small GTPase ADP-ribosylation factor 6. However, it has remained inconclusive if M2 endocytosis is dependent on clathrin or the large GTPase dynamin. We here show by means of knocking down the clathrin heavy chain that M2 uptake upon agonist stimulation requires clathrin. The expression of various dominant-negative dynamin-2 mutants and the use of chemical inhibitors of dynamin function revealed that dynamin expression and membrane localization as such appear to be necessary for M2 endocytosis, whereas dynamin GTPase activity is not required for this process. Based on the data from the present and from previous studies, we propose that M2 endocytosis takes place by means of an atypical clathrin-mediated pathway that may involve a specific subset of clathrin-coated pits/vesicles.

  15. Revisiting the Endocytosis of the M2 Muscarinic Acetylcholine Receptor

    PubMed Central

    Ockenga, Wymke; Tikkanen, Ritva

    2015-01-01

    The agonist-induced endocytosis of the muscarinic acetylcholine receptor M2 is different from that of the other members of the muscarinic receptor family. The uptake of the M2 receptor involves the adapter proteins of the β-arrestin family and the small GTPase ADP-ribosylation factor 6. However, it has remained inconclusive if M2 endocytosis is dependent on clathrin or the large GTPase dynamin. We here show by means of knocking down the clathrin heavy chain that M2 uptake upon agonist stimulation requires clathrin. The expression of various dominant-negative dynamin-2 mutants and the use of chemical inhibitors of dynamin function revealed that dynamin expression and membrane localization as such appear to be necessary for M2 endocytosis, whereas dynamin GTPase activity is not required for this process. Based on the data from the present and from previous studies, we propose that M2 endocytosis takes place by means of an atypical clathrin-mediated pathway that may involve a specific subset of clathrin-coated pits/vesicles. PMID:25985102

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

    PubMed

    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.

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

    SciTech Connect

    Vishnevsky, I. N.; Zheltonozhsky, V. A. Savrasov, A. N.; Mazur, V. M.

    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.

  18. Hypothalamic S1P/S1PR1 axis controls energy homeostasis.

    PubMed

    Silva, Vagner R R; Micheletti, Thayana O; Pimentel, Gustavo D; Katashima, Carlos K; Lenhare, Luciene; Morari, Joseane; Mendes, Maria Carolina S; Razolli, Daniela S; Rocha, Guilherme Z; de Souza, Claudio T; Ryu, Dongryeol; Prada, Patrícia O; Velloso, Lício A; Carvalheira, José B C; Pauli, José Rodrigo; Cintra, Dennys E; Ropelle, Eduardo R

    2014-09-25

    Sphingosine 1-phosphate receptor 1 (S1PR1) is a G-protein-coupled receptor for sphingosine-1-phosphate (S1P) that has a role in many physiological and pathophysiological processes. Here we show that the S1P/S1PR1 signalling pathway in hypothalamic neurons regulates energy homeostasis in rodents. We demonstrate that S1PR1 protein is highly enriched in hypothalamic POMC neurons of rats. Intracerebroventricular injections of the bioactive lipid, S1P, reduce food consumption and increase rat energy expenditure through persistent activation of STAT3 and the melanocortin system. Similarly, the selective disruption of hypothalamic S1PR1 increases food intake and reduces the respiratory exchange ratio. We further show that STAT3 controls S1PR1 expression in neurons via a positive feedback mechanism. Interestingly, several models of obesity and cancer anorexia display an imbalance of hypothalamic S1P/S1PR1/STAT3 axis, whereas pharmacological intervention ameliorates these phenotypes. Taken together, our data demonstrate that the neuronal S1P/S1PR1/STAT3 signalling axis plays a critical role in the control of energy homeostasis in rats.

  19. Multi-wavelength view of an M2.2 solar flare on 26 november 2000

    NASA Astrophysics Data System (ADS)

    Chandra, R.; Verma, V. K.; Rani, S.; Maurya, R. A.

    2017-02-01

    In this paper, we present a study of an M2.2 class solar flare of 26 November 2000 from NOAA AR 9236. The flare was well observed by various ground based observatories (ARIES, Learmonths Solar Observatory) and space borne instruments (SOHO, HXRS, GOES) in time interval between 02:30 UT to 04:00 UT. The flare started with long arc-shape outer flare ribbon. Afterwards the main flare starts with two main ribbons. Initially the outer ribbons start to expand with an average speed (∼20 km s-1) and later it shows contraction. The flare was associated with partial halo coronal mass ejection (CMEs) which has average speed of 495 km s-1. The SOHO/MDI observations show that the active region was in quadrupolar magnetic configuration. The flux cancellation was observed before the flare onset close to flare site. Our analysis indicate the flare was initiated by the magnetic breakout mechanism.

  20. The Global S$_1$ Ocean Tide

    NASA Technical Reports Server (NTRS)

    Ray, Richard D.; Egbert, G. D.

    2003-01-01

    The small S$_1$ ocean tide is caused primarily by diurnal atmospheric pressure loading. Its excitation is therefore unlike any other diurnal tide. The global character of $S-1$ is here determined by numerical modeling and by analysis of Topex/Poseidon satellite altimeter data. The two approaches yield reasonably consistent results, and large ( $ greater than $l\\cm) amplitudes in several regions are further confirmed by comparison with coastal tide gauges. Notwithstanding their excitation differences, S$-1$ and other diurnal tides are found to share several common features, such as relatively large amplitudes in the Arabian Sea, the Sea of Okhotsk, and the Gulf of Alaska. The most noticeable difference is the lack of an S$-1$ Antarctic Kelvin wave. These similarities and differences can be explained in terms of the coherences between near-diurnal oceanic normal modes and the underlying tidal forcings. While gravitational diurnal tidal forces excite primarily a 28-hour Antarctic-Pacific mode, the S$_1$ air tide excites several other near-diurnal modes, none of which has large amplitudes near Antarctica.

  1. Anatomy of a Discovery: M1 and M2 Macrophages

    PubMed Central

    Mills, Charles Dudley

    2015-01-01

    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. PMID:25999950

  2. Computational discovery of stable M2A X phases

    NASA Astrophysics Data System (ADS)

    Ashton, Michael; Hennig, Richard G.; Broderick, Scott R.; Rajan, Krishna; Sinnott, Susan B.

    2016-08-01

    The family of layered Mn +1A Xn compounds provides a large class of materials with applications ranging from magnets to high-temperature coatings to nuclear cladding. In this work, we employ a density-functional-theory-based discovery approach to identify a large number of thermodynamically stable Mn +1A Xn compounds, where n =1 , M =Sc, Ti, V, Cr, Zr, Nb, Mo, Hf, Ta; A =Al, Si, P, S, Ga, Ge, As, Cd, In, Sn, Tl, Pb; and X =C, N. We calculate the formation energy for 216 pure M2A X compounds and 10 314 solid solutions, (MM') 2(A A') (X X') , relative to their competing phases. We find that the 49 experimentally known M2A X phases exhibit formation energies of less than 30 meV/atom. Among the 10 530 compositions considered, 3140 exhibit formation energies below 30 meV/atom, most of which have yet to be experimentally synthesized. A significant subset of 301 compositions exhibits strong exothermic stability in excess of 100 meV/atom, indicating favorable synthesis conditions. We identify empirical design rules for stable M2A X compounds. Among the metastable M2A X compounds are two Cr-based compounds with ferromagnetic ordering and expected Curie temperatures around 75 K. These results can serve as a map for the experimental design and synthesis of different M2A X compounds.

  3. Clustering of breakpoints on chromosome 10 in acute T-cell leukemias with the t(10; 14) chromosome translocation

    SciTech Connect

    Kagan, J.; Finger, L.R.; Letofsky, J.; Finan, J.; Nowell, P.C.; Croce, C.M. )

    1989-06-01

    The T-cell receptor (TCR){alpha}/{delta} chain locus on chromosome 14q11 is nonrandomly involved in translocations and inversions in human T-cell neoplasms. The authors have analyzed three acute T-lymphoblastic leukemia samples carrying a t(10;14)(q24;q11) chromosome translocation by means of somatic cell hybrids and molecular cloning. In all cases studied the translocation splits the TCR {delta} chain locus. Somatic cell hybrids containing the human 10q+ chromosome resulting from the translocation retain the human terminal deoxynucleotidyltransferase gene mapped at 10q23-q24 and the diversity and joining, D{sub {delta}}2-J{sub {delta}}1, regions of the TCR {delta} chain, but not the V{sub {alpha}} region (variable region of the TCR {alpha} chain), demonstrating that the split occurred within the V{sub {alpha}}-D{sub {delta}}2 region. Molecular cloning of the breakpoint junctions revealed that the TCR {delta} chain sequences involved are made from the D{sub {delta}}2 segment. The chromosome breakpoints are clustered within a region of {approx} 263 base pairs of chromosome 10. The results suggest that the translocation of the TCR {delta} chain locus to a locus on 10q, which the authors have designated TCL3, results in deregulation of this putative oncogene, leading to acute T-cell leukemia.

  4. M2-F1 in flight on tow line

    NASA Technical Reports Server (NTRS)

    1964-01-01

    The M2-F1 Lifting Body is seen here under tow at the Flight Research Center (later redesignated the Dryden Flight Research Center), Edwards, California. 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, Flight Research Center 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 M2-F1 project had limited goals. They were to show that a piloted lifting body could be built, that it could not only fly but be controlled in flight, and that it could make a successful landing. While the M2-F1 did prove the concept, with a wooden fuselage and fixed landing gear, it was far from an operational spacecraft. The next step in the lifting-body development was to build a heavyweight, rocket-powered vehicle that was more like an operational lifting body, albeit one without the thermal protection system that would be needed for reentry into the atmosphere from space at near-orbital speeds. 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. These initial tests produced enough flight data about the M2-F1 to proceed with flights behind a NASA C-47 tow plane at greater altitudes. The C-47 took the craft to an altitude of 12,000 where free flights back to Rogers Dry Lake began. Pilot for the first series of flights of the M2-F1 was NASA research pilot Milt Thompson. Typical glide flights with the M2-F1 lasted about two minutes and reached speeds of 110 to

  5. Comparisons of absolute gravimeters (COOMET.M.G-S1)

    NASA Astrophysics Data System (ADS)

    Vinnichenko, Mr Alexander; Germak, Alessandro, Dr

    2017-01-01

    This report describes the results of the RMO supplementary comparison COOMET.M.G-S1 (also known as bilateral comparison COOMET 634/UA/14). The comparison measurements between the two participants NSC 'IM' (pilot laboratory) and INRIM were started in December 2015 and finished in January 2016. Participants of comparisons were conducted at their national standards the measurements of the free fall acceleration in gravimetric point laboratory of absolute gravimetry of INRIM named INRiM.2. Absolute measurements of gravimetric acceleration were conducted by ballistic gravimeters. The agreement between the two participants is good. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

  6. Randomized study comparing full dose monotherapy (S-1 followed by irinotecan) and reduced dose combination therapy (S-1/oxaliplatin followed by S-1/irinotecan) as initial therapy for older patients with metastatic colorectal cancer: NORDIC 9.

    PubMed

    Winther, Stine Braendegaard; Österlund, Pia; Berglund, Åke; Glimelius, Bengt; Qvortrup, Camilla; Sorbye, Halfdan; Pfeiffer, Per

    2017-08-16

    Metastatic colorectal cancer (mCRC) is a disease of older age, but there is a relative lack of knowledge about effects of chemotherapy in older patients as they are under-represented in clinical trials. Little data can guide whether the strategy in older mCRC patients should be a sequential full-dose monotherapy chemotherapy approach or a dose-reduced combination chemotherapy approach. The oral 5FU prodrug S-1 seems to have less side effects than capecitabine and should be an optimal drug for older patients, but few data are available. Improved geriatric assessments are needed to select which older patients should receive therapy. The NORDIC 9 trial is a Nordic multicenter randomized phase II study comparing full dose monotherapy (S-1 30 mg/m(2) twice daily days 1-14 every 3 weeks, followed by second line irinotecan 250-350 mg/m(2) iv day 1 every 3 weeks or 180-250 mg/m(2) iv day 1 every 2 weeks) with reduced dose combination therapy (S-1 20 mg/m(2) days 1-14 + oxaliplatin 100 mg/m(2) iv day 1 every 3 weeks, followed by second line S-1 20 mg/m(2) days 1-14 + irinotecan 180 mg/m(2) day 1 every 3 week) for older patients (≥70 years) with mCRC who are not candidates for full-dose standard combination therapy. Additional bevacizumab (7.5 mg/kg) is optional in first-line. Blood samples and tumor tissue will be collected to investigate predictive markers. Geriatric screening tools (G-8, VES-13, Timed-Up-and-Go and Handgrip strength), Charlson Comorbidty Index and quality of life (EORTC QLQ-C30) will be evaluated as predictors of efficacy and toxicity. The target sample size is 150 patients. The primary endpoint is progression-free survival and secondary endpoints are time-to-failure of strategy, overall survival, response rate, toxicity, and correlations between biomarkers, pre-treatment characteristics and geriatric assessments. The study will add knowledge on how to treat older mCRC patients who are not candidates for standard combination therapy

  7. M2-F2 with test pilot Bruce A. Peterson

    NASA Image and Video Library

    1966-09-22

    Bruce A. Peterson standing beside the M2-F2 lifting body on Rogers Dry Lake. Peterson became the NASA project pilot for the lifting body program after Milt Thompson retired from flying in late 1966. Peterson had flown the M2-F1, and made the first glide flight of the HL-10 heavy-weight lifting body in December 1966. On May 10, 1967, Peterson made his fourth glide flight in the M2-F2. This was also the M2-F2's 16th glide flight, scheduled to be the last one before the powered flights began. However, as pilot Bruce Peterson neared the lakebed, the M2-F2 suffered a pilot induced oscillation (PIO). The vehicle rolled from side to side in flight as he tried to bring it under control. Peterson recovered, but then observed a rescue helicopter that seemed to pose a collision threat. Distracted, Peterson drifted in a cross-wind to an unmarked area of the lakebed where it was very difficult to judge the height over the lakebed because of a lack of the guidance the markers provided on the lakebed runway. Peterson fired the landing rockets to provide additional lift, but he hit the lakebed before the landing gear was fully down and locked. The M2-F2 rolled over six times, coming to rest upside down. Pulled from the vehicle by Jay King and Joseph Huxman, Peterson was rushed to the base hospital, transferred to March Air Force Base and then the UCLA Hospital. He recovered but lost vision in his right eye due to a staph infection.

  8. Mini Magnetospheric Plasma Propulsion (M2P2)

    NASA Technical Reports Server (NTRS)

    Gallagher, Dennis; Winglee, Robert

    2000-01-01

    The M2P2 concept is based on the transfer of momentum from the solar wind to an artificial magnetic field structure like that naturally occurs at all magnetized planets in the Solar System, called the magnetosphere. The objectives of this program include the following: (1) Demonstrate artificial magnetospheric inflation through cold plasma filling in vacuum; (2) Demonstrate deflection of a surrogate solar wind by an artificial magnetosphere in the laboratory vacuum chamber; (3) Compare theoretical calculations for thrust forces with laboratory measurements; (4) Develop flight control algorithms for planning mission specific trajectories; and (5) Develop M2P2 system concept.

  9. M2-F1 on lakebed with pilot Milt Thompson

    NASA Technical Reports Server (NTRS)

    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. M2-F1 ejection seat test at South Edwards

    NASA Technical Reports Server (NTRS)

    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

  11. Defective transient endogenous spleen colony formation in S1/S1d mice.

    PubMed

    Wiktor-Jedrzejczak, W; Ahmed, A; Sharkis, S J; McKee, A; Sell, K W

    1979-04-01

    WCB6F1 mice of the genotype S1/S1d did not form transient 5-day endogenous spleen colonies following midlethal irradiation, either spontaneously or in response to postirradiation bleeding. Their hematologically normal (+/+) littermates produced colonies equivalent in number and morphologic type to a normal strain (D2B6F1), as evaluated by both macroscopic and microscopic criteria. Bone marrow cells from S1/S1d mice, when transplanted into lethally irradiated +/+ mice, were able to generate equivalent numbers of transient endogenous spleen colonies (TE-CFUs), as compared to that obtained when syngeneic +/+ marrow cells were injected into lethally irradiated +/+ recipients. A defective growth of an early class of hematopoietic progenitor cells, resulting in the clinical course of the S1/S1d anemia is suggested and confirms previous reports on the microenvironmental nature of this abnormality.

  12. Metabolism of 1-nitro(U-4,5,9,10-14C)pyrene in the F344 rat

    SciTech Connect

    El-Bayoumy, K.; Hecht, S.S.

    1984-10-01

    1-Nitro(U-4,5,9,10-14C)pyrene was synthesized and administered to male F344 rats by intragastric gavage at a dose of 100 mg/kg of body weight. During the first 48 hr, 41% of the dose was eliminated in the feces, and 16% was eliminated in the urine. The corresponding figures after 120 hr were 51 and 19%. In rats with bile cannulae, 37% of the dose was excreted in the bile after 72 hr, and 6% was excreted in the urine. Fecal metabolites included 1-aminopyrene (isolated amount, 11.7% of the dose), 1-amino-6-hydroxypyrene and 1-amino-8-hydroxypyrene (4.6%), and unchanged 1-nitropyrene (6.6%). 1-Aminopyrene and the 1-aminohydroxypyrenes were identified as their acetyl-derivatives by comparison of their chromatographic retention times, mass spectra, and UV spectra to those of synthetic standards. Biliary metabolites included 1-aminopyrene, 1-amino-6-hydroxypyrene, 1-amino-8-hydroxypyrene, 1-nitro-6(8)-hydroxypyrene, and 1-nitro-3-hydroxypyrene, as well as their glucuronide and sulfate conjugates. The isolated amounts of these metabolites accounted for approximately 5% of the dose. 1-Amino-6-hydroxypyrene and 1-amino-8-hydroxypyrene and their glucuronide and sulfate conjugates were also tentatively identified in the urine and accounted for about 3% of the dose. Significant quantities of unidentified water soluble metabolites were present in the urine and bile. The results of this study indicate that metabolic reduction of the highly mutagenic 1-nitrohydroxypyrenes occurs in vivo in the rat and suggest that this is a possible activation pathway in 1-nitropyrene carcinogenesis.

  13. M2e-Based Universal Influenza A Vaccines

    PubMed Central

    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

  14. M2e-Based Universal Influenza A Vaccines.

    PubMed

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

    2015-02-13

    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.

  15. PK-M2 Makes Cells Sweeter on HIF1.

    PubMed

    Tennant, Daniel A

    2011-05-27

    The transcription factor hypoxia-inducible factor 1 (HIF1) facilitates the induction of enzymes necessary for anaerobic glycolysis. Luo et al. (2011) now identify pyruvate kinase (PK)-M2 as an intriguing new interacting partner for HIF1, revealing a potential mechanism for the Warburg effect, an elevation in aerobic glycolytic metabolism frequently observed in cancer.

  16. M2FS: the Michigan/Magellan Fiber System

    NASA Astrophysics Data System (ADS)

    Mateo, Mario; Bailey, John I.; Crane, Jeffrey; Shectman, Stephen; Thompson, Ian; Roederer, Ian; Bigelow, Bruce; Gunnels, Steve

    2012-09-01

    We describe the Michigan/Magellan Fiber System (M2FS) under construction for use on the Magellan/Clay telescope. M2FS consists of four primary components including: (1) A fiber-fed double spectrograph (MSPec) in which each spectrograph is fed by 128 fibers (for a total multiplexing factor of 256) and each is optimized in to operate from 370- 950 nm; (2) A fiber mounting system (MFib) that supports the fibers and fiber plug plates at the telescope f/11 Nasmyth focal surface and organizes the fibers into `shoes' that are used to place the fibers at the image surface of the MSpec spectrographs;, (3) A new wide-field corrector (WFC) that produces high-quality images over a 30 arcmin diameter field; (4) A unit (MCal) mounted near the telescope secondary that provides wavelength and continuum calibration and that supports a key component in a novel automated fiber identification system. We describe the opto-mechanical properties of M2FS, its modes of operation, and its anticipated performance, as well as potential upgrades including the development of a robotic fiber positioner and an atmospheric dispersion corrector. We describe how the M2FS design could serve as the basis of a powerful wide-field, massively multiplexed spectroscopic survey facility.

  17. Progress On 58m2 Passive Resonant Ring Laser Gyroscope

    NASA Astrophysics Data System (ADS)

    Shaw, G. L.; Rotge, J.; Simmons, B. J.

    1986-01-01

    An update of the large area (now 60m2) Passive Resonant Ring Laser Gyro (PRRLG) is given. Some aspects of last year's design have changed; but performance is still predicted to be in the 10-10 earth rate unit (ERU) range. This is of interest for a number of geophysical applications.

  18. M2-F1 in hangar with Pontiac tow vehicle

    NASA Technical Reports Server (NTRS)

    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

  19. M2-F1 in hangar with Pontiac tow vehicle

    NASA Technical Reports Server (NTRS)

    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

  20. Internal steel structure of M2-F1

    NASA Technical Reports Server (NTRS)

    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-F2 flight preparation and launch

    NASA Technical Reports Server (NTRS)

    1969-01-01

    This movie clip runs about 27 seconds and shows the cockpit canopy close-out by the ground crew, the aircraft hanging from the NB-52B wing pylon, and the M2-F2 being dropped away from the mothership. A fleet of lifting bodies flown at the NASA Flight Research Center (FRC), Edwards, California, from 1963 to l975 demonstrated the ability of pilots to maneuver (in the atmosphere) and safely land a wingless vehicle. These lifting bodies were basically designed so they could fly back to Earth from space and be landed like an aircraft at a pre-determined site. They served as precursors of today's Space Shuttle, the X-33, and the X-38, providing technical and operational engineering data that shaped all three space vehicles. (In 1976 NASA renamed the FRC as the NASA Dryden Flight Research Center (DFRC) in honor of Hugh L. Dryden.) In 1962, FRC Director Paul Bikle 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. Built by Gus Briegleb, a sailplane builder from El Mirage, California, it featured a plywood shell, placed over a tubular steel frame crafted at the FRC. Construction was completed in 1963. The success of Dryden's M2-F1 program led to NASA's development and construction of two heavyweight lifting bodies based on studies at NASA Ames Research Center and NASA and Langley Research Center -- the M2-F2 and the HL-10, both built by the Northrop Corporation, Los Angeles, California. The 'M' refers to 'manned' and 'F' refers to 'flight' version. 'HL' comes from 'horizontal landing' and '10' is for the tenth lifting body model to be investigated by Langley. The first flight of the M2-F2 -- which looked much like the M2-F1 -- occurred on July 12, 1966. Thompson was the pilot. By then, the same B-52 used to air launch the famed X-15 rocket research aircraft had been modified to also carry the lifting bodies into the air and Thompson was

  2. Mock modular index of M2-M5 brane systems

    NASA Astrophysics Data System (ADS)

    Okazaki, Tadashi; Smith, Douglas J.

    2017-07-01

    We present Bogomolny-Prasad-Sommerfield (BPS) indices of the supergroup Wess-Zumino-Witten (WZW) models that live on intersecting M2-M5-brane systems. They can encode data of the stretched M2-branes between M5-branes and count the BPS states. They are generally expressed in terms of mock theta functions via the Kac-Wakimoto character formula of the affine Lie superalgebra. We give an explicit expression of the index for the P S L (2 |2 )k =1 WZW model in terms of the second-order multivariable Appell-Lerch sum. It indicates that wall crossing occurs in the BPS state counting due to the C field on the M5-branes.

  3. On relating multiple M2 and D2-branes

    NASA Astrophysics Data System (ADS)

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

    2008-10-01

    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 fABCD 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 fABCD constructed from the Lie algebra structure constants fabc of an arbitrary gauge group. Although this choice of fABCD 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 gYM-1 upon reduction and, moreover, it sheds new light on the centre of mass coordinates for multiple M2-branes.

  4. Fractional power in the bucket, beam quality and M2

    NASA Astrophysics Data System (ADS)

    Basu, Santanu; Gutheinz, Lee M.

    2010-02-01

    This paper gives expressions to calculate the fraction of power, fPIB, from a given multimode gaussian laser beam that can be deposited within a bucket of radius, rT, on a target at a range, zT, using a focusing optic of diameter, Df. We relate the power in the bucket, fPIB, to the M2 parameter, both of which can be experimentally measured. In this paper, we have also presented relationships between these two parameters and BQ and Strehl, which have not been unambiguously defined for a multimode laser beam in the literature. We propose fPIB and M2 to be used as standard design parameters instead of BQ and Strehl for laser-target interaction tests with multimode laser beams from stable resonators.

  5. IUE observations of the 'Butterfly' Nebula M2-9

    NASA Technical Reports Server (NTRS)

    Feibelman, W. A.

    1984-01-01

    IUE observations of the peculiar 'Butterfy' nebula M2-9 indicate that it is not a normal planetary nebula. The ultraviolet spectrum is characterized by few emission lines and a weak continuum. Mg II 2800 A is the strongest emission line present and may be indicative of a binary nucleus. Lines of N v, Q I, N III, N IV, Si III, and C III are seen, but C IV and O III are conspicuous by their absence. T(e) = 10,250 + or - 400 K was determined for the core. Nitrogen in the core is found to be overabundant by about a factor of 5 over the solar value. M2-9 may be an object in the early stages of becoming a planetary nebula.

  6. M2 world ocean tide from tide gauge measurements

    SciTech Connect

    Francis, O.; Mazzega, P. )

    1991-06-01

    An empirical model of the M2 oceanic tide has been computed form the harmonic constants of a subset of deep sea and coastal tide gauge measurements. The optimal interpolation of these data based on inverse theory' uses a priori covariance functions deduced from a global hydrodynamical model. The inverse solution, produced with its associated error maps and samples of error spectra, is surprisingly good when compared to in situ data and to a hydrodynamical model.

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

    SciTech Connect

    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.

  8. Heme oxygenase-1 and anti-inflammatory M2 macrophages.

    PubMed

    Naito, Yuji; Takagi, Tomohisa; Higashimura, Yasuki

    2014-12-15

    Heme oxygenase-1 (HO-1) catalyzes the first and rate-limiting enzymatic step of heme degradation and produces carbon monoxide, free iron, and biliverdin. HO-1, a stress-inducible protein, is induced by various oxidative and inflammatory signals. Consequently, HO-1 expression has been regarded as an adaptive cellular response against inflammatory response and oxidative injury. Although several transcriptional factors and signaling cascades are involved in HO-1 regulation, the two main pathways of Nrf2/Bach1 system and IL-10/HO-1 axis exist in monocyte/macrophage. Macrophages are broadly divisible into two groups: pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages. More recently, several novel macrophage subsets have been identified including Mhem, Mox, and M4 macrophages. Of these, M2 macrophages, Mhem, and Mox are HO-1 highly expressing macrophages. HO-1 has been recognized as having major immunomodulatory and anti-inflammatory properties, which have been demonstrated in HO-1 deficient mice and human cases of genetic HO-1 deficiency. However, the mechanism underlying the immunomodulatory actions of HO-1 remains poorly defined. This review specifically addresses macrophage polarization. The present current evidence indicates that HO-1 induction mediated by multiple pathways can drive the phenotypic shift to M2 macrophages and suggests that HO-1 induction in macrophages is a potential therapeutic approach to immunomodulation in widely diverse human diseases.

  9. Activation and dynamic network of the M2 muscarinic receptor

    PubMed Central

    Miao, Yinglong; Nichols, Sara E.; Gasper, Paul M.; Metzger, Vincent T.; McCammon, J. Andrew

    2013-01-01

    G-protein-coupled receptors (GPCRs) mediate cellular responses to various hormones and neurotransmitters and are important targets for treating a wide spectrum of diseases. Although significant advances have been made in structural studies of GPCRs, details of their activation mechanism remain unclear. The X-ray crystal structure of the M2 muscarinic receptor, a key GPCR that regulates human heart rate and contractile forces of cardiomyocytes, was determined recently in an inactive antagonist-bound state. Here, activation of the M2 receptor is directly observed via accelerated molecular dynamics simulation, in contrast to previous microsecond-timescale conventional molecular dynamics simulations in which the receptor remained inactive. Receptor activation is characterized by formation of a Tyr2065.58–Tyr4407.53 hydrogen bond and ∼6-Å outward tilting of the cytoplasmic end of transmembrane α-helix 6, preceded by relocation of Trp4006.48 toward Phe1955.47 and Val1995.51 and flipping of Tyr4307.43 away from the ligand-binding cavity. Network analysis reveals that communication in the intracellular domains is greatly weakened during activation of the receptor. Together with the finding that residue motions in the ligand-binding and G-protein-coupling sites of the apo receptor are correlated, this result highlights a dynamic network for allosteric regulation of the M2 receptor activation. PMID:23781107

  10. Flux-driven algebraic damping of m=2 diocotron mode

    NASA Astrophysics Data System (ADS)

    Chim, C. Y.; O'Neil, T. M.

    2016-10-01

    Recent experiments with pure electron plasmas in a Malmberg-Penning trap have observed the algebraic damping of m = 2 diocotron modes. Due to small field asymmetries a low density halo of electrons is transported radially outward from the plasma core, and the mode damping begins when the halo reaches the resonant radius rres, where f = mfE × B (rres) . The damping rate is proportional to the flux of halo particles through the resonant layer. The damping is related to, but distinct from the exponential spatial Landau damping in a linear wave-particle resonance. This poster uses analytic theory and simulations to explain the new flux-driven algebraic damping of the mode. As electrons are swept around the nonlinear ``cat's eye'' orbits of the resonant wave-particle interaction, they form a quadrupole (m = 2) density distribution, which sets up an electric field that acts back on the plasma core. The field causes an E × B drift motion that symmetrizes the core, i.e. damps the m = 2 mode. Supported by NSF Grant PHY-1414570, and DOE Grants DE-SC0002451.

  11. Relativistic electrons high doses at International Space Station and Foton M2/M3 satellites

    NASA Astrophysics Data System (ADS)

    Dachev, T. P.; Tomov, B.; Matviichuk, Yu.; Dimitrov, Pl.; Bankov, N.

    2009-12-01

    The paper presents observation of relativistic electrons. Data are collected by the Radiation Risk Radiometer-Dosimeters (R3D) B2/B3 modifications during the flights of Foton M2/M3 satellites in 2005 and 2007 as well as by the R3DE instrument at the European Technology Exposure Facility (EuTEF) on the Columbus External Payload Adaptor at the International Space Station (ISS) in the period February 20 - April 28, 2008. On the Foton M2/M3 satellites relativistic electrons are observed more frequently than on the ISS because of higher (62.8°) inclination of the orbit. At both Foton satellites the usual duration of the observations are a few minutes long. On the ISS the duration usually is about 1 min or less. The places of observations of high doses due to relativistic electrons are distributed mainly at latitudes above 50° geographic latitude in both hemispheres on Foton M2/M3 satellites. A very high maximum is found in the southern hemisphere at longitudinal range 0°-60°E. At the ISS the maximums are observed between 45° and 52° geographic latitude in both hemispheres mainly at longitudes equatorward from the magnetic poles. The measured absolute maximums of dose rates generated by relativistic electrons are found to be as follows: 304 μGy h -1 behind 1.75 g cm -2 shielding at Foton M2, 2314 μGy h -1 behind 0.71 g cm -2 shielding at Foton M3 and 19,195 μGy h -1 (Flux is 8363 cm -2 s -1) behind les than 0.4 g cm -2 shielding at ISS.

  12. M2-F1 under tow across lakebed by car

    NASA Technical Reports Server (NTRS)

    1963-01-01

    This 20-second clip shows the M2-F1 being towed by the Pontiac across Rogers Dry Lakebed. 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 Shuttles, the X-33 Advanced Technology Demonstrator for the next century's Reusable Launch Vehicle, and the X-38 Technology Demonstrator for crew return from the International Space Station. 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, California, in the mid-1950's, the M2-F1 was built in 1962-63 over a four-month period for a cost of only about $30,000, plus an additional $8,000-$10,000 for an ejection seat. 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 by a souped-up Pontiac convertible until it was airborne. Later a C-47 took over the towing duties. Flown by such famous research pilots as Milt Thompson, Bruce Peterson, Chuck Yeager, and Bill Dana, the lightweight flying bathtub demonstrated that a wingless vehicle shaped for reentry into the Earth's atmosphere from space could be flown and landed safely. Flown from 1963 to 1966, the lightweight M2-F1 paved the way for the heavyweight M2-F2, M2`F3, HL-10, X-24A, and X-24B lifting bodies that flew under rocket power after launch from a B-52 mothership. The heavyweights flew from 1966 to 1975, demonstrating the viability and versatility of the wingless configuration and the ability of a vehicle with low lift-over-drag characteristics to fly to high altitudes and then to land precisely with their

  13. Restless legs syndrome mimicking S1 radiculopathy.

    PubMed

    Zambelis, Th; Wolgamuth, B R; Papoutsi, S N; Economou, N T

    2016-01-01

    Α case of a chronic idiopathic form of a severe type of Restless Legs Syndrome (RLS), which developed during pregnancy and persisted after this, misdiagnosed for 34 years as radiculopathy S1, is reported. In spite of the thorough clinical and laboratory investigation, in addition to constant changes of the therapeutic approach, the diagnosis of S1 radiculopathy could not be confirmed, resulting in a chronic clinical course; the latter was characterized by relapses and remissions not attributed or linked in any way to the treatment (various types of). In fact, it was due to a routine workup in a sleep clinic, where the patient was referred because of a coincident chronic insomnia (Restless Legs Syndrome is a known and important cause of insomnia/chronic insomnia), which resulted in a proper diagnosis and treatment of this case. With the use of Restless Legs Syndrome appropriate treatment (Pramipexole 0.18 mg taken at bedtime, a dopaminergic agent and Level A recommended drug for Restless Legs Syndrome) an excellent response and immediate elimination of symptoms was achieved. Restless Legs Syndrome may present with a variety of symptoms (with the most prominent shortly being reported with the acronym URGE: Urge to move the legs usually associated with unpleasant leg sensations, Rest induces symptoms, Getting active brings relief, Evening and night deteriorate symptoms); given the fact that Restless Legs Syndrome presents with a great variety and heterogeneity of symptoms (mostly pain, dysesthesia and paresthesia), which may occur in several other diseases (the so called "RLS mimics"), proper diagnosis of Restless Legs Syndrome usually fails. Restless Legs Syndrome misinterpreted as S1 radiculopathy, to the best of our knowledge, has not been reported yet in the literature. Here, case history, clinical course and common RLS mimics are presented. Different forms of Restless Legs Syndrome manifestations, which are commonly -as in this case- misinterpreted due to their

  14. M2A and M2C Macrophage Subsets Ameliorate Inflammation and Fibroproliferation in Acute Lung Injury Through Interleukin 10 Pathway.

    PubMed

    Tang, Lunxian; Zhang, Hua; Wang, Chunmei; Li, Hongqiang; Zhang, Qian; Bai, Jianwen

    2016-12-09

    The role of M2 macrophages in the resolution and fibroproliferation of acute lung injury (ALI) is poorly understood. In this study, we investigated the effects of two M2 macrophage subtypes, M2a induced by interleukin (IL)-4/IL-13 and M2c induced by IL-10/transforming growth factor (TGF)-β, on the pathogenesis of ALI. M2a and M2c were adoptively transferred into LPS-induced ALI mice model. Data showed that Vybrant-labeled macrophages appeared in the lungs of ALI mice. Subsequently, we observed that both subsets significantly reduced lung inflammation and injury including a reduction of neutrophil influx into the lung and an augmentation of apoptosis. Interestingly, M2c macrophages more effectively suppressed indices of lung injury than M2a macrophages. M2c macrophages were also more effective than M2a in reduction of lung fibrosis. In addition, we found that M2c but not M2a macrophages increased IL-10 level in lung tissues of the recipient ALI mice partially mediated by activating the JAK1/STAT3/SOCS3 signaling pathway. After blocking IL-10, these superior effects of M2c over M2a were abolished. These data imply that M2c are more potent than M2a macrophages in protecting against lung injury and subsequent fibrosis due to their ability to produce IL-10. Therefore, reprogramming macrophages to M2c subset may be a novel treatment modality with transitional potential.

  15. Hyper III, M2-F2 & RC Mothership

    NASA Technical Reports Server (NTRS)

    1968-01-01

    The Remote Controlled research staff from left to right are: Richard C. Eldredge, Dale Reed, James O. Newman and Bob McDonald. In support of the M2 lifting body program in the early 1960s, Dale Reed had built a number of small lifting body shapes and drop tested them from a radio controlled mothership. By late 1968, 'Mother' had made over 120 launch drops. Next, Reed devised a program in which NASA research pilot Milt Thompson could remotely pilot 'Mother' using an 8-ball attitude indicator from the ground.

  16. Multiple M2-branes and generalized 3-Lie algebras

    SciTech Connect

    Cherkis, Sergey; Saemann, Christian

    2008-09-15

    We propose a generalization of the Bagger-Lambert-Gustavsson action as a candidate for the description of an arbitrary number of M2-branes. The action is formulated in terms of N=2 superfields in three dimensions and corresponds to an extension of the usual superfield formulation of Chern-Simons matter theories. Demanding gauge invariance of the resulting theory does not imply the total antisymmetry of the underlying 3-Lie algebra structure constants. We relax this condition and propose a class of examples for these generalized 3-Lie algebras. We also discuss various associated ordinary Lie algebras.

  17. Light-cone M5 and multiple M2-branes

    NASA Astrophysics Data System (ADS)

    Bandos, Igor A.; Townsend, Paul K.

    2008-12-01

    We present the light-cone gauge fixed Lagrangian for the M5-brane; it has a residual 'exotic' gauge invariance with the group of 5-volume preserving diffeomorphisms, SDiff5, as gauge group. For an M5-brane of topology \\bb{R}^2\\times M_3 , for closed 3-manifold M3, we find an infinite tension limit that yields an SO(8)-invariant (1 + 2)-dimensional field theory with 'exotic' SDiff3 gauge invariance. We show that this field theory is the Carrollian limit of the Nambu bracket realization of the 'BLG' model for multiple M2-branes.

  18. Sphingosine-1-phosphate (S1P) displays sustained S1P1 receptor agonism and signaling through S1P lyase-dependent receptor recycling.

    PubMed

    Gatfield, John; Monnier, Lucile; Studer, Rolf; Bolli, Martin H; Steiner, Beat; Nayler, Oliver

    2014-07-01

    The sphingosine-1-phosphate (S1P) type 1 receptor (S1P1R) is a novel therapeutic target in lymphocyte-mediated autoimmune diseases. S1P1 receptor desensitization caused by synthetic S1P1 receptor agonists prevents T-lymphocyte egress from secondary lymphoid organs into the circulation. The selective S1P1 receptor agonist ponesimod, which is in development for the treatment of autoimmune diseases, efficiently reduces peripheral lymphocyte counts and displays efficacy in animal models of autoimmune disease. Using ponesimod and the natural ligand S1P, we investigated the molecular mechanisms leading to different signaling, desensitization and trafficking behavior of S1P1 receptors. In recombinant S1P1 receptor-expressing cells, ponesimod and S1P triggered Gαi protein-mediated signaling and β-arrestin recruitment with comparable potency and efficiency, but only ponesimod efficiently induced intracellular receptor accumulation. In human umbilical vein endothelial cells (HUVEC), ponesimod and S1P triggered translocation of the endogenous S1P1 receptor to the Golgi compartment. However, only ponesimod treatment caused efficient surface receptor depletion, receptor accumulation in the Golgi and degradation. Impedance measurements in HUVEC showed that ponesimod induced only short-lived Gαi protein-mediated signaling followed by resistance to further stimulation, whereas S1P induced sustained Gαi protein-mediated signaling without desensitization. Inhibition of S1P lyase activity in HUVEC rendered S1P an efficient S1P1 receptor internalizing compound and abrogated S1P-mediated sustained signaling. This suggests that S1P lyase - by facilitating S1P1 receptor recycling - is essential for S1P-mediated sustained signaling, and that synthetic agonists are functional antagonists because they are not S1P lyase substrates.

  19. The functional roles of S1P in immunity.

    PubMed

    Hisano, Yu; Nishi, Tsuyoshi; Kawahara, Atsuo

    2012-10-01

    The lipid mediator sphingosine-1-phosphate (S1P) is generated within cells from sphingosine by two sphingosine kinases (SPHK1 and SPHK2). Intracellularly synthesized S1P is released into the extracellular fluid by S1P transporters, including SPNS2. Released S1P binds specifically to the G protein-coupled S1P receptors (S1PR1/S1P(1)-S1PR5/S1P(5)), which activate a diverse range of downstream signalling pathways. Recent studies have proposed that one of the central physiological functions of intercellular S1P signalling is in lymphocyte trafficking in vivo because genetic disruption of SPHK1/2, SPNS2 or S1PR1/S1P(1) in mice induces a lymphopenia phenotype. In this review, we discuss the current understanding of intercellular S1P signalling in the context of immunity.

  20. Absolute configuration of sex pheromone for tea tussock moth,Euproctis pseudoconspersa (strand)via synthesis of (R)- and (S)-10, 14-dimethyl-1-pentadecyl isobutyrates.

    PubMed

    Ichikawa, A; Yasuda, T; Wakamura, S

    1995-05-01

    (R)- and (S)-10,14-dimethyl-1-pentadecyl isobutyrates were synthesized from (S)- and (R)-citronellols, respectively. TheR enantiomer was as active as the natural pheromone but theS enantiomer was less active in the electrophysiological analyses, which provided conclusive proof that the absolute configuration of the natural pheromone isR.

  1. Nonfatal and Fatal Self-Harm Injuries among Children Aged 10-14 Years--United States and Oregon, 2001-2003

    ERIC Educational Resources Information Center

    Vajani, Madhavi; Annest, Joseph L.; Crosby, Alex E.; Alexander, Janice D.; Millet, Lisa M.

    2007-01-01

    Fatal and nonfatal injuries due to suicidal behavior among younger adolescents are of growing concern for many communities. We examined the incidence and patterns of these injuries among persons aged 10-14 years using three databases, two national and a third from Oregon. Suffocation and firearm gunshot were the leading external causes of suicide;…

  2. Nonfatal and Fatal Self-Harm Injuries among Children Aged 10-14 Years--United States and Oregon, 2001-2003

    ERIC Educational Resources Information Center

    Vajani, Madhavi; Annest, Joseph L.; Crosby, Alex E.; Alexander, Janice D.; Millet, Lisa M.

    2007-01-01

    Fatal and nonfatal injuries due to suicidal behavior among younger adolescents are of growing concern for many communities. We examined the incidence and patterns of these injuries among persons aged 10-14 years using three databases, two national and a third from Oregon. Suffocation and firearm gunshot were the leading external causes of suicide;…

  3. The iron dispersion of the globular cluster M2, revised.

    PubMed

    Lardo, C; Mucciarelli, A; Bastian, N

    2016-03-21

    M2 has been claimed to possess three distinct stellar components that are enhanced in iron relative to each other. We use equivalent width measurements from 14 red giant branch stars from which Yong et al. detect a ∼0.8 dex wide, trimodal iron distribution to redetermine the metallicity of the cluster. In contrast to Yong et al., which derive atmospheric parameters following only the classical spectroscopic approach, we perform the chemical analysis using three different methods to constrain effective temperatures and surface gravities. When atmospheric parameters are derived spectroscopically, we measure a trimodal metallicity distribution, that well resembles that by Yong et al. We find that the metallicity distribution from Fe ii lines strongly differs from the distribution obtained from Fe i features when photometric gravities are adopted. The Fe i distribution mimics the metallicity distribution obtained using spectroscopic parameters, while the Fe ii shows the presence of only two stellar groups with metallicity [Fe/H] ≃ -1.5 and -1.1 dex, which are internally homogeneous in iron. This finding, when coupled with the high-resolution photometric evidence, demonstrates that M2 is composed by a dominant population (∼99 per cent) homogeneous in iron and a minority component (∼1 per cent) enriched in iron with respect to the main cluster population.

  4. M2K Planet Search: Spectroscopic Screening and Transit Photometry

    NASA Astrophysics Data System (ADS)

    Mann, Andrew; Gaidos, E.; Fischer, D.; Lepine, S.

    2010-10-01

    The M2K project is a search for planets orbiting nearby early M and late K dwarf drawn from the SUPERBLINK catalog. M and K dwarfs are highly attractive targets for finding low-mass and habitable planets because (1) close-in planets are more likely to orbit within their habitable zone, (2) planets orbiting them induce a larger Doppler signal and have deeper transits than similar planets around F, G, and early K type stars, (3) planet formation models predict they hold an abundance of super-Earth sized planets, and (4) they represent the vast majority of the stars close enough for direct imaging techniques. In spite of this, only 10% of late K and early M dwarfs are being monitored by current Doppler surveys. As part of the M2K project we have obtained low-resolution spectra for more than 2000 of our sample of 10,000 M and K dwarfs. We vet our sample by screening these stars for high metallicity and low chromospheric activity. We search for transits on targets showing high RMS Doppler signal and photometry candidates provided by SuperWASP project. By using "snapshot” photometry have been able to achieve sub-millimag photometry on numerous transit targets in the same night. With further follow-up observations we will be able to detect planets smaller than 10 Earth masses.

  5. Marginal fluctuations as instantons on M2/D2-branes

    NASA Astrophysics Data System (ADS)

    Naghdi, M.

    2014-03-01

    We introduce some (anti-) M/D-branes through turning on the corresponding field strengths of the 11- and 10-dimensional supergravity theories over spaces, where we use and for the internal spaces. Indeed, when we add M2/D2-branes on the same directions with the near horizon branes of the Aharony-Bergman-Jafferis-Maldacena model, all symmetries and supersymmetries are preserved trivially. In this case, we obtain a localized object just in the horizon. This normalizable bulk massless scalar mode is a singlet of and , and it agrees with a marginal boundary operator of the conformal dimension of . However, after performing a special conformal transformation, we see that the solution is localized in the Euclideanized space and is attributable to the included anti-M2/D2-branes, which are also necessary to ensure that there is no back-reaction. The resultant theory now breaks all supersymmetries to , while the other symmetries are so preserved. The dual boundary operator is then set up from the skew-whiffing of the representations and for the supercharges and scalars, respectively, while the fermions remain fixed in of the original theory. Besides, we also address another alternate bulk to boundary matching procedure through turning on one of the gauge fields of the full gauge group along the same lines with a similar situation to the one faced in the AdS/CFT correspondence. The latter approach covers the difficulty already faced with in the bulk-boundary matching procedure for as well.

  6. M2-F3 with test pilot John A. Manke

    NASA Image and Video Library

    1972-12-20

    NASA research pilot John A. Manke is seen here in front of the M2-F3 Lifting Body. Manke was hired by NASA on May 25, 1962, as a flight research engineer. He was later assigned to the pilot's office and flew various support aircraft including the F-104, F5D, F-111 and C-47. After leaving the Marine Corps in 1960, Manke worked for Honeywell Corporation as a test engineer for two years before coming to NASA. He was project pilot on the X-24B and also flew the HL-10, M2-F3, and X-24A lifting bodies. John made the first supersonic flight of a lifting body and the first landing of a lifting body on a hard surface runway. Manke served as Director of the Flight Operations and Support Directorate at the Dryden Flight Research Center prior to its integration with Ames Research Center in October 1981. After this date John was named to head the joint Ames-Dryden Directorate of Flight Operations. He also served as site manager of the NASA Ames-Dryden Flight Research Facility. John is a member of the Society of Experimental Test Pilots. He retired on April 27, 1984.

  7. S=+1 pentaquarks in QCD sum rules

    NASA Astrophysics Data System (ADS)

    Gubler, Philipp; Jido, Daisuke; Kojo, Toru; Nishikawa, Tetsuo; Oka, Makoto

    2009-10-01

    The QCD sum rule technique is employed to investigate pentaquark states with strangeness S = +1 and IJ^π = 012^±,112^±,032^ ±,132^±. Throughout the calculation, we emphasize the importance of the establishment of a valid Borel window, which corresponds to a region of the Borel mass, where the operator product expansion (OPE) converges and the presumed ground state pole dominates the sum rules. Such a Borel window is achieved by constructing the sum rules from the differenece of two carefully chosen independent correlators and by calculating the OPE up to dimension 14. As a result, we conclude that the state with qauntum numbers 032^+ state appears to be the most probable candidate for the experimantally observed &+circ;(1540), while we also obtain states with 012^-,112^-,132^+ at somewhat higher mass regions. We furthermore discuss the contribution of the KN scattering states to the sum rules, and the possible influence of these states on our results.

  8. S=+1 pentaquarks in QCD sum rules

    NASA Astrophysics Data System (ADS)

    Gubler, Philipp; Jido, Daisuke; Kojo, Toru; Nishikawa, Tetsuo; Oka, Makoto

    2010-04-01

    We study pentaquark states with strangeness S=+1 and IJ=01,11,03,13 within the QCD sum rule technique. In order to obtain reliable results with this method, it is indispensable to establish a valid Borel window, where the operator product expansion (OPE) converges and the presumed ground state pole dominates the sum rules. By constructing the sum rules from the difference of two carefully chosen independent correlators and calculating the OPE up to dimension 14, such a Borel window can be established. This then leads to our main conclusion that the state with qantum numbers 03 appears to be the most probable candidate for the experimentally observed Θ(1540). Furthermore, states with 01,11,13 are also obtained at slightly higher mass regions.

  9. Galaxy Groups within 3500 km s-1

    NASA Astrophysics Data System (ADS)

    Kourkchi, Ehsan; Tully, R. Brent

    2017-01-01

    We present an algorithm to find nearby galaxy groups within 3,500 km s-1 (~45 Mpc). Our algorithm is based on the direct observed scaling relations that relate luminosity, velocity dispersion and dimensions of groups. Using these scaling relations, in an iterative process, galaxies with almost the same radial velocities and in close angular proximity fall into groups. Since peculiar velocities and Hubble expansion rate are comparable at these local distances, radial velocities are not very good proxies for galaxies distances. Therefore, further manual investigations of the identified groups is inevitable to discard interlopers and/or to resolve confusing cases in crowded regions. The goal of this study is to explore the nature of smallest galaxy groups and to investigate the halo mass function below 8x1012 solar mass.

  10. Neutron detection on the Foton-M2 satellite by a track etch detector stack.

    PubMed

    Pálfalvi, J K; Szabó, J; Dudás, B

    2007-01-01

    In the frame of a European Space Agency (ESA) project called 'Biology and Physics in Space', a returning satellite, Foton-M2, was orbiting a container, the BIOPAN-5, loaded with biological experiments and facilities for radiation dosimetry (RADO) in the open space. One of the RADO experiments was dedicated to the detection of the primary cosmic rays and secondary neutrons by a track etch detector stack. The system was calibrated at high-energy particle accelerators and neutron generators. The developed detectors were investigated by an image analyser, and from the track parameters the linear energy transfer spectra and the absorbed dose were determined (26 microGy/d). Also, the neutron flux was estimated below 5 MeV and found to be 2.4 cm(-2) s(-1) directly from the space. The construction of the stack allowed to investigate the neutrons also from the direction of the carrying satellite, where the flux was found somewhat higher.

  11. A phase I study of S-1 in combination with nab-paclitaxel in patients with unresectable or recurrent gastric cancer.

    PubMed

    Nakayama, Norisuke; Ishido, Kenji; Chin, Keisho; Nishimura, Ken; Azuma, Mizutomo; Matsusaka, Satoshi; Inokuchi, Yasuhiro; Tanabe, Satoshi; Kumekawa, Yosuke; Koizumi, Wasaburo

    2017-03-01

    In Japan, S-1, an oral fluoropyrimidine, plus cisplatin is a standard regimen for advanced gastric cancer, whereas nab-paclitaxel is a treatment option. We aimed to evaluate the tolerance, pharmacokinetics, safety, and clinical efficacy of S-1 combined with nab-paclitaxel in patients with advanced gastric cancer in a phase 1 study. The primary objective was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of S-1 plus nab-paclitaxel. The study was designed in accordance with a standard 3 + 3 method. Patients received 3-week cycles of treatment. S-1 was administered orally at 80 mg/m(2) twice daily for 14 days, and nab-paclitaxel was administered as an intravenous infusion at 180, 220, or 260 mg/m(2) on day 1 or 8. Among the 16 patients enrolled, dose-limiting toxicity was observed in one patient at level 2a (S-1 80 mg/m(2) twice daily plus nab-paclitaxel 220 mg/m(2) on day 1). The MTD was not obtained, but the RD was established as level 3a (S-1 80 mg/m(2) twice daily plus nab-paclitaxel 260 mg/m(2) on day 1). The most common grade 3-4 toxicity was neutropenia (62.5 %). The overall response rate was 54.5 %. The pharmacokinetic profiles of coadministered S-1 and paclitaxel were comparable to those of nab-paclitaxel or S-1 alone. Based on the present results, the RD was determined as level 3a (S-1 80 mg/m(2) twice daily plus nab-paclitaxel 260 mg/m(2) on day 1). This combination therapy was well tolerated and showed antitumor efficacy in patients with advanced gastric cancer.

  12. Parkin Regulates the Activity of Pyruvate Kinase M2*

    PubMed Central

    Liu, Kun; Li, Fanzhou; Han, Haichao; Chen, Yue; Mao, Zebin; Luo, Jianyuan; Zhao, Yingming; Zheng, Bin; Gu, Wei; Zhao, Wenhui

    2016-01-01

    Parkin, a ubiquitin E3 ligase, is mutated in most cases of autosomal recessive early onset Parkinson disease. It was discovered that Parkin is also mutated in glioblastoma and other human malignancies and that it inhibits tumor cell growth. Here, we identified pyruvate kinase M2 (PKM2) as a unique substrate for parkin through biochemical purification. We found that parkin interacts with PKM2 both in vitro and in vivo, and this interaction dramatically increases during glucose starvation. Ubiquitylation of PKM2 by parkin does not affect its stability but decreases its enzymatic activity. Parkin regulates the glycolysis pathway and affects the cell metabolism. Our studies revealed the novel important roles of parkin in tumor cell metabolism and provided new insight for therapy of Parkinson disease. PMID:26975375

  13. Beam-Based Production of 178m2Hf

    NASA Astrophysics Data System (ADS)

    Farrell, J. Paul; Dudnikov, V.; Carroll, J. J.; Merkel, G.

    2002-11-01

    In this study, the production yield for the reaction 176Yb(9Be, α3n)178Hf was explored using the FN tandem injected superconducting LINAC at SUNY at Stony Brook at a 9Be energy of 65 MeV. By comparing the experimental yield of 178Hf ground state γ rays with those of 180W as a function of energy, the cross section for production of the incomplete fusion γ rays in 178Hf was evaluated. Coincidence measurements were made to get information about the population strength of the high spin states in 178Hf. From these measurements, the maximum cross section for the reaction 176Yb(9Be, α3n)178m2Hf is estimated to be no larger than 5 mb.

  14. The discovery of an anomalous RGB in M 2.

    NASA Astrophysics Data System (ADS)

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

    Using UV images taken with the Telescopio Nazionale Galileo, we discovered an anomalous sequence in the color-magnitude diagram of M 2. This feature appears as a narrow poor-populated red giant branch, which extends down to the sub giant branch region. We speculate that this new feature could be the extension of the faint component of the split sub giant branch recently discovered by Piotto et al. We identified in our U,V images two CH stars detected in previous studies. These stars, which are both cluster members, fall on this redder sequence, suggesting indeed that the anomalous RGB should have a peculiar chemical pattern. Unfortunately, no additional spectra were obtained for stars in this previously unknown substructure.

  15. Polarimetry of R Aqr and PN M2-9

    NASA Astrophysics Data System (ADS)

    Navarro, Silvana G.; Sabin, Laurence; Ramírez Vélez; , Julio; Hiriart, David

    2014-08-01

    The bipolar or more complex morphology observed in planetary nebulae have been explained by two principal hypothesis: by the existence of a companion and an accreting disk or by the effects of magnetic field, (or a combination of both). Symbiotics are binary systems and some of them show morphologies similar to those observed on planetary nebulae. This fact could support the binary hypothesis for PNe. We have therefore performed polarimetric observations of symbiotic systems and some planetary nebulae in order, first to detect linear polarisation with POLIMA at the San Pedro Mártir observatory, and ultimately to prove the existence and physical properties of those disks. We present here the first results of a project dedicated to the analysis of the polarisation observed in evolved objects starting with the PN M2-9 and R Aqr.

  16. Microglial M1/M2 polarization and metabolic states.

    PubMed

    Orihuela, Ruben; McPherson, Christopher A; Harry, Gaylia Jean

    2016-02-01

    Microglia are critical nervous system-specific immune cells serving as tissue-resident macrophages influencing brain development, maintenance of the neural environment, response to injury and repair. As influenced by their environment, microglia assume a diversity of phenotypes and retain the capability to shift functions to maintain tissue homeostasis. In comparison with peripheral macrophages, microglia demonstrate similar and unique features with regards to phenotype polarization, allowing for innate immunological functions. Microglia can be stimulated by LPS or IFN-γ to an M1 phenotype for expression of pro-inflammatory cytokines or by IL-4/IL-13 to an M2 phenotype for resolution of inflammation and tissue repair. Increasing evidence suggests a role of metabolic reprogramming in the regulation of the innate inflammatory response. Studies using peripheral immune cells demonstrate that polarization to an M1 phenotype is often accompanied by a shift in cells from oxidative phosphorylation to aerobic glycolysis for energy production. More recently, the link between polarization and mitochondrial energy metabolism has been considered in microglia. Under these conditions, energy demands would be associated with functional activities and cell survival and thus, may serve to influence the contribution of microglia activation to various neurodegenerative conditions. This review examines the polarization states of microglia and their relationship to mitochondrial metabolism. Additional supporting experimental data are provided to demonstrate mitochondrial metabolic shifts in primary microglia and the BV-2 microglia cell line induced under LPS (M1) and IL-4/IL-13 (M2) polarization. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

  17. S=+1 pentaquarks in QCD sum rules

    SciTech Connect

    Kojo, T.; Gubler, P.; Jido, D.; Nishikawa, T.; Oka, M.

    2010-04-01

    The QCD sum rule technique is employed to investigate pentaquark states with strangeness S = +1 and IJ{sup {pi}} = 0 1/2{sup {+-}}, 1 1/2{sup {+-}}, 0 3/2{sup {+-}}, 1 3/2{sup {+-}}. Throughout the calculation, we emphasize the importance of the establishment of a valid Borel window, which corresponds to a region of the Borel mass, where the operator product expansion (OPE) converges and the presumed ground state pole dominates the sum rules. Such a Borel window is achieved by constructing the sum rules from the differenece of two carefully chosen independent correlators and by calculating the OPE up to dimension 14. As a result, we conclude that the state with qauntum numbers 0 3/2{sup +} state appears to be the most probable candidate for the experimentally observed {Theta}{sup +}(1540), while we also obtain states with 0 1/2{sup -}, 1 1/2{sup -}, 1 3/2{sup +} at somewhat higher mass regions. We furthermore discuss the contribution of the KN scattering states to the sum rules, and the possible influence of these states on our results.

  18. International Space Station (ISS) S1 Truss

    NASA Technical Reports Server (NTRS)

    2002-01-01

    Shown here is the International Space Station (ISS) S1 Truss in preparation for installation in the payload bay of the Space Shuttle Atlantis at NASA's Kennedy Space Center )KSC)in Florida. The truss launched October 7, 2002 on the STS-112 mission and will be attached during three spacewalks. Constructed primarily of aluminum, it measures 45 feet long, 15 feet wide, 10 feet tall, and weighs over 27,000 pounds. It is one of nine similar truss segments that, combined, will serve as the Station's main backbone, measuring 356 feet from end to end upon completion. Manufactured by the Boeing Company in Huntington Beach, California, the truss was flown to the Marshall Space Flight Center, in Huntsville, Alabama where brackets, cable trays, fluid tubing, and other secondary components and outfitting items were added. In Huntsville, it was screened for manufacturing flaws, including pressure and leak checking tubing, and electrical checks for cabling, before being shipped to KSC for final hardware installation and testing. The Space Station's labs, living modules, solar arrays, heat radiators, and other main components will be attached to the truss.

  19. Phase 1 study on S-1 and oxaliplatin therapy as an adjuvant after hepatectomy for colorectal liver metastases.

    PubMed

    Takahashi, Michiro; Hasegawa, Kiyoshi; Oba, Masaru; Saiura, Akio; Arita, Junichi; Sakamoto, Yoshihiro; Shinozaki, Eiji; Mizunuma, Nobuyuki; Matsuyama, Yutaka; Kokudo, Norihiro

    2016-08-01

    of Background Data The effectiveness of adjuvant chemotherapy in patients with stage II/III colorectal cancer has been confirmed in various studies. However, no adjuvant chemotherapy for colorectal liver metastasis (CLM) classified to stage IV has been established. Objectives We conducted a phase 1 study of S-1 and oxaliplatin to determine the recommended dose (RD) in patients with CLM as adjuvant therapy in two institutes. Methods S-1 and oxaliplatin were administered from day 1 to day 14 of a 3-week cycle as a 2-h infusion every 3 weeks, respectively. The initial doses of S-1 and oxaliplatin were fixed to 80 mg/m(2) and 100 mg/m(2), respectively (level 1). We scheduled in the protocol a dose change of S-1 and oxaliplatin to level 2 (S-1: 80 mg/m(2) and oxaliplatin: 130 mg/m(2)) or level 0 (S-1: 65 mg/m(2) and oxaliplatin: 100 mg/m(2)) depending on the incidence of dose-limiting toxicity (DLT) at level 1 in six patients. Results Because DLT occurred in one among the initial six patients at level 1, the doses were increased to level 2 in the next six patients. At level 2, grade 3 leukopenia and neutropenia occurred in one (16.7 %) and two (33.3 %) patients, respectively, in the absence of non-hematological event. Because no DLT occurred at level 2, we suggest that the RD can be set to the level 2 dose. The median number of cycles delivered at RD was 8. The mean relative dose intensity of S-1 and oxaliplatin at RD was 0.90 and 0.63, respectively. Conclusion In a patient undergoing hepatectomy for CLM, 80 mg/m(2) of S-1 and 130 mg/m(2) of oxaliplatin are recommended as adjuvant therapy. A further study is required to confirm the efficacy and safety of this regimen on a larger scale.

  20. Feasibility of adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent maintenance therapy with S-1 for completely resected non-small-cell lung cancer: results of the Setouchi Lung Cancer Group Study 1001.

    PubMed

    Okumura, Norihito; Sonobe, Makoto; Okabe, Kazunori; Nakamura, Hiroshige; Kataoka, Masafumi; Yamashita, Motohiro; Nakata, Masao; Kataoka, Kazuhiko; Yamashita, Yoshinori; Soh, Junichi; Yoshioka, Hiroshige; Hotta, Katsuyuki; Matsuo, Keitaro; Sakamoto, Junichi; Toyooka, Shinichi; Date, Hiroshi

    2017-04-01

    This multicenter study evaluated the feasibility of novel adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent, long-term maintenance with S-1 in patients with completely resected stage II-IIIA non-small-cell lung cancer (NSCLC). Patients received four cycles of S-1 (80 mg/m(2)/day for 2 weeks, followed by 2 weeks rest) plus carboplatin (area under the curve 5, day 1) followed by S-1 (80 mg/m(2)/day for 2 weeks, followed by a 1-week rest). Patients unable to continue S-1 plus carboplatin because of severe toxicity converted to single-agent S-1 maintenance. The duration of adjuvant chemotherapy was 10 months in both situations. The primary endpoint was feasibility, defined as the proportion of patients who completed four cycles of S-1 plus carboplatin and single-agent S-1 maintenance for 10 months. The treatment completion rate was determined; treatment was considered feasible if the lower 90% confidence interval (CI) was ≥50%. Eighty-nine patients were enrolled, of whom 87 were eligible and assessable. Seventy-eight patients (89.7%) completed four cycles of S-1 plus carboplatin and 55 (63.2%) completed the following S-1 maintenance therapy for a total of 10 months. The treatment completion rate was 63.2% (90% CI, 54.4-71.2%), indicating feasibility. There were no treatment-related deaths. Grade 3/4 toxicities included neutropenia (13.8%), thrombocytopenia (11.5%), and anorexia (4.6%). The 2-year relapse-free survival rate was 59.8%. We concluded that adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent maintenance therapy with S-1 is feasible and tolerable in patients with completely resected NSCLC. UMIN000005041.

  1. Magellan/M2FS Spectroscopy of Tucana 2 and Grus 1

    NASA Astrophysics Data System (ADS)

    Walker, Matthew G.; Mateo, Mario; Olszewski, Edward W.; Koposov, Sergey; Belokurov, Vasily; Jethwa, Prashin; Nidever, David L.; Bonnivard, Vincent; Bailey, John I., III; Bell, Eric F.; Loebman, Sarah R.

    2016-03-01

    We present results from spectroscopic observations with the Michigan/Magellan Fiber System (M2FS) of 147 stellar targets along the line of sight to the newly discovered “ultrafaint” stellar systems Tucana 2 (Tuc 2) and Grus 1 (Gru 1). Based on simultaneous estimates of line of sight velocity and stellar-atmospheric parameters, we identify 8 and 7 stars as probable members of Tuc 2 and and Gru 1, respectively. Our sample for Tuc 2 is sufficient to resolve an internal velocity dispersion of {8.6}-2.7+4.4 km s-1 about a mean of -{129.1}-3.5+3.5 km s-1 (solar rest frame), and to estimate a mean metallicity of [Fe/H] = -{2.23}-0.12+0.18. These results place Tuc 2 on chemodynamical scaling relations followed by dwarf galaxies, suggesting a dominant dark matter component with dynamical mass {2.7}-1.3+3.1× {10}6 {M}⊙ enclosed within the central ˜160 pc, and dynamical mass-to-light ratio {1913}-950+2234 {M}⊙ /{L}V,⊙ . For Gru 1 we estimate a mean velocity of -{140.5}-1.6+2.4 km s-1 and a mean metallicity of [Fe/H] = -{1.42}-0.42+0.55 but our sample does not resolve Gru 1's velocity dispersion. The radial coordinates of Tuc 2 and Gru 1 in Galactic phase space suggest that their orbits are among the most energetic within a distance of ≲ 300 {{kpc}}. Moreover, their proximity to each other in this space arises naturally if both objects are trailing the Large Magellanic Cloud. This paper presents data gathered with the Magellan Telescopes at Las Campanas Observatory, Chile.

  2. [Successful outcome from treatment modality with low-dose S-1 for three oldest old patients with advanced oral cancer].

    PubMed

    Tamura, Takayuki; Tanio, Kazuhiko; Kidani, Kazunori; Ogawa, Nobufumi; Kodani, Isamu; Ryoke, Kazuo

    2012-07-01

    We herein present three oldest old patients with advanced oral cancer for whom low-dose S-1 treatment was effective and improved QOL. The first patient is a 90-year-old female with cancer of the maxilla(T4N0Mx). Because of her generally poor condition, her family did not desire radical therapy. S-1(40mg/m2)was administered for 2 weeks followed by a 1-week interval. Because of a partial response without serious side effects, we increased the dose of S-1 to 50mg/m2. The tumor currently shows a tendency toward reduction. The second patient is a 96-year-old female with cancer of the mandible(T4N0Mx). Because of her old age, her family desired palliative therapy. S-1(40mg/m2)was administered for 2 weeks followed by a 1-week interval. A complete response was obtained at the end of the second course. There has been no recurrence. The third patient is a 94-year-old female with cancer of the maxilla(T3N0M0). Her family selected palliative therapy. S-1(50mg/m2)was administered for 2 weeks followed by a 1-week interval. The tumor size decreased after administration of S-1, without serious side effects. However, the tumor increased after the end of the fifth course. Considering the patient's condition, S-1 administration was discontinued at the end of the eighth course. S-1 is considered to be an effective and safe treatment for the maintenance or improvement of the QOL of old and oldest old patients with advanced oral cancer.

  3. Discrete functions of M2a and M2c macrophage subsets determine their relative efficacy in treating chronic kidney disease.

    PubMed

    Lu, Junyu; Cao, Qi; Zheng, Dong; Sun, Yan; Wang, Changqi; Yu, Xiao; Wang, Ya; Lee, Vincent W S; Zheng, Guoping; Tan, Thian K; Wang, Xin; Alexander, Stephen I; Harris, David C H; Wang, Yiping

    2013-10-01

    Two types of alternatively activated macrophages, M(2a) induced by IL-4/IL-13 and M(2c) by IL-10/TGF-β, exhibit anti-inflammatory functions in vitro and protect against renal injury in vivo. Since their relative therapeutic efficacy is unclear, we compared the effects of these two macrophage subsets in murine adriamycin nephrosis. Both subsets significantly reduced renal inflammation and renal injury; however, M(2c) macrophages more effectively reduced glomerulosclerosis, tubular atrophy, interstitial expansion, and proteinuria than M(2a) macrophages. The M(2c) macrophages were also more effective than M(2a) in reduction of macrophage and CD4(+) T-cell infiltration in kidney. Moreover, nephrotic mice treated with M(2c) had a greater reduction in renal fibrosis than those treated with M(2a). M(2c) but not M(2a) macrophages induced regulatory T cells (Tregs) from CD4(+)CD25(-) T cells in vitro, and increased Treg numbers in local draining lymph nodes of nephrotic mice. To determine whether the greater protection with M(2c) was due to their capability to induce Tregs, the Tregs were depleted by PC61 antibody in nephrotic mice treated with M(2a) or M(2c). Treg depletion diminished the superior effects of M(2c) compared to M(2a) in protection against renal injury, inflammatory infiltrates, and renal fibrosis. Thus, M(2c) are more potent than M(2a) macrophages in protecting against renal injury due to their ability to induce Tregs.

  4. Multiple heterologous M2 extracellular domains presented on virus-like particles confer broader and stronger M2 immunity than live influenza A virus infection.

    PubMed

    Kim, Min-Chul; Lee, Jong-Seok; Kwon, Young-Man; O, Eunju; Lee, Youn-Jeong; Choi, Jun-Gu; Wang, Bao-Zhong; Compans, Richard W; Kang, Sang-Moo

    2013-09-01

    The influenza M2 ectodomain (M2e) is poorly immunogenic and has some amino acid changes among isolates from different host species. We expressed a tandem repeat construct of heterologous M2e sequences (M2e5x) derived from human, swine, and avian origin influenza A viruses on virus-like particles (M2e5x VLPs) in a membrane-anchored form. Immunization of mice with M2e5x VLPs induced protective antibodies cross-reactive to antigenically different influenza A viruses and conferred cross protection. Anti-M2e antibodies induced by heterologous M2e5x VLPs showed a wider range of cross reactivity to influenza A viruses at higher levels than those by live virus infection, homologous M2e VLPs, or M2e monoclonal antibody 14C2. Fc receptors were found to be important for mediating protection by immune sera from M2e5x VLP vaccination. The present study provides evidence that heterologous recombinant M2e5x VLPs can be more effective in inducing protective M2e immunity than natural virus infection and further supports an approach for developing an effective universal influenza vaccine.

  5. Optical spectrum of the planetary nebula M 2-24

    NASA Astrophysics Data System (ADS)

    Zhang, Y.; Liu, X.-W.

    2003-06-01

    We have obtained medium-resolution, deep optical long-slit spectra of the bulge planetary nebula (PN) M 2-24. The spectrum covers the wavelength range from 3610-7330 Å. Over two hundred emission lines have been detected. The spectra show a variety of optical recombination lines (ORLs) from C, N, O and Ne ions. The diagnostic diagram shows significant density and temperature variations across the nebula. Our analysis suggests that the nebula has a dense central emission core. The nebula was thus studied by dividing it into two regions: 1) a high ionization region characterized by an electron temperature of Te=16 300 K and a density of log Ne(cm-3) = 6.3; and 2) a low ionization region represented by Te=11 400 K and log Ne(cm-3) = 3.7. A large number of ORLs from C, N, O and Ne ions have been used to determine the abundances of these elements relative to hydrogen. In general, the resultant abundances are found to be higher than the corresponding values deduced from collisionally excited lines (CELs). This bulge PN is found to have large enhancements in two alpha -elements, magnesium and neon. Full Table 2 is available in electronic form at the CDS via anonymous ftp to cdsarc.u-strasbg.fr (130.79.126.5) or via http://cdsweb.u-strasbg.fr/cgi-bin/qcat?J/A+A/404/545

  6. Pyruvate kinase M2 is a phosphotyrosine-binding protein

    SciTech Connect

    Christofk, H.R.; Vander Heiden, M.G.; Wu, N.; Asara, J.M.; Cantley, L.C.

    2008-06-03

    Growth factors stimulate cells to take up excess nutrients and to use them for anabolic processes. The biochemical mechanism by which this is accomplished is not fully understood but it is initiated by phosphorylation of signalling proteins on tyrosine residues. Using a novel proteomic screen for phosphotyrosine-binding proteins, we have made the observation that an enzyme involved in glycolysis, the human M2 (fetal) isoform of pyruvate kinase (PKM2), binds directly and selectively to tyrosine-phosphorylated peptides. We show that binding of phosphotyrosine peptides to PKM2 results in release of the allosteric activator fructose-1,6-bisphosphate, leading to inhibition of PKM2 enzymatic activity. We also provide evidence that this regulation of PKM2 by phosphotyrosine signalling diverts glucose metabolites from energy production to anabolic processes when cells are stimulated by certain growth factors. Collectively, our results indicate that expression of this phosphotyrosine-binding form of pyruvate kinase is critical for rapid growth in cancer cells.

  7. Fermi surface behavior in the ABJM M2-brane theory

    NASA Astrophysics Data System (ADS)

    DeWolfe, Oliver; Henriksson, Oscar; Rosen, Christopher

    2015-06-01

    We calculate fermionic Green's functions for states of the three-dimensional Aharony-Bergman-Jafferis-Maldacena M2-brane theory at large N using the gauge-gravity correspondence. We embed extremal black brane solutions in four-dimensional maximally supersymmetric gauged supergravity, obtain the linearized Dirac equations for each spin-1 /2 mode that cannot mix with a gravitino, and solve these equations with infalling boundary conditions to calculate retarded Green's functions. For generic values of the chemical potentials, we find Fermi surfaces with universally non-Fermi liquid behavior, matching the situation for four-dimensional N =4 super-Yang-Mills. Fermi surface singularities appear and disappear discontinuously at the point where all chemical potentials are equal, reminiscent of a quantum critical point. One limit of parameter space has zero entropy at zero temperature, and fermionic fluctuations are perfectly stable inside an energy region around the Fermi surface. An ambiguity in the quantization of the fermions is resolved by supersymmetry.

  8. Spherical tokamak Globus-M2: design, integration, construction

    NASA Astrophysics Data System (ADS)

    Minaev, V. B.; Gusev, V. K.; Sakharov, N. V.; Varfolomeev, V. I.; Bakharev, N. N.; Belyakov, V. A.; Bondarchuk, E. N.; Brunkov, P. N.; Chernyshev, F. V.; Davydenko, V. I.; Dyachenko, V. V.; Kavin, A. A.; Khitrov, S. A.; Khromov, N. A.; Kiselev, E. O.; Konovalov, A. N.; Kornev, V. A.; Kurskiev, G. S.; Labusov, A. N.; Melnik, A. D.; Mineev, A. B.; Mironov, M. I.; Miroshnikov, I. V.; Patrov, M. I.; Petrov, Yu. V.; Rozhansky, V. A.; Saveliev, A. N.; Senichenkov, I. Yu.; Shchegolev, P. B.; Shcherbinin, O. N.; Shikhovtsev, I. V.; Sladkomedova, A. D.; Solokha, V. V.; Tanchuk, V. N.; Telnova, A. Yu.; Tokarev, V. A.; Tolstyakov, S. Yu.; Zhilin, E. G.

    2017-06-01

    The Globus-M spherical tokamak has demonstrated practically all of the project objectives during the 15-year period of operation. The main factor limiting further progress in plasma performance is a relatively low toroidal magnetic field. The maximum toroidal magnetic field achieved on Globus-M was 0.4 T with the exception of a limited number of shots with 0.55 T, which led to damage of the toroidal field coil in 2002. The increase of the magnetic field up to 1.0 T together with the plasma current up to 0.5 MA will result in the significant enhancement of the operating parameters in the upgraded Globus-M2 machine. The experimental program will be focused on plasma heating and non-inductive current drive and will contribute to the creation of a physical and technological base for the compact fusion neutron source development. In the article a brief overview of the physical background for the machine upgrade is outlined. The current status of the project implementation is described. First experimental results on moderate magnetic field increase from 0.4 T up to 0.5 T in the existing Globus-M machine are discussed. The improvement of plasma confinement as well as enhancement of efficiency of the beam driven current is observed.

  9. Conversion therapy for pancreatic cancer with peritoneal metastases using intravenous and intraperitoneal paclitaxel with S-1

    PubMed Central

    Kitayama, Hiromitsu; Tsuji, Yasushi; Kondo, Tomohiro; Sugiyama, Junko; Hirayama, Michiaki; Yamamoto, Kazuyuki; Kawarada, You; Oyamada, Yumiko; Hirano, Satoshi

    2016-01-01

    Combination chemotherapy consisting of systemic and intraperitoneal agents against peritoneal metastases from several types of cancer has shown promising results. We herein report a case in which combination therapy with intravenous and intraperitoneal paclitaxel with S-1 converted an unresectable pancreatic cancer with peritoneal metastases into a resectable one. The patient was a 65-year old woman with recurrent pancreatitis for 5 months. Endoscopic ultrasonography-guided fine-needle aspiration revealed minute epithelial masses composed of cells with irregular nuclei in the pancreatic body. The patient underwent abdominal surgery, but no excision was performed, as two peritoneal metastases in the bursa omentalis were detected. Combination therapy was initiated, consisting of intravenous and intraperitoneal paclitaxel with S-1 as a single-center clinical trial. The regimen consisted with 2-week administration of S-1 (80 mg per day) followed by 1 week of rest, intravenous paclitaxel 50 mg/m2, and intraperitoneal paclitaxel 20 mg/m2 by a peritoneal access device on days 1 and 8. Over the seven cycles of the chemotherapy, the primary lesion did not change in size, and peritoneal lavage cytology remained negative. After confirming the disappearance of the peritoneal lesions by exploratory laparoscopy, the patient underwent distal pancreatectomy combined with resection of the transverse mesocolon and stomach wall. Thus, the 2-way chemotherapy of intravenous and intraperitoneal paclitaxel with S-1 was well-tolerated and was able to convert pancreatic cancer with peritoneal metastases to resectable disease. PMID:28105356

  10. On the 𝔞𝔣𝔣(m|1)-relative cohomology of the orthosymplectic superalgebra 𝔬𝔰𝔭(m|2) and 𝔞𝔣𝔣(m|1)-trivial deformation

    NASA Astrophysics Data System (ADS)

    Khalfoun, Hafedh; Faidi, Thamer

    Over the (1,m)-dimensional supercircle S1|m,m = 0, 1, 2, we consider the action of the orthosymplectic Lie superalgebra 𝔬𝔰𝔭(m|2), by the Lie derivative on the superpseudodifferential operators 𝒮Ψ𝒟𝒪(S1|m). We compute the 𝔞𝔣𝔣(m|1)-relative cohomology spaces H1(𝔬𝔰𝔭(m|2), 𝔞𝔣𝔣(m|1); 𝒮Ψ𝒟𝒪(S1|m)), where 𝔞𝔣𝔣(m|1) is the affine Lie superalgebra on S1|m. We explicitly give cocycles spanning these cohomology spaces. We study the 𝔞𝔣𝔣(m|1)-trivial deformations of the structure of the 𝔬𝔰𝔭(m|2)-modules 𝒮Ψ𝒟𝒪(S1|m).

  11. Metric 3-Leibniz algebras and M2-branes

    NASA Astrophysics Data System (ADS)

    Méndez-Escobar, Elena

    2010-08-01

    This thesis is concerned with superconformal Chern-Simons theories with matter in 3 dimensions. The interest in these theories is two-fold. On the one hand, it is a new family of theories in which to test the AdS/CFT correspondence and on the other, they are important to study one of the main objects of M-theory (M2-branes). All these theories have something in common: they can be written in terms of 3-Leibniz algebras. Here we study the structure theory of such algebras, paying special attention to a subclass of them that gives rise to maximal supersymmetry and that was the first to appear in this context: 3-Lie algebras. In chapter 2, we review the structure theory of metric Lie algebras and their unitary representations. In chapter 3, we study metric 3-Leibniz algebras and show, by specialising a construction originally due to Faulkner, that they are in one to one correspondence with pairs of real metric Lie algebras and unitary representations of them. We also show a third characterisation for six extreme cases of 3-Leibniz algebras as graded Lie (super)algebras. In chapter 4, we study metric 3-Lie algebras in detail. We prove a structural result and also classify those with a maximally isotropic centre, which is the requirement that ensures unitarity of the corresponding conformal field theory. Finally, in chapter 5, we study the universal structure of superpotentials in this class of superconformal Chern-Simons theories with matter in three dimensions. We provide a uniform formulation for all these theories and establish the connection between the amount of supersymmetry preserved and the gauge Lie algebra and the appropriate unitary representation to be used to write down the Lagrangian. The conditions for supersymmetry enhancement are then expressed equivalently in the language of representation theory of Lie algebras or the language of 3-Leibniz algebras.

  12. Phase II study of induction gemcitabine and S-1 followed by chemoradiotherapy and systemic chemotherapy using S-1 for locally advanced pancreatic cancer.

    PubMed

    Sudo, Kentaro; Hara, Ryusuke; Nakamura, Kazuyoshi; Kita, Emiri; Tsujimoto, Akiko; Yamaguchi, Taketo

    2017-07-01

    S-1 has systemic activity for locally advanced pancreatic cancer (LAPC). Here, the efficacy and safety of induction gemcitabine (GEM) and S-1 (GS) followed by chemoradiotherapy (CRT) and systemic chemotherapy using S-1 for LAPC were assessed. The treatment consisted of four cycles of induction GS (S-1 60, 80, or 100 mg/day based on body surface area for 14 days every 3 weeks plus GEM 1000 mg/m(2) on days 8 and 15), followed by S-1 (80, 100, or 120 mg/day based on body surface area on days 1-14 and 22-35) and concurrent radiotherapy (50.4 Gy in 28 fractions). Maintenance chemotherapy with S-1 was started 1-4 weeks after CRT until disease progression or unacceptable toxicity was observed. The primary endpoint was 1-year survival. A total of 30 patients with LAPC were enrolled. The median survival and progression-free survival were 21.3 and 12.7 months, respectively. Overall survival rates at 1, 2, 3, and 4 years were 73.3, 36.7, 23.3, and 16.7%, respectively. The median survival of 23 patients who received CRT was 22.9 months, with a 3-year survival rate of 30.4%. The two most common grade 3 or 4 adverse events during induction GS were neutropenia (63.3%) and biliary tract infection (20%). Toxicities during CRT or maintenance chemotherapy were generally mild. This regimen was feasible and highly active resulting in encouraging survival in patients with LAPC. Further investigations are warranted to elucidate the effectiveness of this treatment strategy in future studies. Clinical trials information: UMIN000006332.

  13. Exit Strategies: S1P Signaling and T Cell Migration.

    PubMed

    Baeyens, Audrey; Fang, Victoria; Chen, Cynthia; Schwab, Susan R

    2015-12-01

    Whereas the role of sphingosine 1-phosphate receptor 1 (S1PR1) in T cell egress and the regulation of S1P gradients between lymphoid organs and circulatory fluids in homeostasis are increasingly well understood, much remains to be learned about S1P signaling and distribution during an immune response. Recent data suggest that the role of S1PR1 in directing cells from tissues into circulatory fluids is reprised again and again, particularly in guiding activated T cells from non-lymphoid tissues into lymphatics. Conversely, S1P receptor 2 (S1PR2), which antagonizes migration towards chemokines, confines cells within tissues. Here we review the current understanding of the roles of S1P signaling in activated T cell migration. In this context, we outline open questions, particularly regarding the shape of S1P gradients in different tissues in homeostasis and inflammation, and discuss recent strategies to measure S1P.

  14. Frequency measurement of the 2S(1/2)-2D(3/2) electric quadrupole transition in a single 171Yb+ ion.

    PubMed

    Webster, Stephen; Godun, Rachel; King, Steven; Huang, Guilong; Walton, Barney; Tsatourian, Veronika; Margolis, Helen; Lea, Stephen; Gill, Patrick

    2010-03-01

    We report on precision laser spectroscopy of the 2S(1/2)(F = 0)-2D(3/2) (F = 2, m(F) = 0) clock transition in a single ion of 171Yb+. The absolute value of the transition frequency, determined using an optical frequency comb referenced to a hydrogen maser, is 688358979309310 +/- 9 Hz. This corresponds to a fractional frequency uncertainty of 1.3 x 10(-14).

  15. Characterization of inhibition of M2 ion channel activity by BL-1743, an inhibitor of influenza A virus.

    PubMed Central

    Tu, Q; Pinto, L H; Luo, G; Shaughnessy, M A; Mullaney, D; Kurtz, S; Krystal, M; Lamb, R A

    1996-01-01

    The influenza A virus M2 integral membrane protein has ion channel activity that can be inhibited by the antiviral drug amantadine. Recently, a spirene-containing compound, BL-1743 (2-[3-azaspiro (5,5)undecanol]-2-imidazoline), that inhibits influenza virus growth was identified (S. Kurtz, G. Lao, K. M. Hahnenberger, C. Brooks, O. Gecha, K. Ingalls, K.-I. Numata, and M. Krystal, Antimicrob. Agents Chemother. 39:2204-2209, 1995). We have examined the ability of BL-1743 to inhibit the M2 ion channel when expressed in oocytes of Xenopus laevis. BL-1743 inhibition is complete as far as can be measured by electrophysiological methods and is reversible, with a reverse reaction rate constant of 4.0 x 10(-3) s(-1). In contrast, amantadine inhibition is irreversible within the time frame of the experiment. However, BL-1743 inhibition and amantadine inhibition have similar properties. The majority of isolated influenza viruses resistant to BL-1743 are also amantadine resistant. In addition, all known amino acid changes which result in amantadine resistance also confer BL-1743 resistance. However, one BL-1743-resistant virus isolated, designated M2-I35T, contained the change Ile-35-->Thr. This virus is >70-fold more resistant to BL-1743 and only 10-fold more resistant to amantadine than the wild-type virus. When the ion channel activity of M2-I35T was examined in oocytes, it was found that M2-I35T is BL-1743 resistant but is reversibly inhibited by amantadine. These findings suggest that these two drugs interact differently with the M2 protein transmembrane pore region. PMID:8676445

  16. Exogenous S1P Exposure Potentiates Ischemic Stroke Damage That Is Reduced Possibly by Inhibiting S1P Receptor Signaling.

    PubMed

    Moon, Eunjung; Han, Jeong Eun; Jeon, Sejin; Ryu, Jong Hoon; Choi, Ji Woong; Chun, Jerold

    2015-01-01

    Initial and recurrent stroke produces central nervous system (CNS) damage, involving neuroinflammation. Receptor-mediated S1P signaling can influence neuroinflammation and has been implicated in cerebral ischemia through effects on the immune system. However, S1P-mediated events also occur within the brain itself where its roles during stroke have been less well studied. Here we investigated the involvement of S1P signaling in initial and recurrent stroke by using a transient middle cerebral artery occlusion/reperfusion (M/R) model combined with analyses of S1P signaling. Gene expression for S1P receptors and involved enzymes was altered during M/R, supporting changes in S1P signaling. Direct S1P microinjection into the normal CNS induced neuroglial activation, implicating S1P-initiated neuroinflammatory responses that resembled CNS changes seen during initial M/R challenge. Moreover, S1P microinjection combined with M/R potentiated brain damage, approximating a model for recurrent stroke dependent on S1P and suggesting that reduction in S1P signaling could ameliorate stroke damage. Delivery of FTY720 that removes S1P signaling with chronic exposure reduced damage in both initial and S1P-potentiated M/R-challenged brain, while reducing stroke markers like TNF-α. These results implicate direct S1P CNS signaling in the etiology of initial and recurrent stroke that can be therapeutically accessed by S1P modulators acting within the brain.

  17. RBP-J is required for M2 macrophage polarization in response to chitin and mediates expression of a subset of M2 genes.

    PubMed

    Foldi, Julia; Shang, Yingli; Zhao, Baohong; Ivashkiv, Lionel B; Hu, Xiaoyu

    2016-03-01

    Development of alternatively activated (M2) macrophage phenotypes is a complex process that is coordinately regulated by a plethora of pathways and factors. Here, we report that RBP-J, a DNA-binding protein that integrates signals from multiple pathways including the Notch pathway, is critically involved in polarization of M2 macrophages. Mice deficient in RBP-J in the myeloid compartment exhibited impaired M2 phenotypes in vivo in a chitin-induced model of M2 polarization. Consistent with the in vivo findings, M2 polarization was partially compromised in vitro in Rbpj-deficient macrophages as demonstrated by reduced expression of a subset of M2 effector molecules including arginase 1. Functionally, myeloid Rbpj deficiency impaired M2 effector functions including recruitment of eosinophils and suppression of T cell proliferation. Collectively, we have identified RBP-J as an essential regulator of differentiation and function of alternatively activated macrophages.

  18. S1-equivariant Chern-Weil constructions on loop space

    NASA Astrophysics Data System (ADS)

    McCauley, Thomas

    2017-02-01

    We study the existence of S1-equivariant characteristic classes on certain natural infinite rank bundles over the loop space LM of a manifold M. We discuss the different S1-equivariant cohomology theories in the literature and clarify their relationships. We attempt to use S1-equivariant Chern-Weil techniques to construct S1-equivariant characteristic classes. The main result is the construction of a sequence of S1-equivariant characteristic classes on the total space of the bundles, but these classes do not descend to the base LM. Nevertheless, we conclude by identifying a class of bundles for which the S1-equivariant first Chern class does descend to LM.

  19. Blocking S1P interaction with S1P{sub 1} receptor by a novel competitive S1P{sub 1}-selective antagonist inhibits angiogenesis

    SciTech Connect

    Fujii, Yasuyuki; Ueda, Yasuji; Ohtake, Hidenori; Ono, Naoya; Takayama, Tetsuo; Nakazawa, Kiyoshi; Igarashi, Yasuyuki; Goitsuka, Ryo

    2012-03-23

    Highlights: Black-Right-Pointing-Pointer The effect of a newly developed S1P{sub 1}-selective antagonist on angiogenic responses. Black-Right-Pointing-Pointer S1P{sub 1} is a critical component of VEGF-related angiogenic responses. Black-Right-Pointing-Pointer S1P{sub 1}-selective antagonist showed in vitro activity to inhibit angiogenesis. Black-Right-Pointing-Pointer S1P{sub 1}-selective antagonist showed in vivo activity to inhibit angiogenesis. Black-Right-Pointing-Pointer The efficacy of S1P{sub 1}-selective antagonist for anti-cancer therapies. -- Abstract: Sphingosine 1-phosphate receptor type 1 (S1P{sub 1}) was shown to be essential for vascular maturation during embryonic development and it has been demonstrated that substantial crosstalk exists between S1P{sub 1} and other pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor. We developed a novel S1P{sub 1}-selective antagonist, TASP0277308, which is structurally unrelated to S1P as well as previously described S1P{sub 1} antagonists. TASP0277308 inhibited S1P- as well as VEGF-induced cellular responses, including migration and proliferation of human umbilical vein endothelial cells. Furthermore, TASP0277308 effectively blocked a VEGF-induced tube formation in vitro and significantly suppressed tumor cell-induced angiogenesis in vivo. These findings revealed that S1P{sub 1} is a critical component of VEGF-related angiogenic responses and also provide evidence for the efficacy of TASP0277308 for anti-cancer therapies.

  20. Conformationally Constrained, Stable, Triplet Ground State (S = 1) Nitroxide Diradicals. Antiferromagnetic Chains of S = 1 Diradicals

    SciTech Connect

    Rajca, Andrzej; Takahashi, Masahiro; Pink, Maren; Spagnol, Gaelle; Rajca, Suchada

    2008-06-30

    Nitroxide diradicals, in which nitroxides are annelated to m-phenylene forming tricyclic benzobisoxazine-like structures, have been synthesized and characterized by X-ray crystallography, magnetic resonance (EPR and {sup 1}H NMR) spectroscopy, as well as magnetic studies in solution and in solid state. For the octamethyl derivative of benzobisoxazine nitroxide diradical, the conformationally constrained nitroxide moieties are coplanar with the m-phenylene, leading to large values of 2J (2J/k > 200 K in solution and 2J/k >> 300 K in the solid state). For the diradical, in which all ortho and para positions of the m-phenylene are sterically shielded, distortion of the nitroxide moieties from coplanarity is moderate, such that the singlet-triplet gaps remain large in both solution (2J/k > 200 K) and the solid state (2J/k {approx} 400-800 K), though an onset of thermal depopulation of the triplet ground state is detectable near room temperature. These diradicals have robust triplet ground states with strong ferromagnetic coupling and good stability at ambient conditions. Magnetic behavior of the nitroxide diradicals at low temperature is best fit to the model of one-dimensional S = 1 Heisenberg chains with intrachain antiferromagnetic coupling. The antiferromagnetic coupling between the S = 1 diradicals may be associated with the methyl nitroxide C-H {hor_ellipsis} O contacts, including nonclassical hydrogen bonds. These unprecedented organic S = 1 antiferromagnetic chains are highly isotropic, compared to those of the extensively studied Ni(II)-based chains.

  1. [Response in a case of inoperable bile duct cancer treated by combined chemotherapy of S-1 and gemcitabine].

    PubMed

    Akiyama, Nobuhiro; Ayata, Sakura; Maruyama, Yuzuru; Tsukada, Yoshihisa

    2010-08-01

    A 60-year-old male patient was diagnosed as bile duct cancer with left neck and abdominal para-aortic lymph node metastasis. He was treated by combined chemotherapy of S-1 and gemcitabine(GEM). S-1 (120 mg/day) was administered 14 days followed by 14 days rest as one course. GEM (1,000 mg/m2) was administered at 8 and 15 days after the start of S-1. Combined therapy could be continued, though S-1 and GEM were reduced for neutropemia. After 5 courses of treatment, CT and MRCP revealed a partial response. S-1/GEM combined therapy was effective for inoperable biliary tract carcinoma.

  2. Cross-section activation measurement for U-238 through protons and deuterons in energy interval 10-14 MeV

    SciTech Connect

    Guzhovskii, B.Y.; Abramovich, S.N.; Zvenigorodskii, A.G.

    1995-10-01

    There were presented results of cross-section measurements for nuclear reactions {sup 238}U(p,n){sup 238}Np, {sup 238}U(d,2n){sup 238}Np, {sup 238}U(d,t){sup 237}U, {sup 238}U(d,p){sup 239}U, and {sup 238}U(d,n){sup 239}Np. Interval of projectile energy was 10-14 MeV. For measurements of cross-sections it was used the activatio methods. The registration of {beta}- and {gamma}-activity was made with using of plastic scintillation detector and Ge(Li)-detector.

  3. Femtosecond optical-to-microwave frequency divider with a relative instability of 10^{-14}{-} 10^{-16}(\\tau = 1 {-} 100\\ {\\text{s}})

    NASA Astrophysics Data System (ADS)

    Kireev, A. N.; Tausenev, A. V.; Tyurikov, D. A.; Shelkovnikov, A. S.; Shepelev, D. V.; Konyashchenko, A. V.; Gubin, M. A.

    2016-12-01

    We have developed a low-noise optical-to-microwave frequency divider based on a femtosecond erbium fibre laser. The source of an optical signal was a {\\text{He}} - {\\text{Ne/CH}}4 frequency standard. Comparison of two frequency dividers showed that the relative instability of output microwave signals, introduced by the dividers, is 10-14- 10-16 for the averaging time τ = 1 - 100 {\\text{s}}. The instability obtained corresponds to the requirements imposed on interrogative oscillators for time and frequency standards based on Cs or Rb atomic fountains.

  4. S1P in HDL promotes interaction between SR-BI and S1PR1 and activates S1PR1-mediated biological functions: calcium flux and S1PR1 internalization.

    PubMed

    Lee, Mi-Hye; Appleton, Kathryn M; El-Shewy, Hesham M; Sorci-Thomas, Mary G; Thomas, Michael J; Lopes-Virella, Maria F; Luttrell, Louis M; Hammad, Samar M; Klein, Richard L

    2017-02-01

    HDL normally transports about 50-70% of plasma sphingosine 1-phosphate (S1P), and the S1P in HDL reportedly mediates several HDL-associated biological effects and signaling pathways. The HDL receptor, SR-BI, as well as the cell surface receptors for S1P (S1PRs) may be involved partially and/or completely in these HDL-induced processes. Here we investigate the nature of the HDL-stimulated interaction between the HDL receptor, SR-BI, and S1PR1 using a protein-fragment complementation assay and confocal microscopy. In both primary rat aortic vascular smooth muscle cells and HEK293 cells, the S1P content in HDL particles increased intracellular calcium concentration, which was mediated by S1PR1. Mechanistic studies performed in HEK293 cells showed that incubation of cells with HDL led to an increase in the physical interaction between the SR-BI and S1PR1 receptors that mainly occurred on the plasma membrane. Model recombinant HDL (rHDL) particles formed in vitro with S1P incorporated into the particle initiated the internalization of S1PR1, whereas rHDL without supplemented S1P did not, suggesting that S1P transported in HDL can selectively activate S1PR1. In conclusion, these data suggest that S1P in HDL stimulates the transient interaction between SR-BI and S1PRs that can activate S1PRs and induce an elevation in intracellular calcium concentration.

  5. 26 CFR 1.414(s)-1 - Definition of compensation.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Definition of compensation. 1.414(s)-1 Section 1.414(s)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.414(s)-1 Definition...

  6. 26 CFR 1.414(s)-1 - Definition of compensation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Definition of compensation. 1.414(s)-1 Section 1.414(s)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.414(s)-1 Definition of...

  7. Chemical and genetic tools to explore S1P biology.

    PubMed

    Cahalan, Stuart M

    2014-01-01

    The zwitterionic lysophospholipid Sphingosine 1-Phosphate (S1P) is a pleiotropic mediator of physiology and pathology. The synthesis, transport, and degradation of S1P are tightly regulated to ensure that S1P is present in the proper concentrations in the proper location. The binding of S1P to five G protein-coupled S1P receptors regulates many physiological systems, particularly the immune and vascular systems. Our understanding of the functions of S1P has been aided by the tractability of the system to both chemical and genetic manipulation. Chemical modulators have been generated to affect most of the known components of S1P biology, including agonists of S1P receptors and inhibitors of enzymes regulating S1P production and degradation. Genetic knockouts and manipulations have been similarly engineered to disrupt the functions of individual S1P receptors or enzymes involved in S1P metabolism. This chapter will focus on the development and utilization of these chemical and genetic tools to explore the complex biology surrounding S1P and its receptors, with particular attention paid to the in vivo findings that these tools have allowed for.

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

    PubMed

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

    2016-10-01

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

  9. cap alpha. -chain locus of the T-cell antigen receptor is involved in the t(10; 14) chromosome translocation of T-cell acute lymphocytic leukemia

    SciTech Connect

    Kagan, J.; Finan, J.; Letofsky, J.; Besa, E.C.; Nowell, P.C.; Croce, C.M.

    1987-07-01

    Human leukemic T cells carrying a t(10;14)(q24;q11) chromosome translocation were fused with mouse leukemic T cells, and the hybrids were examined for genetic markers of human chromosomes 10 and 14. Hybrids containing the human 10q+ chromosome had the human genes for terminal deoxynucleotidyltransferase that has been mapped at 10q23-q25 and for C/sub ..cap alpha../ (the constant region of TCRA (the ..cap alpha..-chain locus of the T-cell antigen receptor gene)), but not for V/sub ..cap alpha../ (the variable region of TCRA). Hybrids containing the human 14q- chromosome retained the V/sub ..cap alpha../genes. Thus the 14q11 breakpoint in the t(10;14) chromosome translocation directly involves TCRA, splitting the locus in a region between the V/sub ..cap alpha../ and the C/sub ..cap alpha../ genes. These results suggest that the translocation of the C/sub ..cap alpha../ locus to a putative cellular protooncogene located proximal to the breakpoint at 10q24, for which the authors propose the name TCL3, results in its deregulation, leading to T-cell leukemia. Since hybrids with the 10q+ chromosome also retained the human terminal deoxynucleotidyltransferase gene, it is further concluded that the terminal deoxynucleotidyltransferase locus is proximal to the TCL3 gene, at band 10q23-q24.

  10. Mitochondrial Ultrastructural Alterations and Declined M2 Receptor Density Were Involved in Cardiac Dysfunction in Rats after Long Term Treatment with Autoantibodies against M2 Muscarinic Receptor

    PubMed Central

    Wang, Jin; Wang, Li; Wu, Ye; Wang, Jie; Lv, Tingting; Liu, Huirong

    2015-01-01

    Background Previous studies showed that autoantibodies (M2-AA) against the second extracellular loop of M2 muscarinic receptor (M2AChR-el2) from dilated cardiomyopathy (DCM) serum could induce DCM-like morphological changes in mice hearts. However, the effects of M2-AA on the cardiac function during the process of DCM and the potential mechanisms are not fully known. The present study was designed to dynamically observe the cardiac function, mitochondrial changes, and M2 receptor binding characteristics in rats long-term stimulated with M2-AA in vivo. Methods M2-AA-positive model was established by actively immunizing healthy male Wistar rats with synthetic M2AChR-el2 peptide for 18 months. Meanwhile, vehicle group rats were administrated with physiological saline. The change of mitochondrial membrane potential (ΔΨm) was detected by radionuclide imaging. The ultrastructure of mitochondria was observed under electron microscopy. The M2 receptor binding characteristics were determined by radioactive ligand binding assay. Results After immunization for 12 months, compared with vehicle group, M2AChR-el2-immunized rats showed decreased myocardial contractility and cardiac diastolic function evidenced by declined maximal rate of rise of ventricular pressure and increased left ventricular end-diastolic pressure, respectively. Additionally, mitochondrial swelling and vacuolation were observed. At 18 months, M2AChR-el2-immunized rats manifested significant decreased cardiac systolic and diastolic function and pathological changes such as enlargement of right ventricular cavity and wall thinning; and the mitochondrial damage was aggravated. Furthermore, the M2 receptor maximum binding capacity (Bmax) of the M2AChR-el2-immunized rats significantly decreased, while the M2 receptor dissociation constant (Kd) was increased. Conclusions Our study suggested that long-term stimulation with M2-AA leaded to the ventricular dilatation and gradual deterioration of cardiac dysfunction

  11. Randomized Phase II Study of Adjuvant Chemotherapy with Long-term S-1 versus Cisplatin+S-1 in Completely Resected Stage II-IIIA Non-Small Cell Lung Cancer.

    PubMed

    Iwamoto, Yasuo; Mitsudomi, Tetsuya; Sakai, Kazuko; Yamanaka, Takeharu; Yoshioka, Hiroshige; Takahama, Makoto; Yoshimura, Masahiro; Yoshino, Ichiro; Takeda, Masayuki; Sugawara, Shunichi; Kawaguchi, Tomoya; Takahashi, Toshiaki; Ohta, Mitsunori; Ichinose, Yukito; Atagi, Shinji; Okada, Morihito; Saka, Hideo; Nakagawa, Kazuhiko; Nakanishi, Yoichi; Nishio, Kazuto

    2015-12-01

    The aims of this study were to evaluate the efficacy and safety of S-1 versus cisplatin (CDDP)+S-1 in patients with completely resected stage II and IIIA non-small cell lung cancer, and to identify predictive biomarkers whose expression in the tumors was significantly associated with patient outcome. A total of 200 patients were randomly assigned to receive either S-1 (40 mg/m(2) twice per day) for 2 consecutive weeks repeated every 3 weeks for 1 year (S group) or CDDP (60 mg/m(2)) on day 1 plus oral S-1 (40 mg/m(2) twice per day) for 2 consecutive weeks repeated every 3 weeks for four cycles (CS group) within 8 weeks after surgery. The primary endpoints were relapse-free survival (RFS) at 2 years and identification of predictive biomarkers whose expressions have been reported to be associated with CDDP or fluoropyrimidine sensitivity. The RFS rate at 2 years was 65.6% (95% confidence intervals; CI, 55.3-74.0%) in the S group and 58.1% (95% CI, 47.7-67.2%) in the CS group. The only gene with interaction of P < 0.05 was uridine monophosphate synthase (UMPS; P = 0.0348). The benefit that members of the S group had over members of the CS group was higher expression of UMPS. In vitro and in vivo experiments confirmed that overexpression of UMPS enhanced the antitumor effect of fluoropyrimidine. Adjuvant S-1 monotherapy might be preferable to CDDP+S-1 for patients with completely resected NSCLC. UMPS expression may define a patient subset that would benefit from long-term postoperative S-1 monotherapy. ©2015 American Association for Cancer Research.

  12. Targeting sphingosine 1-phosphate (S1P) levels and S1P receptor functions for therapeutic immune interventions.

    PubMed

    Gräler, Markus H

    2010-01-01

    Sphingosine 1-phosphate (S1P) is an important regulator of many different immune functions including lymphocyte circulation, antigen presentation, and T cell development. It stimulates five G protein-coupled receptors designated S1P(1-5), which are also expressed by immune cells. S1P receptors couple to different heterotrimeric G proteins including G alpha i, q, and 12/13, and elicit cellular signalling events by activating the small GTPases Rac and Rho and protein kinases Akt, ERK, and JNK, and by inducing cellular calcium flux and inhibiting cAMP accumulation, amongst others. S1P is the exit signal for lymphocytes leaving lymphoid organs and present in blood and lymph at high nanomolar concentrations due to the S1P-producing activity of sphingosine kinases (SK). The S1P-degrading enzyme S1P-lyase maintains low amounts of S1P in lymphoid organs. Disrupting this concentration difference by S1P receptor agonists and antagonists like FTY720, SEW2871, and VPC23019, by an anti-S1P antibody, or by inhibiting the S1P-lyase has therapeutic potential for autoimmune diseases like multiple sclerosis (MS) and rheumatoid arthritis and for many other disorders like cancer, fibrosis, inflammation, macular degeneration, diabetic retinopathy, and glaucoma. This report aims to provide a brief overview of concepts, approaches, pharmaceutical compounds, and targets that are currently used to modulate S1P-driven immune functions.

  13. Biomechanical Comparison of Sacral Fixation Characteristics of Standard S1-Pedicle Screw Fixation versus a Novel Constrained S1-Dual-Screw Anchorage in the S1-Pedicle and S1-Alar Bone.

    PubMed

    Mayer, Michael; Stephan, Daniel; Resch, Herbert; Augat, Peter; Auffarth, Alexander; Blocher, Martina; Ernstbrunner, Lukas; Hitzl, Wolfgang; Defossez, Henri; Rouge, Renaud; Koller, Heiko

    2015-12-01

    Biomechanical Laboratory Study. Analysis of the biomechanical characteristics of a novel sacral constrained dual-screw fixation device (S1-PALA), combining a S1-pedicle screw and a S1-ala screw, compared to a standard bicortical S1-pedicle screw (S1-PS) fixation. Instrumented fusions to the sacrum are biomechanically challenging and plagued by a high risk of nonunion when S1-PS is used as the sole means of fixation. Thus, lumbopelvic fixation is increasingly selected instead, although associated with a reasonable number of instrumentation-related complications. Around 30 fresh-frozen human sacral bones were harvested and embedded after CT scans. Instrumentation was conducted in alternating order with bicortical 7.0 mm S1-PS and with the S1-PALA including a S1-PS screw and a S1-ala screw, of 7.0 and 6.0 mm diameter, respectively. Specimens were subjected to cyclic loading with increasing loads (25-250 N) until a maximum of 2000 cycles or displacement >2 mm occurred. All implant sacral units (ISUs) were subject to coaxial pullout tests. Failure load, number of ISUs surpassing 2000 cycles, number of cycles, and loads at failure were recorded and compared. Donors' age averaged 77 ± 14.2 years, and BMD was 115 ± 64.8 mgCA-HA/ml. Total working length of screws implanted was 90 ± 8.6 mm in the S1-PALA group and 46 ± 5 mm in the S1-PS group (P = 0.0002). In the S1-PALA group, displacement >2 mm occurred after 845 ± 325 cycles at 149 ± 41 N compared to 512 ± 281 cycles at 106 ± 36 N in the S1-PS group (P = 0.004; P = 0.002). In coaxial pull-out testing, failure load was 2118.1 ± 1166 N at a displacement of 2.5 ± 1 mm in the S1-PALA group compared to 1375.6 ± 750.1 N at a displacement of 1.6 ± 0.5 mm in the S1-PS group (P = 0.0007; P = 0.0003). The novel sacral constrained dual-screw anchorage (S1-PALA) significantly improved holding strength after cyclic loading compared to S1-PS. The S1-PALA demonstrated mechanical potential as a useful adjunct in the

  14. M2b monocytes predominated in peripheral blood of severely burned patients.

    PubMed

    Kobayashi, Makiko; Jeschke, Marc G; Shigematsu, Kenji; Asai, Akira; Yoshida, Shohei; Herndon, David N; Suzuki, Fujio

    2010-12-15

    Severely burned patients were shown to be carriers of M2 monocytes, and all of the monocytes isolated from peripheral blood of severely burned patients (19 of 19 patients) were demonstrated as M2b monocytes (IL-12(-)IL-10(+)CCL1(+) monocytes). Low levels of M2a (IL-12(-)IL-10(+)CCL17(+) monocytes) and M2c monocytes (IL-12(-)IL-10(+)CXCL13(+) monocytes) were demonstrated in peripheral blood of severely burned patients (M2a, 2 of 19 patients; M2c, 5 of 19 patients). M2b, M2a, and M2c monocytes were not detected in peripheral blood of healthy donors. However, M2b monocytes appeared when healthy donor monocytes were cultured in media supplemented with burn patient serum (15%). CCL2 was detected in sera of all burn patients, and M2b monocytes were not generated from healthy donor monocytes cultured with media containing 15% burn patient sera that were previously treated with anti-CCL2 mAb. In addition, M2b monocytes were generated from healthy donor monocytes in cultures supplemented with rCCL2. These results indicate that M2b monocytes are predominant in peripheral blood of severely burned patients who are carriers of CCL2 that functions to stimulate monocyte conversion from resident monocytes to M2b monocytes.

  15. Host Cellular Protein TRAPPC6AΔ Interacts with Influenza A Virus M2 Protein and Regulates Viral Propagation by Modulating M2 Trafficking.

    PubMed

    Zhu, Pengyang; Liang, Libin; Shao, Xinyuan; Luo, Weiyu; Jiang, Shuitao; Zhao, Qingqing; Sun, Nan; Zhao, Yuhui; Li, Junping; Wang, Jinguang; Zhou, Yuan; Zhang, Jie; Wang, Guangwen; Jiang, Li; Chen, Hualan; Li, Chengjun

    2017-01-01

    Influenza A virus (IAV) matrix protein 2 (M2) plays multiple roles in the early and late phases of viral infection. Once synthesized, M2 is translocated to the endoplasmic reticulum (ER), travels to the Golgi apparatus, and is sorted at the trans-Golgi network (TGN) for transport to the apical plasma membrane, where it functions in virus budding. We hypothesized that M2 trafficking along with its secretory pathway must be finely regulated, and host factors could be involved in this process. However, no studies examining the role of host factors in M2 posttranslational transport have been reported. Here, we used a yeast two-hybrid (Y2H) system to screen for host proteins that interact with the M2 protein and identified transport protein particle complex 6A (TRAPPC6A) as a potential binding partner. We found that both TRAPPC6A and its N-terminal internal-deletion isoform, TRAPPC6A delta (TRAPPC6AΔ), interact with M2. Truncation and mutation analyses showed that the highly conserved leucine residue at position 96 of M2 is critical for mediating this interaction. The role of TRAPPC6AΔ in the viral life cycle was investigated by the knockdown of endogenous TRAPPC6AΔ with small interfering RNA (siRNA) and by generating a recombinant virus that was unable to interact with TRAPPC6A/TRAPPC6AΔ. The results indicated that TRAPPC6AΔ, through its interaction with M2, slows M2 trafficking to the apical plasma membrane, favors viral replication in vitro, and positively modulates virus virulence in mice. The influenza A virus M2 protein regulates the trafficking of not only other proteins but also itself along the secretory pathway. However, the host factors involved in the regulation of the posttranslational transport of M2 are largely unknown. In this study, we identified TRAPPC6A and its N-terminal internal-deletion isoform, TRAPPC6AΔ, as interacting partners of M2. We found that the leucine (L) residue at position 96 of M2 is critical for mediating this interaction

  16. Host Cellular Protein TRAPPC6AΔ Interacts with Influenza A Virus M2 Protein and Regulates Viral Propagation by Modulating M2 Trafficking

    PubMed Central

    Zhu, Pengyang; Liang, Libin; Shao, Xinyuan; Luo, Weiyu; Jiang, Shuitao; Zhao, Qingqing; Sun, Nan; Zhao, Yuhui; Li, Junping; Wang, Jinguang; Zhou, Yuan; Zhang, Jie; Wang, Guangwen; Jiang, Li

    2016-01-01

    ABSTRACT Influenza A virus (IAV) matrix protein 2 (M2) plays multiple roles in the early and late phases of viral infection. Once synthesized, M2 is translocated to the endoplasmic reticulum (ER), travels to the Golgi apparatus, and is sorted at the trans-Golgi network (TGN) for transport to the apical plasma membrane, where it functions in virus budding. We hypothesized that M2 trafficking along with its secretory pathway must be finely regulated, and host factors could be involved in this process. However, no studies examining the role of host factors in M2 posttranslational transport have been reported. Here, we used a yeast two-hybrid (Y2H) system to screen for host proteins that interact with the M2 protein and identified transport protein particle complex 6A (TRAPPC6A) as a potential binding partner. We found that both TRAPPC6A and its N-terminal internal-deletion isoform, TRAPPC6A delta (TRAPPC6AΔ), interact with M2. Truncation and mutation analyses showed that the highly conserved leucine residue at position 96 of M2 is critical for mediating this interaction. The role of TRAPPC6AΔ in the viral life cycle was investigated by the knockdown of endogenous TRAPPC6AΔ with small interfering RNA (siRNA) and by generating a recombinant virus that was unable to interact with TRAPPC6A/TRAPPC6AΔ. The results indicated that TRAPPC6AΔ, through its interaction with M2, slows M2 trafficking to the apical plasma membrane, favors viral replication in vitro, and positively modulates virus virulence in mice. IMPORTANCE The influenza A virus M2 protein regulates the trafficking of not only other proteins but also itself along the secretory pathway. However, the host factors involved in the regulation of the posttranslational transport of M2 are largely unknown. In this study, we identified TRAPPC6A and its N-terminal internal-deletion isoform, TRAPPC6AΔ, as interacting partners of M2. We found that the leucine (L) residue at position 96 of M2 is critical for mediating

  17. Sphingosine-1-Phosphate (S1P) and S1P Signaling Pathway: Therapeutic Targets in Autoimmunity and Inflammation.

    PubMed

    Tsai, Hsing-Chuan; Han, May H

    2016-07-01

    Sphingosine-1-phosphate (S1P) and S1P receptors (S1PR) are ubiquitously expressed. S1P-S1PR signaling has been well characterized in immune trafficking and activation in innate and adaptive immune systems. However, the full extent of its involvement in the pathogenesis of autoimmune diseases is not well understood. FTY720 (fingolimod), a non-selective S1PR modulator, significantly decreased annualized relapse rates in relapsing-remitting multiple sclerosis (MS). FTY720, which primarily targets S1P receptor 1 as a functional antagonist, arrests lymphocyte egress from secondary lymphoid tissues and reduces neuroinflammation in the central nervous system (CNS). Recent studies suggest that FTY720 also decreases astrogliosis and promotes oligodendrocyte differentiation within the CNS and may have therapeutic benefit to prevent brain atrophy. Since S1P signaling is involved in multiple immune functions, therapies targeting S1P axis may be applicable to treat autoimmune diseases other than MS. Currently, over a dozen selective S1PR and S1P pathway modulators with potentially superior therapeutic efficacy and better side-effect profiles are in the pipeline of drug development. Furthermore, newly characterized molecules such as apolipoprotein M (ApoM) (S1P chaperon) and SPNS2 (S1P transporter) are also potential targets for treatment of autoimmune diseases. Finally, the application of therapies targeting S1P and S1P signaling pathways may be expanded to treat several other immune-mediated disorders (such as post-infectious diseases, post-stroke and post-stroke dementia) and inflammatory conditions beyond their application in primary autoimmune diseases.

  18. The structure of the third intracellular loop of the muscarinic acetylcholine receptor M2 subtype.

    PubMed

    Ichiyama, Susumu; Oka, Yoshiaki; Haga, Kazuko; Kojima, Shuichi; Tateishi, Yukihiro; Shirakawa, Masahiro; Haga, Tatsuya

    2006-01-09

    We have examined whether the long third intracellular loop (i3) of the muscarinic acetylcholine receptor M2 subtype has a rigid structure. Circular dichroism (CD) and nuclear magnetic resonance spectra of M2i3 expressed in and purified from Escherichia coli indicated that M2i3 consists mostly of random coil. In addition, the differential CD spectrum between the M2 and M2deltai3 receptors, the latter of which lacks most of i3 except N- and C-terminal ends, gave no indication of secondary structure. These results suggest that the central part of i3 of the M2 receptor has a flexible structure.

  19. Ising Model Spin S = 1 ON Directed BARABÁSI-ALBERT Networks

    NASA Astrophysics Data System (ADS)

    Lima, F. W. S.

    On directed Barabási-Albert networks with two and seven neighbours selected by each added site, the Ising model with spin S = 1/2 was seen not to show a spontaneous magnetisation. Instead, the decay time for flipping of the magnetisation followed an Arrhenius law for Metropolis and Glauber algorithms, but for Wolff cluster flipping the magnetisation decayed exponentially with time. On these networks the Ising model spin S = 1 is now studied through Monte Carlo simulations. However, in this model, the order-disorder phase transition is well defined in this system. We have obtained a first-order phase transition for values of connectivity m = 2 and m = 7 of the directed Barabási-Albert network.

  20. The cytoplasmic domain of influenza M2 protein interacts with caveolin-1.

    PubMed

    Zou, Peng; Wu, Fan; Lu, Lu; Huang, Jing-He; Chen, Ying-Hua

    2009-06-15

    The cytoplasmic domain of influenza M2 protein (M2c) consists of 54 amino acid (aa) residues from aa44 to aa97. In this paper, M2c and its deletion mutant M2c(delta47-55) were expressed using prokaryotic expression system. First, glutaraldehyde crosslinking assay showed that M2c had multimerization potential mediated by aa47-55. Then, M2c, instead of M2c(delta47-55), directed eGFP from the whole cell localization to a predominately perinuclear region in CHO cells, which indicated that aa47-55 of M2c mediated the localization. Moreover, M2c colocalized with caveolin-1 (Cav) when CHO cells were cotransfected with Cav. A caveolin-1 binding motif phixxxxphixxphi (phi represents aromatic amino acid residues) in aa47-55 of M2c was found by sequence alignment and analysis. Further overlay ELISA result showed that M2c, but not M2c(delta47-55), bound to prokaryotically expressed cholesterol-free Cav(2-101), which illustrated the interaction could be cholesterol-independent. That was the first report of cellular protein bound to M2c.

  1. Tertiary trisomy of 10p15.pter and 14pter.ql3 due to maternal translocation t(10;14)(p15;q13).

    PubMed

    Cetin, Z; Mihci, E; Keser, I; Luleci, G

    2012-01-01

    Double partial trisomy resulting from 3:1 segregation of the respective chromosomal segments of the chromosomes involved in a balanced translocation in meiosis is rarely reported in the literature. We present here a first patient with multiple congenital malformations associated with double partial trisomy of 10pter-p15 and 14pter-q13 resulting from 3:1 segregation of maternal balanced translocation t(10;14)(p15;q13). Proximal partial trisomy of chromosome 14 and subterminal trisomy of the short arm of the chromosome 10 are rare. The present case is the first case with double partial trisomy of these segments resulting from 3:1 segregation of a maternal balanced translocation.

  2. Focusing coherent soft-x-ray radiation to a micrometer spot size with an intensity of 10(14) W/cm2.

    PubMed

    Mashiko, Hiroki; Suda, Akira; Midorikawa, Katsumi

    2004-08-15

    We investigate the focusability of intense coherent soft-x-ray radiation generated by high-order harmonic conversion. The 27th-harmonic wave at 29.6 nm is focused by an off-axis parabolic mirror with a SiC/Mg multilayer coating. Focal-spot images are observed from the visible fluorescence induced by the soft-x-ray photons on a Ce:YAG scintillator. We demonstrate focusing of the soft-x-ray beam to a 1-microm spot size with a peak intensity of 1 x 10(14) W/cm2, which is to our knowledge the highest ever reported in the soft-x-ray region.

  3. Motion-to-Energy (M2Eâ„¢) Power Generation Technology

    SciTech Connect

    Idaho National Laboratory

    2008-05-30

    INL researchers developed M2E, a new technology that converts motion to energy. M2E uses an innovative, optimized microgenerator with power management circuitry that kinetically charges mobile batteries from natural motion such as walking. To learn more,

  4. Representations of Nets of C*-Algebras over S 1

    NASA Astrophysics Data System (ADS)

    Ruzzi, Giuseppe; Vasselli, Ezio

    2012-11-01

    In recent times a new kind of representations has been used to describe superselection sectors of the observable net over a curved spacetime, taking into account the effects of the fundamental group of the spacetime. Using this notion of representation, we prove that any net of C*-algebras over S 1 admits faithful representations, and when the net is covariant under Diff( S 1), it admits representations covariant under any amenable subgroup of Diff( S 1).

  5. S1P and the birth of platelets.

    PubMed

    Hla, Timothy; Galvani, Sylvain; Rafii, Shahin; Nachman, Ralph

    2012-11-19

    Recent work has highlighted the multitude of biological functions of sphingosine 1-phosphate (S1P), which include roles in hematopoietic cell trafficking, organization of immune organs, vascular development, and neuroinflammation. Indeed, a functional antagonist of S1P(1) receptor, FTY720/Gilenya, has entered the clinic as a novel therapeutic for multiple sclerosis. In this issue of the JEM, Zhang et al. highlight yet another function of this lipid mediator: thrombopoiesis. The S1P(1) receptor is required for the growth of proplatelet strings in the bloodstream and the shedding of platelets into the circulation. Notably, the sharp gradient of S1P between blood and the interstitial fluids seems to be essential to ensure the production of platelets, and S1P appears to cooperate with the CXCL12-CXCR4 axis. Pharmacologic modulation of the S1P(1) receptor altered circulating platelet numbers acutely, suggesting a potential therapeutic strategy for controlling thrombocytopenic states. However, the S1P(4) receptor may also regulate thrombopoiesis during stress-induced accelerated platelet production. This work reveals a novel physiological action of the S1P/S1P(1) duet that could potentially be harnessed for clinical translation.

  6. PPARγ Ligands Switched High Fat Diet-Induced Macrophage M2b Polarization toward M2a Thereby Improving Intestinal Candida Elimination

    PubMed Central

    Olagnier, David; Bernad, José; Perez, Laurence; Burcelin, Rémy; Valentin, Alexis; Auwerx, Johan; Pipy, Bernard; Coste, Agnès

    2010-01-01

    Obesity is associated with a chronic low-grade inflammation that predisposes to insulin resistance and the development of type 2 diabetes. In this metabolic context, gastrointestinal (GI) candidiasis is common. We recently demonstrated that the PPARγ ligand rosiglitazone promotes the clearance 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 macrophages and on the outcome of GI candidiasis. We demonstrated that the peritoneal macrophages and the cell types present in the cecal tissue from HF fed mice present a M2b polarization (TNF-αhigh, IL-10high, MR, Dectin-1). Interestingly, rosiglitazone induces a phenotypic M2b-to-M2a (TNF-αlow, IL-10low, MRhigh, Dectin-1high) switch of peritoneal macrophages and of the cells present in the cecal tissue. The incapacity of WY14643 to switch this polarization toward M2a state, strongly suggests the specific involvement of PPARγ in this mechanism. We showed that in insulin resistant mice, M2b polarization of macrophages present on the site of infection is associated with an increased susceptibility to GI candidiasis, whereas M2a polarization after rosiglitazone treatment favours the GI fungal elimination independently of reduced blood glucose. In conclusion, our data demonstrate a dual benefit of PPARγ ligands because they promote mucosal defence mechanisms against GI candidiasis through M2a macrophage polarization while regulating blood glucose level. PMID:20877467

  7. Faecal pyruvate kinase isoenzyme type M2 for colorectal cancer screening: A meta-analysis

    PubMed Central

    Tonus, Carolin; Sellinger, Markus; Koss, Konrad; Neupert, Gero

    2012-01-01

    AIM: To present a critical discussion of the efficacy of the faecal pyruvate kinase isoenzyme type M2 (faecal M2-PK) test for colorectal cancer (CRC) screening based on the currently available studies. METHODS: A literature search in PubMed and Embase was conducted using the following search terms: fecal Tumor M2-PK, faecal Tumour M2-PK, fecal M2-PK, faecal M2-PK, fecal pyruvate kinase, faecal pyruvate kinase, pyruvate kinase stool and M2-PK stool. RESULTS: Stool samples from 704 patients with CRC and from 11 412 healthy subjects have been investigated for faecal M2-PK concentrations in seventeen independent studies. The mean faecal M2-PK sensitivity was 80.3%; the specificity was 95.2%. Four studies compared faecal M2-PK head-to-head with guaiac-based faecal occult blood test (gFOBT). Faecal M2-PK demonstrated a sensitivity of 81.1%, whereas the gFOBT detected only 36.9% of the CRCs. Eight independent studies investigated the sensitivity of faecal M2-PK for adenoma (n = 554), with the following sensitivities: adenoma < 1 cm in diameter: 25%; adenoma > 1 cm: 44%; adenoma of unspecified diameter: 51%. In a direct comparison with gFOBT of adenoma > 1 cm in diameter, 47% tested positive with the faecal M2-PK test, whereas the gFOBT detected only 27%. CONCLUSION: We recommend faecal M2-PK as a routine test for CRC screening. Faecal M2-PK closes a gap in clinical practice because it detects bleeding and non-bleeding tumors and adenoma with high sensitivity and specificity. PMID:22912551

  8. Kinematic Structure of H2 and [Fe II] in the Bipolar Planetary Nebula M2-9

    NASA Astrophysics Data System (ADS)

    Smith, Nathan; Balick, Bruce; Gehrz, Robert D.

    2005-08-01

    We present new high-dispersion, long-slit, infrared (IR) spectra of the double-shell bipolar planetary nebula M2-9 in the emission lines [Fe II] λ16435 and H2v=1-0 S(1) λ21218. H2 spectra reveal for the first time the kinematic structure of the outer shell in M2-9. Kinematics of the inner shell, traced by [Fe II], resemble those of optical forbidden lines like [N II] λ6583, although we note subtle differences. [Fe II] and H2 shells have expansion speeds roughly proportional to distance from the star (``Hubble'' flows) and share the same dynamical age of 1200-2000 yr, depending on the distance to M2-9. Thus, the inner ionized lobes and outer molecular lobes, as well as the molecular torus and ``outer loops'' measured by other observers, were all formed around the same time. Consequently, their nested structure likely arises from an excitation gradient rather than independent ejections. H2 and [Fe II] emission is distributed more uniformly than [N II], and IR lines are not dominated by the moving ionization pattern like visual-wavelength lines. We suggest that this is because IR lines of [Fe II] and H2 are excited by relatively isotropic far-UV radiation (Balmer continuum), whereas optical lines respond to a directed rotating beam of Lyman continuum. Finally, we highlight intriguing similarities between M2-9 and the Homunculus of η Car, despite the different central engines powering the two nebulae.

  9. Direct Interaction of GABAB Receptors with M2 Muscarinic Receptors Enhances Muscarinic Signaling

    PubMed Central

    Boyer, Stephanie B.; Clancy, Sinead M.; Terunuma, Miho; Revilla-Sanchez, Raquel; Thomas, Steven M.; Moss, Stephen J.; Slesinger, Paul A.

    2009-01-01

    Down-regulation of G protein coupled receptors (GPCR) provides an important mechanism for reducing neurotransmitter signaling during sustained stimulation. Chronic stimulation of M2 muscarinic receptors (M2R) causes internalization of M2R and G protein-activated inwardly rectifying potassium (GIRK) channels in neuronal PC12 cells, resulting in loss of function. Here, we show that co-expression of GABAB R2 receptors (GBR2) rescues both surface expression and function of M2R, including M2R-induced activation of GIRKs and inhibition of cAMP production. GBR2 showed significant association with M2R at the plasma membrane but not other GPCRs (M1R, μOR), as detected by FRET measured with TIRF microscopy. Unique regions of the proximal C-terminal domains of GBR2 and M2R mediate specific binding between M2R and GBR2. In the brain, GBR2, but not GBR1, biochemically coprecipitates with M2R and overlaps with M2R expression in cortical neurons. This novel heteromeric association between M2R and GBR2 provides a possible mechanism for altering muscarinic signaling in the brain and represents a previously unrecognized role for GBR2. PMID:20016095

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

    PubMed Central

    Rőszer, Tamás

    2015-01-01

    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. PMID:26089604

  11. Diagnostic advantage of S1 foramen-evoked H-reflex for S1 radiculopathy in patients with diabetes mellitus.

    PubMed

    Zheng, Chaojun; Zhu, Yu; Lu, Feizhou; Xia, Xinlei; Jin, Xiang; Weber, Robert; Jiang, Jianyuan

    2013-11-01

    Hoffmann reflex to tibial nerve stimulation at the popliteal fossa (tibial H-reflex) is routinely used to evaluate S1 radiculopathy. However, it lacks sensitivity because other lesions along this reflex circuit affect the H-reflex bilaterally. This study was undertaken to determine whether the H-reflex evoked by stimulating proximally at the S1 foramen (S1 foramen H-reflex) could improve S1 root lesion evaluation sensitivity in patients with diabetes mellitus. A randomized paired study was designed to evaluate tibial and S1 foramen H-reflexes; bilateral H-M interval (HMI) and H-reflex latency were compared in 22 diabetic patients with unilateral S1 radiculopathy. Other electrophysiological evaluations included standard tibial conduction studies, sural conduction studies and needle electromyography (EMG). The S1 foramen H-reflex had a significantly higher sensitivity (91.0%, 20 of 22) in evaluating S1 radiculopathy than the conventional tibial H-reflex (63.6%, 14 of 22, p < 0.05). Bilateral tibial compound muscle action potential amplitudes were reduced in 3 patients, and sural sensory nerve action potential amplitudes decreased in 7 patients. Needle EMG revealed denervation restricted to the paraspinal muscle and myotomes supplied by the S1 nerve root on the ipsilateral side in 18 patients, and multiple lumbosacral nerve roots were involved bilaterally in the other 4 patients. Our results demonstrate that the S1 foramen H-reflex is a more sensitive assessment of S1 compressive radiculopathy in patients with diabetes mellitus.

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

    PubMed

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

    2017-02-20

    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

  13. QnrS1 structure–activity relationships

    PubMed Central

    Tavío, María M.; Jacoby, George A.; Hooper, David C.

    2014-01-01

    Objectives Loop B is important for low-level quinolone resistance conferred by Qnr proteins. The role of individual amino acids within QnrS1 loop B in quinolone resistance and gyrase protection was assessed. Methods qnrS1 and 11 qnrS1 alleles with site-directed Ala mutations in loop B were expressed in Escherichia coli BL21(DE3) and proteins were purified by affinity chromatography. Ciprofloxacin MICs were determined with and without IPTG. Gyrase DNA supercoiling was measured with and without ciprofloxacin IC50 and with various concentrations of QnrS1 proteins. Results Wild-type QnrS1 and QnrS1 with Asn-110→Ala and Arg-111→Ala substitutions increased the ciprofloxacin MIC 12-fold in BL21(DE3), although QnrS1 with Gln-107→Ala replacement increased it 2-fold more than wild-type did. However, QnrS1 with Ala substitutions at His-106, Val-108, Ser-109, Met-112, Tyr-113, Phe-114, Cys-115 and Ser-116 increased ciprofloxacin MIC 1.4- to 8-fold less than wild-type QnrS1. Induction by 10–1000 μM IPTG increased ciprofloxacin MICs for all mutants, reaching values similar to those for wild-type. Purified wild-type and mutated proteins differed in protection of gyrase from ciprofloxacin action. Wild-type QnrS1 produced complete protection of gyrase supercoiling from ciprofloxacin (1.8 μM) action at 0.05 nM and half protection at 0.5 pM, whereas QnrS1 with Ala replacements that conferred the least increase in ciprofloxacin MICs also required the highest QnrS1 concentrations for protection. Conclusions Key individual residues in QnrS1 loop B affect ciprofloxacin resistance and gyrase protection from ciprofloxacin action, supporting the concept that loop B is key for interaction with gyrase necessary for quinolone resistance. PMID:24729602

  14. Robustness of S1 with Hodges-Lehmann

    NASA Astrophysics Data System (ADS)

    Ahad, Nor Aishah; Yahaya, Sharipah Soaad Syed; Yin, Lee Ping

    2015-12-01

    The classical methods for comparing groups can be highly inefficient under the influence of non-normal and heteroscedastic settings. Investigators are looking for alternatives which are more flexible in terms of assumptions. Robust methods are known to be one such alternative. This study looks into S1 statistic, flexible method for comparing groups using median as the location estimator. Works on S1 mostly focussed on the searching of a more favorable alternative of the standard error of sample medians to achieve better control of Type I error. In this study, instead of targetting on the standard error, the investigation on the S1 statistic focusses on the sample median itself. The modified S1 statistic replaced the medians with Hodges-Lehmann and the default scale estimator with the variance of Hodges-Lehmann and MADn to produce two different test statistics for comparing groups. Since the sampling distributions of these modified S1 statistics are unknown, bootstrap method was used for testing the hypotheses. The performance of the proposed statistic was measured in terms of Type I error and compared against the original S1 statistic. The propose procedures, generated conservative Type I error rates and on par with the original S1 statistic for most of the conditions.

  15. Degenerative Sacrolisthesis of S1-S2: A Case Report.

    PubMed

    Rajendra, Thakre Kunwar; Issac, Thomas; Swamy, B Mallikarjuna

    2015-01-01

    Degenerative spondylolisthesis (DS) is usually seen at L4-L5 level and less frequently at L5-S1 level. This is a rare case report of spondylolisthesis of S1 over S2 with lumbarization of S1. Lumbarization of S1 is seen in just 1-2% of the population and to have spondylolisthesis in this segment is even rarer. The purpose is to report a rare case of DS at S1-S2 level. This is a single case report of a 66-year-old gentleman who presented with complains of lower backache for 2 years and acute retention of urine to the emergency department. Detailed clinical and radiological evaluation of the spine was done which revealed lumbarization of S1 with spondylolisthesis at S1-S2 and facetal hypertrophy at L5, S1, and S2. He underwent decompression and stabilization at L5, S1, and S2 along with placement of autologous bone graft. The bladder symptoms disappeared after 3 weeks. At 1-year follow-up, patient's clinical symptoms were relieved, and he improved clinically. To the best of our knowledge, this is probably the first case of DS of sacral vertebrae to be reported in English literature. The prevalence of complete lumbarization is around 1.8% and to get spondylolisthesis in this segment is even rarer, hence the lack of literature in this regard. Since this is the first of its kind of case, further case series or longitudinal studies of such cases may help understand better the pathomechanics related to spondylolisthesis at this level.

  16. Increased Immunogenicity and Protective Efficacy of Influenza M2e Fused to a Tetramerizing Protein

    PubMed Central

    Andersson, Anne-Marie Carola; Håkansson, Kjell O.; Jensen, Benjamin Anderschou Holbech; Christensen, Dennis; Andersen, Peter; Thomsen, Allan Randrup; Christensen, Jan Pravsgaard

    2012-01-01

    The ectodomain of the matrix 2 protein (M2e) of influenza A virus represents an attractive target for developing a universal influenza A vaccine, with its sequence being highly conserved amongst human variants of this virus. With the aim of targeting conformational epitopes presumably shared by diverse influenza A viruses, a vaccine (M2e-NSP4) was constructed linking M2e (in its consensus sequence) to the rotavirus fragment NSP498–135; 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 M2e as presented in membranes. M2e-NSP4 was then evaluated side-by-side with synthetic M2e peptide for its immunogenicity and protective efficacy in a murine influenza challenge model. Here we demonstrate that M2e fused to the tetramerizing protein induces an accelerated, augmented and more broadly reactive antibody response than does M2e peptide as measured in two different assays. Most importantly, vaccination with M2e-NSP4 caused a significant decrease in lung virus load early after challenge with influenza A virus and maintained its efficacy against a lethal challenge even at very low vaccine doses. Based on the results presented in this study M2e-NSP4 merits further investigation as a candidate for or as a component of a universal influenza A vaccine. PMID:23049700

  17. Novel Markers to Delineate Murine M1 and M2 Macrophages

    PubMed Central

    Jablonski, Kyle A.; Amici, Stephanie A.; Webb, Lindsay M.; Ruiz-Rosado, Juan de Dios; Popovich, Phillip G.; Partida-Sanchez, Santiago; Guerau-de-Arellano, Mireia

    2015-01-01

    Classically (M1) and alternatively activated (M2) macrophages exhibit distinct phenotypes and functions. It has been difficult to dissect macrophage phenotypes in vivo, where a spectrum of macrophage phenotypes exists, and also in vitro, where low or non-selective M2 marker protein expression is observed. To provide a foundation for the complexity of in vivo macrophage phenotypes, we performed a comprehensive analysis of the transcriptional signature of murine M0, M1 and M2 macrophages and identified genes common or exclusive to either subset. We validated by real-time PCR an M1-exclusive pattern of expression for CD38, G-protein coupled receptor 18 (Gpr18) and Formyl peptide receptor 2 (Fpr2) whereas Early growth response protein 2 (Egr2) and c-Myc were M2-exclusive. We further confirmed these data by flow cytometry and show that M1 and M2 macrophages can be distinguished by their relative expression of CD38 and Egr2. Egr2 labeled more M2 macrophages (~70%) than the canonical M2 macrophage marker Arginase-1, which labels 24% of M2 macrophages. Conversely, CD38 labeled most (71%) in vitro M1 macrophages. In vivo, a similar CD38+ population greatly increased after LPS exposure. Overall, this work defines exclusive and common M1 and M2 signatures and provides novel and improved tools to distinguish M1 and M2 murine macrophages. PMID:26699615

  18. Current Development of Anti-Cancer Drug S-1

    PubMed Central

    Giri, Anil; Shakya, Suraj; Shakya, Sujana; Sapkota, Binaya; Pramod, KC

    2016-01-01

    S-1 is a novel oral fluoropyrimidine derivative, widely used for treating gastric, pancreatic, lung, head, neck and breast carcinomas. It is designed to enhance the clinical utility of an oral fluoropyrimidine and is associated with low gastrointestinal toxicity. S-1 consists of three pharmacological agents (at a molar ratio of 1:0.4:1)-Tegafur (FT), a prodrug of 5-Fluorouracil (5-FU), 5-Chloro-2-4-Dihydroxypyridine (CDHP), which inhibits the activity of Dihydropyrimidine Dehydrogenase (DPD) and Oxonic Acid (Oxo), which reduces Gastrointestinal (GI) toxicity of 5-FU. The present article reviews the current development of clinical study of S-1. PMID:28050491

  19. Screening for trisomy 13 by fetal nuchal translucency and maternal serum free beta-hCG and PAPP-A at 10-14 weeks of gestation.

    PubMed

    Spencer, K; Ong, C; Skentou, H; Liao, A W; H Nicolaides, K

    2000-05-01

    In 42 cases of trisomy 13 at 10-14 weeks of gestation, compared with 947 controls, the median multiple of the median (MoM) of maternal serum free beta-human chorionic gonadotrophin (beta-hCG) and pregnancy associated plasma protein A (PAPP-A) was significantly decreased (0.506 MoM and 0.248 MoM respectively), whilst fetal nuchal translucency was increased (2.872 MoM). In 38% and 71% of cases of trisomy 13 maternal serum free beta-hCG and PAPP-A was below the 5th centile of the appropriate normal range for gestation and in 62% of cases the nuchal translucency was above the 95th centile. When combined together in a multivariate algorithm with maternal age, 90% of cases of trisomy 13 could be detected at a 0.5% false positive rate or 84% at a 0.1% false positive rate. We conclude that specific trisomy 13 risks should be part of developing risk algorithms combining maternal serum biochemistry and nuchal translucency for use in first trimester screening alongside those for trisomy 21 and trisomy 18. Copyright 2000 John Wiley & Sons, Ltd.

  20. Effect on oral pH changes and taste perception in 10-14-year-old children, after calcium fortification of a fruit juice.

    PubMed

    Franklin, S; Masih, S; Thomas, A M

    2015-12-01

    The aim was to determine the effect of calcium fortification of a commercially available mixed-fruit juice on oral pH changes and taste perception in a group of 10 to 14 year-old Indian children. A controlled, blinded, non-randomised clinical trial was adopted, consisting of a sample of 100 healthy children (DMFT <3; age 10-14 years), who were exposed to three test juices one by one [Group A: original fruit juice (control group); Group B: calcium-fortified fruit juice and Group C: calcium + vitamin D fortified fruit juice]. Oral pH, collection of saliva and plaque sampling was undertaken, before and after the juice exposure by each subject at 0, 1, 5, 15, 30 and 45 min. The respective pH was measured with a digital pH meter. For taste perception, a scoring system was used after exposure of the juices to the subjects in a blind manner. The statistical evaluation was done using one-way ANOVA for salivary and plaque pH and Kruskal-Wallis test for buffer capacity and taste perception. There was a smaller drop in salivary and plaque pH (p < 0.5) and a significant reduction in perceived taste (p < 0.001) by the subjects after calcium modification of fruit juice. The calcium-modified mixed fruit juices was less acidogenic compared with the unfortified juice, and hence will be less cariogenic and erosive towards teeth.

  1. Causes and prevalence of traumatic injuries to the permanent incisors of school children aged 10-14 years in Maseru, Lesotho.

    PubMed

    Lin, H; Naidoo, Sudeshni

    2008-04-01

    Traumatic dental injuries are widespread in the population and the prevalence of traumatic dental injuries among school children in different parts of the world varies from about 3% to 45%. Most injuries involve the anterior teeth, which may lead to eating restrictions, changes in physical appearance, speech defects and psychological impacts that affect the child's quality of life. A cross-sectional survey was carried out to investigate the prevalence, aetiology and types of injuries to permanent incisors among schoolchildren aged 10-14 years from Maseru, Lesotho. Upper and lower permanent incisors were examined for dental injuries. The prevalence of traumatic injuries to the permanent incisor teeth was 9.3% (13.3% boys and 6.3% girls). Significantly more boys than girls suffered injury. The most common type of injury was enamel fractures and most common cause was falls. Health promotion policies should aim to create an appropriate and safe environment for children. Soft playground surfaces, school-crossing patrols, marked zebra crossings and bicycle lanes would help create a safe environment. Speed limits for cars and the use of seat belts, air bags, special car seats for children and bicycle helmets should be enforced. Mouth guards should be used when playing sport, in particular contact sports. Education regarding the epidemiology of dental injuries and their prevention through health promotion may play a major role in reducing the prevalence of dental injury and avoiding the financial costs of treatment, especially in developing countries.

  2. Accelerometry-assessed sedentary behaviour and physical activity levels during the segmented school day in 10-14-year-old children: the HAPPY study.

    PubMed

    Bailey, Daniel P; Fairclough, Stuart J; Savory, Louise A; Denton, Sarah J; Pang, Dong; Deane, Colleen S; Kerr, Catherine J

    2012-12-01

    The school day offers several different time periods that provide varying opportunities for sedentary time (SED) and engagement in physical activity (PA), yet little is known about the PA and sedentary behaviour patterns of boys and girls during these times. The volume, intensity and temporal distributions of SED and PA undertaken by 135 schoolchildren aged 10-14 years, during different segments of the school day: (a) school transport, (b) morning recess, (c) lunch break, (d) class time and (e) after school, were explored using triaxial accelerometry. PA was categorised into SED, light PA (LPA), moderate PA (MPA) and vigorous PA (VPA). Girls engaged in significantly more SED and LPA than boys during recess and lunch break (p < 0.05), while boys engaged in significantly higher levels of VPA during recess (p < 0.001) and MPA and VPA during lunch break (p < 0.001). PA engagement was similar between sexes during other segments of the day. PA patterns appear more beneficial for health in boys during less structured school-based time periods and interventions may therefore target opportunities for girls to be physically active during these times to overcome this observed sex deficit.

  3. Associations between prolonged sedentary time and breaks in sedentary time with cardiometabolic risk in 10-14-year-old children: The HAPPY study.

    PubMed

    Bailey, Daniel P; Charman, Sarah J; Ploetz, Thomas; Savory, Louise A; Kerr, Catherine J

    2016-11-28

    This study examines the association between prolonged sedentary time and breaks in sedentary time with cardiometabolic risk in 10-14-year-old children. This cross-sectional design study analysed accelerometry-determined sedentary behaviour and physical activity collected over 7 days from 111 (66 girls) UK schoolchildren. Objective outcome measures included waist circumference, fasting lipids, fasting glucose, blood pressure, and cardiorespiratory fitness. Logistic regression was used for the main data analysis. After adjustment for confounders, the odds of having hypertriglyceridaemia (P = 0.03) and an increased clustered cardiometabolic risk score (P = 0.05) were significantly higher in children who engaged in more prolonged sedentary bouts per day. The number of breaks in sedentary time per day was not associated with any cardiometabolic risk factor, but longer mean duration of daily breaks in sedentary time were associated with a lower odds of having abdominal adiposity (P = 0.04) and elevated diastolic blood pressure (P = 0.01). These associations may be mediated by engagement in light activity. This study provides evidence that avoiding periods of prolonged uninterrupted sedentary time may be important for reducing cardiometabolic disease risk in children.

  4. M2e-immobilized gold nanoparticles as influenza A vaccine: role of soluble M2e and longevity of protection

    PubMed Central

    Tao, Wenqian; Gill, Harvinder S.

    2015-01-01

    Influenza virus causes seasonal epidemics and also poses a high risk for pandemics. To develop a broadly cross-protective influenza vaccine we have previously shown that a formulation consisting of the extracellular domain of M2 membrane protein (M2e) immobilized on gold nanoparticles (AuNPs) and soluble CpG as an adjuvant can elicit protective immunity against different influenza A subtypes. The vaccine formulation contains M2e that is immobilized on AuNPs, and an excess amount that is freely dissolved in solution, whose role in inducing protective immunity against virus infection is unclear. Using a mouse model, the current study shows that inclusion of excess soluble M2e antigen along with M2e immobilized on AuNPs is vital for inducing high levels of antibody response, and in providing complete protection against lethal influenza virus challenge. We also show that the vaccine induces long-lasting protection against mortality and morbidity upon lethal challenge with influenza A virus. PMID:25842219

  5. Δ-isobar effects on M2 strength in 208Pb

    NASA Astrophysics Data System (ADS)

    Cha, D.; Septh, J.

    1984-02-01

    The strength distribution of the 2- states in 208Pb is calculated including the Δ-isobar quenching effects. The theoretical B (M2) values up to 8 MeV are dominated by the orbital angular momentum part of the M2 operator. Therefore we find only little quenching in this energy region owing to the Δ-particle nucleon-hole admixtures. [NUCLEAR STRUCTURE 208Pb; Δ-isobar effects on M2 strength.

  6. Protection against Influenza A Virus Challenge with M2e-Displaying Filamentous Escherichia coli Phages

    PubMed Central

    Deng, Lei; Ibañez, Lorena Itatí; Van den Bossche, Veronique; Roose, Kenny; Youssef, Sameh A.; de Bruin, Alain; Fiers, Walter; Saelens, Xavier

    2015-01-01

    Human influenza viruses are responsible for annual epidemics and occasional pandemics that cause severe illness and mortality in all age groups worldwide. Matrix protein 2 (M2) of influenza A virus is a tetrameric type III membrane protein that functions as a proton-selective channel. The extracellular domain of M2 (M2e) is conserved in human and avian influenza A viruses and is being pursued as a component for a universal influenza A vaccine. To develop a M2e vaccine that is economical and easy to purify, we genetically fused M2e amino acids 2–16 to the N-terminus of pVIII, the major coat protein of filamentous bacteriophage f88. We show that the resulting recombinant f88−M2e2-16 phages are replication competent and display the introduced part of M2e on the phage surface. Immunization of mice with purified f88−M2e2-16 phages in the presence of incomplete Freund’s adjuvant, induced robust M2e-specific serum IgG and protected BALB/c mice against challenge with human and avian influenza A viruses. Thus, replication competent filamentous bacteriophages can be used as efficient and economical carriers to display conserved B cell epitopes of influenza A. PMID:25973787

  7. A Novel Vaccine Using Nanoparticle Platform to Present Immunogenic M2e against Avian Influenza Infection

    PubMed Central

    Babapoor, Sankhiros; Neef, Tobias; Mittelholzer, Christian; Girshick, Theodore; Garmendia, Antonio; Shang, Hongwei; Khan, Mazhar I.; Burkhard, Peter

    2011-01-01

    Using peptide nanoparticle technology, we have designed two novel vaccine constructs representing M2e in monomeric (Mono-M2e) and tetrameric (Tetra-M2e) forms. Groups of specific pathogen free (SPF) chickens were immunized intramuscularly with Mono-M2e or Tetra-M2e with and without an adjuvant. Two weeks after the second boost, chickens were challenged with 107.2 EID50 of H5N2 low pathogenicity avian influenza (LPAI) virus. M2e-specific antibody responses to each of the vaccine constructs were tested by ELISA. Vaccinated chickens exhibited increased M2e-specific IgG responses for each of the constructs as compared to a non-vaccinated group. However, the vaccine construct Tetra-M2e elicited a significantly higher antibody response when it was used with an adjuvant. On the other hand, virus neutralization assays indicated that immune protection is not by way of neutralizing antibodies. The level of protection was evaluated using quantitative real time PCR at 4, 6, and 8 days post-challenge with H5N2 LPAI by measuring virus shedding from trachea and cloaca. The Tetra-M2e with adjuvant offered statistically significant (P < 0.05) protection against subtype H5N2 LPAI by reduction of the AI virus shedding. The results suggest that the self-assembling polypeptide nanoparticle shows promise as a potential platform for a development of a vaccine against AI. PMID:23074652

  8. Serum from patients with systemic vasculitis induces alternatively activated macrophage M2c polarization.

    PubMed

    Ohlsson, Susanne M; Linge, Carl Petrus; Gullstrand, Birgitta; Lood, Christian; Johansson, Asa; Ohlsson, Sophie; Lundqvist, Andrea; Bengtsson, Anders A; Carlsson, Fredric; Hellmark, Thomas

    2014-01-01

    Anti-neutrophil cytoplasmic antibody associated vasculitides (AAV) are conditions defined by an autoimmune small vessel inflammation. Dying neutrophils are found around the inflamed vessels and the balance between infiltrating neutrophils and macrophages is important to prevent autoimmunity. Here we investigate how sera from AAV patients may regulate macrophage polarization and function. Macrophages from healthy individuals were differentiated into M0, M1, M2a, M2b or M2c macrophages using a standardized protocol, and phenotyped according to their expression surface markers and cytokine production. These phenotypes were compared with those of macrophages stimulated with serum from AAV patients or healthy controls. While the healthy control sera induced a M0 macrophage, AAV serum promoted polarization towards the M2c subtype. No sera induced M1, M2a or M2b macrophages. The M2c subtype showed increased phagocytosis capacity compared with the other subtypes. The M2c polarization found in AAV is consistent with previous reports of increased levels of M2c-associated cytokines.

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

    PubMed

    Suzuki, Kotaro; Meguro, Kazuyuki; Nakagomi, Daiki; Nakajima, Hiroshi

    2017-03-17

    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.

  10. 7S(1/2) ? 9S(1/2) two-photon spectroscopy of trapped francium.

    PubMed

    Simsarian, J E; Shi, W; Orozco, L A; Sprouse, G D; Zhao, W Z

    1996-12-01

    We report on the spectroscopic measurement of the (210)Fr 9S(1/2) energy obtained by two-photon excitation of atoms confined and cooled in a magneto-optic trap. The resonant intermediate level 7P(3/2) is the upper state of the trapping transition. We have measured the energy difference between the 9S(1/2) state and the 7S(1/2) ground state to be 25 671.021 +/- 0.006 cm(-1).

  11. Roles of the PVM M2-1, M2-2 and P gene ORF 2 (P-2) proteins in viral replication.

    PubMed

    Dibben, Oliver; Thorpe, Lindsay C; Easton, Andrew J

    2008-01-01

    A plasmid-based reverse genetics system for pneumonia virus of mice (PVM) using a synthetic minigenome is described. The system was used to investigate the functions of several viral proteins. The M2-1 protein of PVM was shown to enhance reporter gene expression when present at low levels, similar to the situation for the equivalent respiratory syncytial virus (RSV) M2-1 protein, but at high levels was shown to reduce gene expression from the minigenome activity, which differs significantly form the situation with RSV. Analysis of levels of nucleocapsid complex RNA showed that high levels of the PVM M2-1 protein inhibits RNA replication rather than transcription. In contrast, expression of the PVM M2-2 protein in conjunction with the polymerase proteins in a minigenome assay greatly reduced the levels of CAT reporter protein. This is similar to the situation with the RSV M2-2 protein although there is no significant sequence identity between the M2-2 proteins of the pneumoviruses. A significant difference between the genome organisations of RSV and PVM is that the P gene of PVM contains a second open reading frame, encoding the P-2 protein, which has no counterpart in the RSV P gene. Co-expression of the PVM P-2 protein with the minigenome inhibited virus gene expression. This resembles the situation seen with the accessory proteins expressed from alternate reading frames of the P gene of other paramyxoviruses. Analysis of levels of antigenome RNA and CAT mRNA produced by the minigenome in the presence of the P2 protein indicated that the protein inhibits viral transcription in a dose-dependent fashion.

  12. Early results of a randomized two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with two and four courses of cisplatin/S-1 and docetaxel/cisplatin/S-1 as neoadjuvant chemotherapy for locally advanced gastric cancer.

    PubMed

    Aoyama, T; Nishikawa, K; Fujitani, K; Tanabe, K; Ito, S; Matsui, T; Miki, A; Nemoto, H; Sakamaki, K; Fukunaga, T; Kimura, Y; Hirabayashi, N; Yoshikawa, T

    2017-08-01

    Neoadjuvant chemotherapy (NAC) is a promising method of improving the survival of resectable gastric cancer. Cisplatin/S-1 (CS) and docetaxel/cisplatin/S-1 (DCS) are both effective against metastatic gastric cancer. This report clarified the impact of these regimens on early endpoints, including the pathological responses, chemotherapy-related toxicities, and surgical results. Patients with M0 and either T4 or T3 in case of junctional cancer or scirrhous type received two or four courses of cisplatin (60 mg/m2 at day 8)/S-1 (80 mg/m2 for 21 days with 1 week rest) or docetaxel (40 mg/m2 at day 1)/cisplatin (60 mg/m2 at day 1)/S-1 (80 mg/m2 for 14 days with 2 weeks rest) as NAC. Patients then underwent D2 gastrectomy and adjuvant S-1 chemotherapy for 1 year. The primary endpoint was the 3-year overall survival. Between October 2011 and September 2014, 132 patients were assigned to receive CS (n = 66; 33 in 2 courses and 33 in 4 courses) or DCS (n = 66; 33 in 2 courses and 33 in 4 courses). The respective major grade 3 or 4 hematological toxicities (CS/DCS) were leukocytopenia (14.1%/26.2%), neutropenia (29.7%/47.7%), anemia (14.1%/12.3%), and platelet reduction (3.1%/1.5%). The rate of pathological response, defined as a complete response or < 10% residual cancer remaining, was 19.4% in the CS group and 15.4% in the DCS group, and 15.6% in the two-course group and 19.0% in the 4-course group. The R0 resection rate was 72.7% in the CS group and 81.8% in the DCS group and 80.3% in the two-course group and the 74.2% in the four-course group. No treatment-related deaths were observed. Our results do not support three-drug therapy with a taxane over two-drug therapy, or any further treatment beyond two cycles as an attractive candidate for the test arm of NAC.

  13. Magellan/M2FS Spectroscopy of Galaxy Clusters: Stellar Population Model and Application to Abell 267

    NASA Astrophysics Data System (ADS)

    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.

  14. S-1 in combination with docetaxel and oxaliplatin in patients with advanced gastro-esophageal adenocarcinoma: two parallel phase 1/2a studies.

    PubMed

    Pfeiffer, Per; Qvortrup, Camilla; Krogh, Merete; Schoennemann, Katrine; Vestermark, Lene W; Jensen, Helle A; Bjerregaard, Jon K

    2017-01-01

    Docetaxel in combination with cisplatin and 5-fluorouracil (5-FU) is one of several standard chemotherapy regimens for patients with advanced gastro-esophageal adenocarcinoma (aGEA) in Europe. To enable outpatient treatment, we evaluated the maximum tolerated dose (MTD), recommended dose (RD), dose limiting toxicity (DLT) and safety of docetaxel in combination with oxaliplatin (O) and S-1 (DOS) in Caucasian patients with aGEA. We present final results of two parallel phase 1/2a studies (3 + 3 design). Escalating doses of docetaxel and S-1 with fixed dose O were given for 18 weeks every second week (DOS2w) or every third week (DOS3w) followed by S-1 maintenance therapy. Thirty-four patients (18 in DOS2w and 16 in DOS3w) were enrolled between October 2013 and June 2015. Median age was 65 years (range 49-78). DLT was most often febrile neutropenia. Most common severe non-hematological adverse events were diarrhea (9%) and fatigue (6%). The RD of DOS3w was: docetaxel 50 mg/m(2), O 100 mg/m(2) and S-1 25 mg/m(2) twice daily and of DOS2w was: docetaxel 40 mg/m(2), O 70 mg/m(2) and S-1 35 mg/m(2) twice daily. Overall, response rate was 56%; median progression-free survival was 9.1 months; and median overall survival was 13.2 months in 34 patients. At the RD, DOS2w and DOS3w showed an acceptable safety profile in patients with aGEA. Clinical trials ID: NCT-01928524 and EudraCT 2012-005187-10.

  15. Draft Genome Sequence of Bacillus ginsengihumi Strain M2.11 with Phytase Activity

    PubMed Central

    Suleimanova, Aliya D.; Boulygina, Eugenia A.; Kazakov, Sergey V.; Baranova, Daria S.; Akhmetova, Alina I.; Mardanova, Ayslu M.

    2015-01-01

    This paper announces the genome sequence of Bacillus ginsengihumi strain M2.11, which has been characterized as a strain which produces the enzyme with the ability to degrade phytase. The genome of the strain M2.11 is 3.7 Mb and harbors 3,082 coding sequences. PMID:26272561

  16. Performance oriented packaging report for charge, demolition, shaped, 15 pound, M2A4. Final report

    SciTech Connect

    Sniezek, F.M.

    1992-11-02

    This POP report is for the Charge, Demolition, Shaped, 15 Pound, M2A4 which is packaged 4 charges/Mil-B-2427 wood box. This report describes the results of testing conducted. Performance Oriented Packaging, POP, Charge, Demolition, Shaped, 15 Pound, M2A4, Mil-B-2427 Wood box.

  17. EspM2 is a RhoA guanine nucleotide exchange factor

    PubMed Central

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

    2010-01-01

    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. PMID:20039879

  18. LASER BEAMS: Calculation of the laser-beam M2 factor by the method of moments

    NASA Astrophysics Data System (ADS)

    Potemkin, A. K.; Khazanov, E. A.

    2005-11-01

    The method is proposed for calculating the M2 factor by using the averaged description of wave beams (the method of moments). The values of M2 are calculated for the super-Gaussian intensity distribution with phase distortions caused by the electron and thermal self-focusing and spherical aberration.

  19. Phonological Substitution Errors in L2 ASL Sentence Processing by Hearing M2L2 Learners

    ERIC Educational Resources Information Center

    Williams, Joshua; Newman, Sharlene

    2016-01-01

    In the present study we aimed to investigate phonological substitution errors made by hearing second language (M2L2) learners of American Sign Language (ASL) during a sentence translation task. Learners saw sentences in ASL that were signed by either a native signer or a M2L2 learner. Learners were to simply translate the sentence from ASL to…

  20. Pilot Milt Thompson and the M2-F2 Lifting Body

    NASA Technical Reports Server (NTRS)

    1966-01-01

    Jay L. King, Joseph D. Huxman and Orion D. Billeter assist NASA research pilot Milt Thompson (on the ladder) into the cockpit of the M2-F2 lifting body research aircraft at the NASA Flight Research Center (now the Dryden Flight Research Center). The M2-F2 is attached to a wing pylon under the wing of NASA's B-52 mothership.

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

    PubMed

    Jetten, Nadine; Roumans, Nadia; Gijbels, Marion J; Romano, Andrea; Post, Mark J; de Winther, Menno P J; van der Hulst, Rene R W J; Xanthoulea, Sofia

    2014-01-01

    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.

  2. Orosomucoid 1 drives opportunistic infections through the polarization of monocytes to the M2b phenotype.

    PubMed

    Nakamura, Kiwamu; Ito, Ichiaki; Kobayashi, Makiko; Herndon, David N; Suzuki, Fujio

    2015-05-01

    Orosomucoid (ORM, composed of two isoforms, ORM1 and ORM2) has been described as an inducer of M2 macrophages, which are cells that decrease host antibacterial innate immunities. However, it is unknown which phenotypes of M2 macrophages are induced by ORM. In this study, healthy donor monocytes stimulated with ORM (ORM-monocytes) were characterized phenotypically and biologically. CCL1 (a biomarker of M2b macrophages) and IL-10 were detected in monocyte cultures supplemented with ORM1; however, CCL17 (a biomarker of M2a macrophages) and CXCL13 (a biomarker of M2c macrophages) were not produced in these cultures. All of these soluble factors were not detected in the culture fluids of monocytes stimulated with ORM2. Monocytes stimulated with ORM1 were characterized as CD64(-)CD209(-)CD163(+)CCL1(+) cells. MRSA and Enterococcus faecalis infections were accelerated in chimeras (NOD/scid IL-2Rγ(null) mice reconstituted with white blood cells) after inoculation with monocytes stimulated with ORM1 or treatment with ORM1; however, the infections were greatly mitigated in both chimeras inoculated with ORM1-stimulated monocytes and treated with ORM1, after an additional treatment with an inhibitor of M2b macrophages (CCL1 antisense ODN). These results indicate that ORM1 stimulates quiescent monocytes to polarize to M2b monocytes. The regulation of M2b macrophages may be beneficial in controlling opportunistic infections in patients with a large amount of plasma ORM1.

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

    ERIC Educational Resources Information Center

    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…

  4. Postsynaptic muscarinic m2 receptors at cholinergic and glutamatergic synapses of mouse brainstem motoneurons.

    PubMed

    Csaba, Zsolt; Krejci, Eric; Bernard, Véronique

    2013-06-15

    In many brain areas, few cholinergic synapses are identified. Acetylcholine is released into the extracellular space and acts through diffuse transmission. Motoneurons, however, are contacted by numerous cholinergic terminals, indicating synaptic cholinergic transmission on them. The muscarinic m2 receptor is the major acetylcholine receptor subtype of motoneurons; therefore, we analyzed the localization of the m2 receptor in correlation with synapses by electron microscopic immunohistochemistry in the mouse trigeminal, facial, and hypoglossal motor nuclei. In all nuclei, m2 receptors were localized at the membrane of motoneuronal perikarya and dendrites. The m2 receptors were concentrated at cholinergic synapses located on the perikarya and most proximal dendrites. However, m2 receptors at cholinergic synapses represented only a minority (<10%) of surface m2 receptors. The m2 receptors were also enriched at glutamatergic synapses in both motoneuronal perikarya and dendrites. A relatively large proportion (20-30%) of plasma membrane-associated m2 receptors were located at glutamatergic synapses. In conclusion, the effect of acetylcholine on motoneuron populations might be mediated through a synaptic as well as diffuse type of transmission.

  5. Phonological Substitution Errors in L2 ASL Sentence Processing by Hearing M2L2 Learners

    ERIC Educational Resources Information Center

    Williams, Joshua; Newman, Sharlene

    2016-01-01

    In the present study we aimed to investigate phonological substitution errors made by hearing second language (M2L2) learners of American Sign Language (ASL) during a sentence translation task. Learners saw sentences in ASL that were signed by either a native signer or a M2L2 learner. Learners were to simply translate the sentence from ASL to…

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

    ERIC Educational Resources Information Center

    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…

  7. [Evaluation of Drug Interaction between S-1 and Warfarin].

    PubMed

    Yamamoto, Kaori; Suzuki, Shinya; Ikegawa, Kiwako; Nomura, Hisanaga; Fuse, Nozomu; Saito, Shinichiro

    2016-01-01

    Prolonged prothrombin time is observed in patients taking warfarin (WF) with a fluoropyrimidine, such as S-1. When WF is combined with S-1, the prothrombin time-international normalized ratio (PT-INR) and dose adjustment of WF should be closely monitored. To date, no clinical data have been reported in terms of the relation between temporal variation of PT-INR and its therapeutic range. In this study, we retrospectively collected patients' clinical data including PT-INR. We identified 21 patients receiving WF therapy before the start of S-1 treatment. Patient characteristics were male/female: 18/3, median age: 69 (range 48-81) years old, cancer of gastric/lung/pancreatic/other: 8/5/4/4, and history of deep vein thrombosis (DVT)/atrial fibrillation (AF)/cerebral infarction (CI)/other: 11/6/2/2. The PT-INR of 16 patients exceeded normal upper limits after taking S-1 with WF. The median time to exceed the PT-INR upper therapeutic range is 25 (range 3-77) days. Patients receiving WF anticoagulant therapy concomitant with S-1 should have their PT-INR closely monitored and WF doses adjusted accordingly.

  8. Regional distribution of M1, M2 and non-M1, non-M2 subtypes of muscarinic binding sites in rat brain

    SciTech Connect

    Ehlert, F.J.; Tran, L.P. )

    1990-12-01

    The distribution of subtypes of the muscarinic receptor in homogenates of the rat brain was investigated by measuring the competitive inhibition of the binding (3H)N-methylscopolamine by pirenzepine and AF-DX 116 (11((2-((diethylamino)methyl)-1-piperidinyl)acetyl)-5, 11-dihydro-6H-pyrido(2,3-b)(1,4)benzodiazepine-6-one). In most brain regions, the competitive binding curves for AF-DX 116 and pirenzepine were consistent with a two-site model. The dissociation constant of pirenzepine for its high-affinity site (M1 receptor) was approximately 10(-8) M, whereas the dissociation constant of AF-DX 116 for its high affinity site (M2 receptor) was approximately 10(-7) M. In many regions, particularly those in the forebrain, the sum of the densities of the M1 and M2 binding sites was substantially less than 100% of the total sites, indicating the existence of a third population of sites lacking high affinity for both pirenzepine and AF-DX 116. We have designated these latter sites as non-M1, non-M2 muscarinic receptors. In general, the densities of the M1 and non-M1, non-M2 binding sites were highest in cerebral cortex, corpus striatum and hippocampus, intermediate in thalamus and hypothalamus, and lowest in midbrain, medulla-pons and cerebellum, whereas the M2 binding site had a relatively low, uniform density throughout the brain. The binding capacity of (3H)N-methylquinuclidinyl benzilate was estimated to be 20 to 30% lower than that of (3H)quinuclidinyl benzilate in various regions of the forebrain, but not in more caudal regions of the brain where the two radioligands had approximately the same binding capacities.

  9. Diagnostic and prognostic value of tumor M2-pyruvate kinase levels in patients with colorectal canhcer.

    PubMed

    Demır, Ahmet Suat; Erdenen, Füsun; Müderrısoğlu, Cüneyt; Toros, Ahmet Burak; Bektaş, Hasan; Gelışgen, Remise; Tabak, Ömür; Altunoğlu, Esma; Uzun, Hafize; Erdem Huq, Gülben Erdem; Aral, Hale

    2013-01-01

    Screening for precancerous lesions is important for the diagnosis and treatment of colorectal tumors. We investigated M2-pyruvate kinase levels in patients with colorectal polyps and carcinoma and assessed factors affecting M2-pyruvate kinase levels. Eighty-five patients who had undergone colonoscopic examination and who were diagnosed with a neoplastic lesion were included. Patients were divided into two groups according to the macroscopic diagnosis of polyp or carcinoma. According to histopathological evaluation, specimens were grouped as nonneoplastic lesions, tubular adenoma, tubulovillous adenoma and adenocarcinoma. M2-pyruvate kinase levels were measured with the Tumor M2-pyruvate kinase ELISA kit. Mean M2-pyruvate kinase levels were 76.1±57.73 (13.1-288.22) IU/ml. We did not find a correlation between M2-pyruvate kinase levels and age, gender, smoking, alcohol and aspirin consumption and colorectal cancer family history. There was a relationship between body mass index and M2-pyruvate kinase level (p=0.022). The carcinoma group had the highest levels of M2-pyruvate kinase both endoscopically and histopathologically (p=0.009, p=0.019 respectively). M2-pyruvate kinase levels of patients who died were significantly higher than patients who survived (p=0.001). Enzyme values were significantly lower in diabetic patients than nondiabetics (p=0.04); and chronic renal failure patients had higher levels (p=0.045). Serum M2-pyruvate kinase levels may be useful in distinguishing malignant and benign lesions of the colon and may provide insight in terms of survival.

  10. The S=1 Underscreened Anderson Lattice model for Uranium compounds

    NASA Astrophysics Data System (ADS)

    Thomas, C.; Simões, A. S. R.; Iglesias, J. R.; Lacroix, C.; Perkins, N. B.; Coqblin, B.

    2011-01-01

    Magnetic properties of uranium and neptunium compounds showing coexistence of the Kondo effect and ferromagnetic order are investigated within the degenerate Anderson Lattice Hamiltonian, describing a 5f2 electronic configuration with S = 1 spins. Through the Schrieffer-Wolff transformation, both an exchange Kondo interaction for the S = 1 f-spins and an effective f-band term are obtained, allowing to describe the coexistence of Kondo effect and ferromagnetic ordering and a weak delocalization of the 5f-electrons. We calculate the Kondo and Curie temperatures and we can account for the pressure dependence of the Curie temperature of UTe.

  11. Degradation of G(M1) and G(M2) by mammalian sialidases.

    PubMed Central

    Li, S C; Li, Y T; Moriya, S; Miyagi, T

    2001-01-01

    In mammalian tissues, the pathway known for the catabolism of G(M1) [Galbeta3GalNAcbeta4(Neu5Acalpha3)Galbeta4GlcCer; where Cer is ceramide] is the conversion of this ganglioside into G(M2) [GalNAcbeta4(Neu5Acalpha3)Galbeta4GlcbetaCer] by beta-galactosidase followed by the conversion of G(M2) into G(M3) (Neu5Acalpha3Galbeta4GlcbetaCer) by beta-N-acetylhexosaminidase A (Hex A). However, the question of whether or not G(M1) and G(M2) can also be respectively converted into asialo-G(M1) (Galbeta3GalNAcbeta4Galbeta4GlcCer; G(A1)) and asialo-G(M2) (GalNAcbeta4Galbeta4GlcbetaCer, G(A2)) by mammalian sialidases has not been resolved. This is due to the fact that sialidases purified from mammalian tissues always contained detergents that interfered with the in vitro hydrolysis of G(M1) and G(M2) in the presence of an activator protein. The mouse model of human type B Tay-Sachs disease created by the disruption of the Hexa gene showed no neurological abnormalities, with milder clinical symptoms than the human counterpart, and the accumulation of G(M2) in the brains of affected mice was only limited to certain regions [Sango, Yamanaka, Hoffmann, Okuda, Grinberg, Westphal, McDonald, Crawley, Sandhoff, Suzuki and Proia (1995) Nat. Genet. 11, 170-176]. These results suggest the possible presence of an alternative catabolic pathway (the G(A2) pathway) in mouse to convert G(M2) into G(A2) by sialidase. To show the existence of this pathway, we have used recombinant mammalian cytosolic sialidase and membrane-associated sialidase to study the desialylation of G(M1) and G(M2). We found that the mouse membrane-bound sialidase was able to convert G(M1) and G(M2) into their respective asialo-derivatives in the presence of human or mouse G(M2) activator protein. The cytosolic sialidase did not exhibit this activity. Our results suggest that, in vivo, the stable NeuAc of G(M1) and G(M2) may be removed by the mammalian membrane-associated sialidase in the presence of G(M2) activator

  12. L5 – S1 Segmental Kinematics After Facet Arthroplasty

    PubMed Central

    Voronov, Leonard I.; Havey, Robert M.; Rosler, David M.; Sjovold, Simon G.; Rogers, Susan L.; Carandang, Gerard; Ochoa, Jorge A.; Yuan, Hansen; Webb, Scott

    2009-01-01

    Background Facet arthroplasty is a motion restoring procedure. It is normally suggested as an alternative to rigid fixation after destabilizing decompression procedures in the posterior lumbar spine. While previous studies have reported successful results in reproducing normal spine kinematics after facet replacement at L4-5 and L3-4, there are no data on the viability of facet replacement at the lumbosacral joint. The anatomy of posterior elements and the resulting kinematics at L5-S1 are distinctly different from those at superior levels, making the task of facet replacement at the lumbosacral level challenging. This study evaluated the kinematics of facet replacement at L5-S1. Methods Six human cadaveric lumbar spines (L1-S1, 46.7 ± 13.0 years) were tested in the following sequence: (1) intact (L1-S1), (2) complete laminectomy and bilateral facetectomy at L5-S1, and (3) implantation of TFAS-LS (Lumbosacral Total Facet Arthroplasty System, Archus Orthopedics, Redmond, Washington) at L5-S1 using pedicle screws. Specimens were tested in flexion (8Nm), extension (6Nm), lateral bending (LB, ± 6Nm), and axial rotation (AR, ± 5Nm). The level of significance was α = .017 after Bonferroni correction for three comparisons: (1) intact vs. destabilized, (2) destabilized vs. reconstructed, and (3) intact vs. reconstructed. Results Laminectomy-facetectomy at L5-S1 increased the L5-S1 angular range of motion (ROM) in all directions. Flexion-extension (F-E) ROM increased from 15.3 ± 2.9 to 18.7 ± 3.5 degrees (P < .017), LB from 8.2 ± 1.8 to 9.3 ± 1.6 degrees (P < .017), and AR from 3.7 ± 2.0 to 5.9 ± 1.8 degrees (P < .017). The facet arthroplasty system decreased ROM compared to the laminectomy-facetectomy condition in all tested directions (P < .017). The facet arthroplasty system restored the L5-S1 ROM to its intact levels in LB and AR (P > .017). F-E ROM after the facet arthroplasty system implantation was smaller than the intact value (10.1 ± 2.2 vs. 15.3 ± 2

  13. [Comparison of distribution of cholinergic nerves and M2 receptors between rat atria and ventricles].

    PubMed

    Xu, Xiao-li; Zang, Wei-jin; Kang, Xin-qin; Li, Ming; Yu, Xiao-jiang; Chen, Li-na; Luo, Hong-li

    2006-08-01

    To investigate the general pattern of cholinergic nerve distribution and M(2) receptors in adult rat heart. Karnovsky-Roots histochemical staining combining point counting method and immunochemical SABC method with image analysis were used to identify the cholinergic nerves and M(2) receptors, respectively, in adult rat heart. Positive staining of cholinergic nerves and M(2) receptors was found in all regions of the rat heart, and the point count of cholinergic nerves in the atria was 4.6 times as much as that in ventricles, and the area of immunoreactive substance for M(2) receptors two-fold higher in the atria than in the ventricles. The point counts of the cholinergic nerves in the medial-layer myocardium were fewer than that in subepicardial and endocardial tissues of the left ventricular free wall. However, M(2) receptors were comparable among the 3 layers of the left free ventricular wall. Cholinergic nerves and M(2) receptors are located in both rat atria and ventricles, but their density is much higher in the atria than in the ventricles. Transmural heterogeneity characterizes cholinergic nerve innervation in the left ventricular free wall without significant differences in M(2) receptor density.

  14. HMGB1 enhances the protumoral activities of M2 macrophages by a RAGE-dependent mechanism.

    PubMed

    Rojas, Armando; Delgado-López, Fernando; Perez-Castro, Ramón; Gonzalez, Ileana; Romero, Jacqueline; Rojas, Israel; Araya, Paulina; Añazco, Carolina; Morales, Erik; Llanos, Jorge

    2016-03-01

    The monocyte-macrophage lineage shows a high degree of diversity and plasticity. Once they infiltrate tissues, they may acquire two main functional phenotypes, being known as the classically activated type 1 macrophages (M1) and the alternative activated type 2 macrophages (M2). The M1 phenotype can be induced by bacterial products and interferon-γ and exerts a cytotoxic effect on cancer cells. Conversely, the alternatively activated M2 phenotype is induced by Il-4/IL13 and promotes tumor cell growth and vascularization. Although receptor for advanced glycation end-products (RAGE) engagement in M1 macrophages has been reported by several groups to promote inflammation, nothing is known about the functionality of RAGE in M2 macrophages. In the current study, we demonstrate that RAGE is equally expressed in both macrophage phenotypes and that RAGE activation by high-mobility group protein box1 (HMGB1) promotes protumoral activities of M2 macrophages. MKN45 cells co-cultured with M2 macrophages treated with HMGB1 at different times displayed higher invasive abilities. Additionally, conditioned medium from HMGB1-treated M2 macrophages promotes angiogenesis in vitro. RAGE-targeting knockdown abrogates these activities. Overall, the present findings suggest that HMGB1 may contribute, by a RAGE-dependent mechanism, to the protumoral activities of the M2 phenotype.

  15. Kinked structures of isolated nicotinic receptor M2 helices: a molecular dynamics study.

    PubMed

    Sankararamakrishnan, R; Samsom, M S

    1994-12-01

    The pore-lining M2 helix of the nicotinic acetylcholine receptor exhibits a pronounced kink when the corresponding ion channel is in a closed conformation [N. Unwin (1993) Journal of Molecular Biology, Vol. 229, pp. 1101-1124]. We have performed molecular dynamics simulations of isolated 22-residue M2 helices in order to identify a possible molecular origin of this kink. In order to sample a wide range of conformational space, a simulated annealing protocol was used to generate five initial M2 helix structures, each of which was subsequently used as the basis of 300 ps MD simulations. Two helix sequences (M2 alpha and M2 delta) were studied in this manner, resulting in a total of ten 300 ps trajectories. Kinked helices present in the trajectories were identified and energy minimized to yield a total of five different stable kinked structures. For comparison, a similar molecular dynamics simulation of a Leu23 helix yielded no stable kinked structures. In four of the five kinked helices, the kink was stabilized by H bonds between the helix backbone and polar side-chain atoms. Comparison with data from the literature on site-directed mutagenesis of M2 residues suggests that such polar side-chain to main-chain H bonds may also contribute to kinking of M2 helices in the intact channel protein.

  16. Ozone-induced hyperresponsiveness and blockade of M2 muscarinic receptors by eosinophil major basic protein.

    PubMed

    Yost, B L; Gleich, G J; Fryer, A D

    1999-10-01

    Control of airway smooth muscle is provided by parasympathetic nerves that release acetylcholine onto M(3) muscarinic receptors. Acetylcholine release is limited by inhibitory M(2) muscarinic receptors. In antigen-challenged guinea pigs, hyperresponsiveness is due to blockade of neuronal M(2) receptors by eosinophil major basic protein (MBP). Because exposure of guinea pigs to ozone also causes M(2) dysfunction and airway hyperresponsiveness, the role of eosinophils in ozone-induced hyperresponsiveness was tested. Animals were exposed to filtered air or to 2 parts/million ozone for 4 h. Twenty-four hours later, the muscarinic agonist pilocarpine no longer inhibited vagally induced bronchoconstriction in ozone-exposed animals, indicating M(2) dysfunction. M(2) receptor function in ozone-exposed animals was protected by depletion of eosinophils with antibody to interleukin-5 and by pretreatment with antibody to guinea pig MBP. M(2) function was acutely restored by removal of MBP with heparin. Ozone-induced hyperreactivity was also prevented by antibody to MBP and was reversed by heparin. These data show that loss of neuronal M(2) receptor function after ozone is due to release of eosinophil MBP.

  17. M2BP inhibits HIV-1 virion production in a vimentin filaments-dependent manner

    PubMed Central

    Wang, Qin; Zhang, Xiaolin; Han, Yuling; Wang, Xinlu; Gao, Guangxia

    2016-01-01

    M2BP (also called 90K) is an interferon-stimulated gene product that is upregulated in HIV-1 infection. A recent study revealed that M2BP reduces the infectivity of HIV-1 by inhibiting the processing of the viral envelope protein. Here we report that in addition to reducing viral infectivity, M2BP inhibits HIV-1 virion production. We provide evidence showing that M2BP inhibits HIV-1 Gag trafficking to the plasma membrane in a vimentin-dependent manner. When vimentin filaments were collapsed by treating cells with acrylamide or by overexpression of a dominant-negative mutant of vimentin, M2BP inhibition of HIV-1 virion production was significantly relieved. We further show that M2BP interacts with both HIV-1 Gag and vimentin and thereby mediates their interactions. We propose that M2BP traps HIV-1 Gag to vimentin filaments to inhibit the transportation of HIV-1 Gag to the plasma membrane. These findings uncover a novel mechanism by which a host antiviral factor inhibits HIV-1 virion production. PMID:27604950

  18. Superparamagnetic iron oxide nanoparticle uptake alters M2 macrophage phenotype, iron metabolism, migration and invasion.

    PubMed

    Rojas, José M; Sanz-Ortega, Laura; Mulens-Arias, Vladimir; Gutiérrez, Lucía; Pérez-Yagüe, Sonia; Barber, Domingo F

    2016-05-01

    Superparamagnetic iron oxide nanoparticles (SPIONs) have shown promise as contrast agents and nanocarriers for drug delivery. Their impact on M2-polarised macrophages has nonetheless not been well studied. Here we explored the effects of SPIONs coated with dimercaptosuccinic acid, aminopropyl silane or aminodextran in two M2 macrophage models (murine primary IL-4-activated bone marrow-derived macrophages and human M2-like differentiated THP-1 cells). All SPIONs were internalised and no cell toxicity was observed. SPION treatment produced reactive oxygen species and activated the extracellular signal-regulated kinase and AKT pathways. After 24-h SPION incubation, M2 macrophages switched their iron metabolism towards an iron-replete state. SPION treatment in both M2 macrophage models altered their M2 activation profiles, promoted IL-10 production, and stimulated protease-dependent invasion. These results highlight the need to evaluate the interactions between SPIONs and cells to take full advantage of the intrinsic properties of these nanoparticles in biological systems. Superparamagnetic iron oxide nanoparticles (SPIONs) have been used as an MRI contrast agent in many experimental studies. The authors here investigated the effects of these nanoparticles on M2 macrophages after cellular uptake. The findings of cell activation further enhanced our current knowledge on the interaction of SPIONS with macrophages. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Solidification Microstructure of AISI M2 High Speed Steel Manufactured by the Horizontal Continuous Casting Process

    NASA Astrophysics Data System (ADS)

    Zhou, X. F.; Fang, F.; Jiang, J. Q.

    2011-01-01

    In the present work, AISI M2 high speed steel is produced by the horizontal continuous casting process. The difference of solidification microstructure in ingots by mould casting and continuous casting has been examined by means of scanning electron microscope (SEM), electron back-scatter diffraction (EBSD), transmission electron microscope (TEM) and high resolution electron microscope (HREM). The results show that the as-cast structure consists of iron matrix and networks of M2C eutectic carbides, which are greatly refined in the continuous casting ingot compared to the case of ingot by mould casting. Meanwhile, the morphology of M2C eutectic carbides changes from the plate-like shape into the fibrous one. Micro-twining and stacking faults are observed in the plate-like M2C, whereas they are rarely identified in the fibrous M2C. Based on the characteristic of morphology and microstructure, it is expected that the plate-like M2C is a faceted phase while the fibrous M2C is a non-faceted phase.

  20. Propranolol as a modulator of M2b monocytes in severely burned patients.

    PubMed

    Kobayashi, Makiko; Jeschke, Marc G; Asai, Akira; Kogiso, Mari; Yoshida, Shohei; Herndon, David N; Suzuki, Fujio

    2011-05-01

    A role of immunosuppressive M2 monocytes (IL-12(-)IL-10(+)) on the increased susceptibility of severely burned patients to various opportunistic pathogens has been described. Among M2 monocyte subpopulations, M2b monocytes (IL-17(-)CCL1(+)CXCL13(-)) are predominantly present in the peripheral blood of severely burned patients. In the present study, the rise and fall of M2b monocytes were examined in severely burned patients treated with propranolol. Catecholamine is known as an inducer of M2 monocytes, and propranolol is a competitive blocker of catecholamine binding to β-adrenergic receptors. Twenty-two children with 30% or more TBSA burn were enrolled in the study. Propranolol at a dose of 4 mg/kg/day was administered to these patients by feeding-tube or mouth. Burn patient monocytes exhibited weak bactericidal activity. IL-12 was produced by propranolol-treated patient monocytes after stimulation with Staphylococcus aureus antigen, and the production of IL-10, CCL1, CCL17, or CXCL13 by these monocytes was not demonstrated. These results indicate that a predominance of M2b monocytes in severely burned patients is intervened by the propranolol treatment. The increased susceptibility, to be associated with the appearance of M2b monocytes, of severely burned patients to opportunistic pathogens might be controlled by propranolol.

  1. Respiratory syncytial virus M2-1 protein induces the activation of nuclear factor kappa B

    SciTech Connect

    Reimers, Kerstin . E-mail: reimers.kerstin@mh-hannover.de; Buchholz, Katja; Werchau, Hermann

    2005-01-20

    Respiratory syncytial virus (RSV) induces the production of a number of cytokines and chemokines by activation of nuclear factor kappa B (NF-{kappa}B). The activation of NF-{kappa}B has been shown to depend on viral replication in the infected cells. In this study, we demonstrate that expression of RSV M2-1 protein, a transcriptional processivity and anti-termination factor, is sufficient to activate NF-{kappa}B in A549 cells. Electromobility shift assays show increased NF-{kappa}B complexes in the nuclei of M2-1-expressing cells. M2-1 protein is found in nuclei of M2-1-expressing cells and in RSV-infected cells. Co-immunoprecipitations of nuclear extracts of M2-1-expressing cells and of RSV-infected cells revealed an association of M2-1 with Rel A protein. Furthermore, the activation of NF-{kappa}B depends on the C-terminus of the RSV M2-1 protein, as shown by NF-{kappa}B-induced gene expression of a reporter gene construct.

  2. M2muscarinic receptors inhibit cell proliferation and migration in urothelial bladder cancer cells

    PubMed Central

    Pacini, Luca; De Falco, Elena; Di Bari, Maria; Coccia, Andrea; Siciliano, Camilla; Ponti, Donatella; Pastore, Antonio Luigi; Petrozza, Vincenzo; Carbone, Antonio; Tata, Ada Maria; Calogero, Antonella

    2014-01-01

    The role of muscarinic receptors in several diseases including cancer has recently emerged. To evaluate the hypothesis that muscarinic acetylcholine receptors may play a role in bladder cancer as well as in other tumor types, we investigated their expression in bladder tumor specimens. All examined samples expressed the M1, M2 and M3 receptor subtypes. We also found that the level of M2 transcripts, but not those of M1 or M3, significantly increased with the tumor histologic grade. In view of these results, we proceeded to investigate whether the M2 agonist Arecaidine had any effect on in vitro cell growth and migration of T24 cells, a bladder tumor cell line expressing the muscarinic receptors, including the M2 subtype. We observed that Arecaidine significantly reduced T24 and 5637 cell proliferation and migration in a concentration dependent manner. The silencing of M2 receptor by siRNA in T24 and 5637 cell lines showed the inability of Arecaidine (100 μM) to inhibit cell proliferation after 48 hours, whereas the use of M1 and M3 antagonists in T24 appeared not to counteract the Arecaidine effect, suggesting that the inhibition of cell proliferation was directly dependent on M2 receptor activation. These data suggest that M2 muscarinic receptors may play a relevant role in bladder cancer and represent a new attractive therapeutic target. PMID:25482946

  3. The chemotaxis of M1 and M2 macrophages is regulated by different chemokines.

    PubMed

    Xuan, Wenjuan; Qu, Qing; Zheng, Biao; Xiong, Sidong; Fan, Guo-Huang

    2015-01-01

    The homing of proinflammatory (M1) and the "alternatively activated" anti-inflammatory (M2) macrophages plays a different role in the process of inflammation. Chemokines are the major mediators of macrophage chemotaxis, but how they differentially regulate M1 and M2 macrophages remains largely unclear. In the present study, we attempted to screen chemokines that differentially induce chemotaxis of M1 and M2 macrophages and to explore the underlying mechanism. Among the 41 chemokines that specifically bind to 20 chemokine receptors, CCL19, CCL21, CCL24, CCL25, CXCL8, CXCL10, and XCL2 specifically induced M1 macrophage chemotaxis, whereas CCL7 induced chemotaxis of both M1 and M2 macrophages. Whereas the differential effects of these chemokines on M1/M2 macrophage chemotaxis could be attributable to the predominant expression of their cognate receptors on the macrophage subsets, CCR7, the receptor for CCL19/CCL21, appeared to be an exception. Immunoblot analysis indicated an equivalent level of CCR7 in the whole cell lysate of M1 and M2 macrophages, but CCL19 and CCL21 only induced M1 macrophage chemotaxis. Both immunoblot and confocal microscopy analyses demonstrated that CCR7 was predominantly expressed on the cell surface of M1 but in the cytosol of M2 macrophages before ligand stimulation. As a result, CCL19 or CCL21 induced activation of both MEK1-ERK1/2 and PI3K-AKT cascades in M1 but not in M2 macrophages. Intriguingly, CCL19/CCL21-mediated M1 macrophage chemotaxis was blocked by specific inhibition of PI3K rather than MEK1. Together, these findings suggest that recruitment of M1 and M2 macrophages is fine tuned by different chemokines with the involvement of specific signaling pathways. © Society for Leukocyte Biology.

  4. Expression of the human muscarinic receptor gene m2 in Dictyostelium discoideum

    SciTech Connect

    Voith, G.; Dingermann, T.

    1995-11-01

    We have expressed a functional human muscarinic M2 receptor, under the control of the homologous discoidin I{gamma} promoter, in the cellular slime mold Dictyostelium discoideum. The use of a contact site A leader peptide ensured insertion of the newly synthesized receptor protein into the plasma membrane. Due to the characteristics of the discoidin I{gamma} promoter, the M2 receptor is expressed during late growth and early development. The heterologously expressed M2 receptors show binding characteristics similar to authentic receptors. Membranes as well as whole cells can be used in ligand binding assays. 36 refs., 4 figs.

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

    SciTech Connect

    Bradbury, Andrew M; Velappan, Nileena; Schmidt, Jurgen G

    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.

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

    NASA Image and Video Library

    1963-08-30

    Following the first M2-F1 airtow flight on 16 August 1963, the Flight Research Center used the vehicle for both research flights and to check out new lifting-body pilots. These included Bruce Peterson, Don Mallick, Fred Haise, and Bill Dana from NASA. Air Force pilots who flew the M2-F1 included Chuck Yeager, Jerry Gentry, Joe Engle, Jim Wood, and Don Sorlie, although Wood, Haise, and Engle only flew on car tows. In the three years between the first and last flights of the M2-F1, it made about 400 car tows and 77 air tows.

  7. Experimental estimation of S-1 photocathode beam strength

    NASA Astrophysics Data System (ADS)

    Lebedev, Vitaly B.

    1999-06-01

    The threshold value of the energy density qthr at wavelength of 1.06 micrometer which led to unrecoverable sensitivity loss of the first generation S-1 photocathode of single-chamber module image converter tube (ICT) with fiber disks at input and output was determined experimentally. The value amounted to 2 X 10-2J/cm2.

  8. Primary structure of chicken cardiac myosin S-1 heavy chain.

    PubMed

    Nakayama, S; Tanaka, H; Yajima, E; Maita, T

    1994-05-01

    The sequence of the NH2-terminal 830 amino acid residues of chicken cardiac ventricular muscle myosin subfragment-1 (S-1) was determined. S-1 was obtained by limited chymotryptic digestion, and cleaved into three characteristics fragments (23, 41, and 22 kDa fragments) by limited tryptic digestion. These fragments were isolated by gel filtration on a Sephadex G-100 column, followed by cation-exchange chromatography on a CM-52 column and reverse-phase HPLC. The isolated fragments were sequenced completely. Peptides overlapping the 23 and 41 kDa fragments and also overlapping the 41 and 22 kDa fragments were obtained by cleaving S-1 with cyanogen bromide, and sequenced completely. We also obtained a minor fragment, the 20 kDa fragment, in addition to the three characteristic fragments. Amino acid compositions of the cyanogen bromide peptides of the 20 kDa fragment indicated that a portion of S-1 heavy chains had lost their COOH-terminal 21 residues during limited tryptic digestion. Methylated amino acid residues were found at four positions: epsilon-N-monomethyllysine at position 32, epsilon-N-trimethyllysine residues at 127 and 549, and 3-N-methylhistidine at 754.

  9. Excitation of nutation by the global radiational S1 tide

    NASA Astrophysics Data System (ADS)

    Schindelegger, M.; Salstein, D. A.; Einspigel, D.; Boehm, J.

    2014-12-01

    Cyclic mass redistributions in the atmosphere and oceans related to the global radiational S1 tide elicit seasonal perturbations of Earth's nutation at a level of 0.1 mas (milliarcseconds). The present study provides an up-to-date assessment of these excitation effects on the basis of 10-year surface and isobaric level data from three, previously unavailable global atmospheric reanalysis systems. We retrieve numerical values of in- and out-of-phase nutation corrections for seasonally modulated S1 variations and indicate how model improvements, specifically in terms of the representation of tidal oscillations, lead to different estimates with respect to earlier reanalyses. Motion term signals in nutation display a close agreement across all probed datasets, whereas larger disparities remain among mass term excitation estimates due to their dependency on small-scale diurnal surface pressure oscillations. A simple time-stepping model for barotropic ocean dynamics, based on the shallow water equations and driven by air pressure tide climatologies, represents an appropriate means to determine global S1 estimates of sea level heights and currents that are consistent with the respective forcing fields from each reanalysis. We address the intricacies of constructing such a model and compare our preliminary oceanic angular momentum solutions to those from more established hydrodynamic forward integrations. The combined influence of the S1 tide on Earth's nutation, associated with both atmosphere and ocean dynamics, is found to yield a rough agreement with observations from geodetic VLBI (Very Long Baseline Interferometry) measurements.

  10. Regulation of insulin and type 1 insulin-like growth factor signaling and action by the Grb10/14 and SH2B1/B2 adaptor proteins.

    PubMed

    Desbuquois, Bernard; Carré, Nadège; Burnol, Anne-Françoise

    2013-02-01

    The effects of insulin and type 1 insulin-like growth factor (IGF-1) on metabolism, growth and survival are mediated by their association with specific receptor tyrosine kinases, which results in both receptor and substrate phosphorylation. Phosphotyrosine residues on receptors and substrates provide docking sites for signaling proteins containing SH2 (Src homology 2) domains, including molecular adaptors. This review focuses on the regulation of insulin/IGF-1 signaling and action by two adaptor families with a similar domain organization: the growth factor receptor-bound proteins Grb7/10/14 and the SH2B proteins. Both Grb10/14 and SH2B1/B2 associate with the activation loop of insulin/IGF-1 receptors through their SH2 domains, but association of Grb10/14 also involves their unique BPS domain. Consistent with Grb14 binding as a pseudosubstrate to the kinase active site, insulin/IGF-induced activation of receptors and downstream signaling pathways in cultured cells is inhibited by Grb10/14 adaptors, but is potentiated by SH2B1/B2 adaptors. Accordingly, Grb10 and Grb14 knockout mice show improved insulin/IGF sensitivity in vivo, and, for Grb10, overgrowth and increased skeketal muscle and pancreatic β-cell mass. Conversely, SH2B1-depleted mice display insulin and IGF-1 resistance, with peripheral depletion leading to reduced adiposity and neuronal depletion leading to obesity through associated leptin resistance. Grb10/14 and SH2B1 adaptors also modulate insulin/IGF-1 action by interacting with signaling components downstream of receptors and exert several tissue-specific effects. The identification of Grb10/14 and SH2B1 as physiological regulators of insulin signaling and action, together with observations that variants at their gene loci are associated with obesity and/or insulin resistance, highlight them as potential therapeutic targets for these conditions.

  11. Late-stage optimization of a tercyclic class of S1P3-sparing, S1P1 receptor agonists.

    PubMed

    Horan, Joshua C; Kuzmich, Daniel; Liu, Pingrong; DiSalvo, Darren; Lord, John; Mao, Can; Hopkins, Tamara D; Yu, Hui; Harcken, Christian; Betageri, Raj; Hill-Drzewi, Melissa; Patenaude, Lori; Patel, Monica; Fletcher, Kimberly; Terenzzio, Donna; Linehan, Brian; Xia, Heather; Patel, Mita; Studwell, Debbie; Miller, Craig; Hickey, Eugene; Levin, Jeremy I; Smith, Dustin; Kemper, Raymond A; Modis, Louise K; Bannen, Lynne C; Chan, Diva S; Mac, Morrison B; Ng, Stephanie; Wang, Yong; Xu, Wei; Lemieux, René M

    2016-01-15

    Poor solubility and cationic amphiphilic drug-likeness were liabilities identified for a lead series of S1P3-sparing, S1P1 agonists originally developed from a high-throughput screening campaign. This work describes the subsequent optimization of these leads by balancing potency, selectivity, solubility and overall molecular charge. Focused SAR studies revealed favorable structural modifications that, when combined, produced compounds with overall balanced profiles. The low brain exposure observed in rat suggests that these compounds would be best suited for the potential treatment of peripheral autoimmune disorders.

  12. Development of transgenic lines of Eimeria tenella expressing M2e-enhanced yellow fluorescent protein (M2e-EYFP).

    PubMed

    Liu, Xianyong; Zou, Jun; Yin, Guangwen; Su, Huali; Huang, Xiaoxi; Li, Jianan; Xie, Li; Cao, Yingqiong; Cui, Yujuan; Suo, Xun

    2013-03-31

    Eimeria parasites are obligate intracellular apicomplexan protists that can cause coccidiosis, resulting in substantial economic losses in the poultry industry annually. As the component of anticoccidial vaccines, seven Eimeria spp. of chickens are characterized with potent immunogenicity. Whether genetically modified Eimeria spp. maintains this property or not needs to be verified. In this study, two identical transgenic lines of Eimeria tenella were developed by virtue of single sporocyst isolation from a stably transfected population expressing fused protein of M2 ectodomain of avian influenza virus (M2e) and enhanced yellow fluorescent protein (EYFP). The chromosomal integration and expression of M2e-EYFP were confirmed by Southern blot, plasmid rescue and Western blot analysis. We found that the reproduction of transgenic parasites was higher than that of the parental strain. Chickens challenged with wild type E. tenella after immunization with 200 oocysts of transgenic parasites had similar performance compared to those in non-immunized and non-challenged group. In another trial, the performance of transgenic parasite-immunized birds was also comparable to that of the Decoquinate Premix-treated chickens. These results suggest that this transgenic line of E. tenella is capable of inducing potent protection against homologous challenge as a live anticoccidial vaccine. Taking together, our study indicates that transgenic eimerian parasites have the potential to be developed as a vaccine vehicle for animal use in the future.

  13. Continuation maintenance therapy with S-1 in chemotherapy-naïve patients with advanced squamous cell lung cancer.

    PubMed

    Suzuki, Seiichiro; Karayama, Masato; Inui, Naoki; Fujisawa, Tomoyuki; Enomoto, Noriyuki; Nakamura, Yutaro; Kuroishi, Shigeki; Matsuda, Hiroyuki; Yokomura, Koshi; Koshimizu, Naoki; Toyoshima, Mikio; Imokawa, Shiro; Asada, Kazuhiro; Masuda, Masafumi; Yamada, Takashi; Watanabe, Hiroshi; Suda, Takafumi

    2016-08-01

    Objectives Maintenance therapy is a standard therapeutic strategy in non-squamous non-small-cell lung cancer. However, there is no consensus regarding the benefit of maintenance therapy for patients with squamous cell lung cancer. We assessed maintenance therapy with S-1, an oral fluoropyrimidine agent, following induction therapy with carboplatin and S-1 in patients with squamous cell lung cancer. Methods In this phase II trial, chemotherapy-naïve patients with squamous cell lung cancer were enrolled to induction therapy with four cycles of carboplatin (at an area under the curve of 5 on day 1) and S-1 (80 mg/m(2)/day on days 1-14) in a 28-day cycle. Patients who achieved disease control after induction therapy received maintenance therapy with S-1 in a 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival after administration of maintenance therapy. Results Fifty-one patients were enrolled in the study. The median progression-free survival from the start of maintenance therapy was 3.0 months (95 % confidence interval, 2.5-3.5). The most common toxicities associated with maintenance therapy were anemia, thrombocytopenia, and fatigue, but they were not severe. Conclusion S-1 maintenance therapy might be a feasible treatment option in patients with squamous cell lung cancer.

  14. Vanishing Str M2 in the presence of anomalous U A(1)

    NASA Astrophysics Data System (ADS)

    Lopez, Jorge L.; Nanopoulos, D. V.

    1996-02-01

    We show that the presence of an anomalous U A(1) factor in the gauge group of string-derived models may have the new and important phenomenological consequence of allowing the vanishing of Str M2 in the “shifted” vacuum that results in the process of cancelling the anomalous U A(1). The feasibility of this effect seems to be enhanced by a vanishing vacuum energy, and by a “small” value of Str M2 in the original vacuum. In the class of free-fermionic models with vanishing vacuum energy that we focus on, a necessary condition for this mechanism to be effective is that Str M2 > 0 in the original vacuum. A vanishing Str M2 ameliorates the cosmological constant problem and is a necessary element in the stability of the no-scale mechanism.

  15. Direct observation of the M2 phase with its Mott transition in a VO2 film

    NASA Astrophysics Data System (ADS)

    Kim, Hoon; Slusar, Tetiana V.; Wulferding, Dirk; Yang, Ilkyu; Cho, Jin-Cheol; Lee, Minkyung; Choi, Hee Cheul; Jeong, Yoon Hee; Kim, Hyun-Tak; Kim, Jeehoon

    2016-12-01

    In VO2, the explicit origin of the insulator-to-metal transition is still disputable between Peierls and Mott insulators. Along with the controversy, its second monoclinic (M2) phase has received considerable attention due to the presence of electron correlation in undimerized vanadium ions. However, the origin of the M2 phase is still obscure. Here, we study a granular VO2 film using conductive atomic force microscopy and Raman scattering. Upon the structural transition from monoclinic to rutile, we observe directly an intermediate state showing the coexistence of monoclinic M1 and M2 phases. The conductivity near the grain boundary in this regime is six times larger than that of the grain core, producing a donut-like landscape. Our results reveal an intra-grain percolation process, indicating that VO2 with the M2 phase is a Mott insulator.

  16. Effects of orbital and spin current interference in E1 and M2 nuclear excitations

    SciTech Connect

    Goncharova, N. G.

    2015-12-15

    The interference of contributions from the orbital and spin currents to the E1 and M2 resonances is investigated. The results of the current interference analysis within the shell model are compared with the experimental data.

  17. MIS M2 initiation and termination link to the shallow CAS open and close?

    NASA Astrophysics Data System (ADS)

    Tan, Ning; Ramstein, Gilles; Dumas, Christophe; Contoux, Camille

    2016-04-01

    The Marine Isotope Stage M2 (3.264 -3.312 Ma) occurred just prior to the well documented warm mid-Pliocene (mPWP). With a 0.5‰ benthic foraminiferal δ180 shift (Lisiecki and Raymo, 2005), MIS M2 is thought to be a glacial comparable period associated with huge but uncertain sea-level records of 20-60m below present levels (Naish et al. 2009; Miller et al. 2012; Dwyer et al. 2009). However, the mechanism of M2 initiation and termination are still an enigma, since CO2 records were relatively higher than the Quaternary glaciation period and the minima summer insolation during M2 was stronger than other glacial periods. By inferring from data records, De Schepper (2013) proposed that the shallow open Central American Seaway (CAS) observed during M2 could play as a trigger in M2 initiation, then the closure of this shallow CAS resulted from M2 large ice sheet build-up terminates this glacial period. But this assumption has not been test by the model. In this study, we apply IPSL-CM5A Atmosphere-Ocean coupled General Circulation Model (AOGCM) and GRISLI ice sheet model to investigate mechanisms of M2 initiation and termination. We firstly investigate the role of "shallow open CAS" (De Schepper et al. 2013) on M2 initiation. In the mean time we also take into account the main forcing during M2, which includes astronomical parameters, Greenhouse gases and vegetation. Our results show that shallow open CAS plays an important role in reducing northward heat transport in Atlantic low latitudes by 0.05 - 0.1 PW, but it is not a key factor in NH ice sheet build-up; Astronomical parameters and CO2 concentration are essential to create a basic global cooling environment for M2 (cooling by ~3.65 K than mPWP); Cold vegetation replacement amplifies the cooling in north high latitudes by ~ 8 K, which finally allows large ice sheet building up in Northern Hemisphere (12.25 m sea level drop is simulated with considering ice sheet feedback on the climate). The simulated ice sheet

  18. NASA SOFIA Captures Images of the Planetary Nebula M2-9

    NASA Image and Video Library

    2012-03-29

    Researchers using NASA Stratospheric Observatory for Infrared Astronomy SOFIA have captured infrared images of the last exhalations of a dying sun-like star. This image is of the planetary Nebula M2-9.

  19. Gut dysbiosis promotes M2 macrophage polarization and allergic airway inflammation via fungi-induced PGE₂.

    PubMed

    Kim, Yun-Gi; Udayanga, Kankanam Gamage Sanath; Totsuka, Naoya; Weinberg, Jason B; Núñez, Gabriel; Shibuya, Akira

    2014-01-15

    Although imbalances in gut microbiota composition, or "dysbiosis," are associated with many diseases, the effects of gut dysbiosis on host systemic physiology are less well characterized. We report that gut dysbiosis induced by antibiotic (Abx) treatment promotes allergic airway inflammation by shifting macrophage polarization in the lung toward the alternatively activated M2 phenotype. Adoptive transfer of alveolar macrophages derived from Abx-treated mice was sufficient to increase allergic airway inflammation. Abx treatment resulted in the overgrowth of a commensal fungal Candida species in the gut and increased plasma concentrations of prostaglandin E₂ (PGE₂), which induced M2 macrophage polarization in the lung. Suppression of PGE₂ synthesis by the cyclooxygenase inhibitors aspirin and celecoxib suppressed M2 macrophage polarization and decreased allergic airway inflammatory cell infiltration in Abx-treated mice. Thus, Abx treatment can cause overgrowth of particular fungal species in the gut and promote M2 macrophage activation at distant sites to influence systemic responses including allergic inflammation.

  20. Inhibition of Notch Signaling Attenuates Schistosomiasis Hepatic Fibrosis via Blocking Macrophage M2 Polarization

    PubMed Central

    Chen, Yixiong; Zheng, Shaojiang; Zheng, Liping; Weng, Zhihong

    2016-01-01

    Macrophages play a key role in the pathogenesis of liver granuloma and fibrosis in schistosomiasis. However, the underlying mechanisms have not been fully characterized. This study revealed that the macrophages infiltrating the liver tissues in a murine model of Schistosoma japonica infection exhibited M2 functional polarization, and Notch1/Jagged1 signaling was significantly upregulated in the M2 polarized macrophages in vivo and in vitro. Furthermore, the blockade of Notch signaling pathway by a γ–secretase inhibitor could reverse macrophage M2 polarization in vitro and alleviate liver granuloma and fibrosis in the murine model of schistosomiasis. These results implied that the Notch1/Jagged1 signaling-dependent M2 polarization of macrophages might play an important role in liver granuloma and fibrosis in schistosomiasis, and the inhibition of Notch1/Jagged1 signaling might provide a novel therapeutic approach to administrate patients with schistosomiasis. PMID:27875565

  1. Secular changes of the M2 tide in the Gulf of Maine

    NASA Technical Reports Server (NTRS)

    Ray, Richard D.

    2005-01-01

    Analyses of long time series of hourly tide-gauge data at four stations in the Gulf of Maine reveal that the amplitude of the M2 tide underwent a nearly linear secular increase throughout most of the twentieth century. In the early 1980s, however, the amplitude of M2 abruptly dropped. Sea level changes alone appear inadequate to explain either the long-term trend or the recent trend discontinuity. Tidal models that account for Holocene sea level rise do predict an amplification of M2, but much smaller than the currently observed trends. Nor do recent annual mean sea levels correlate with the recent trend discontinuity. Some unknown fraction of the open Atlantic may be similarly affected, since the M2 discontinuity, but not the long-term secular increase in the tide, is evident also at Halifax.

  2. Influenza virus A M2 protein generates negative Gaussian membrane curvature necessary for budding and scission

    PubMed Central

    Schmidt, Nathan W.; Mishra, Abhijit; Wang, Jun; DeGrado, William F.; Wong, Gerard C. L.

    2013-01-01

    The M2 protein is a multi-functional protein, which plays several roles in the replication cycle of the influenza A virus. Here we focus on its ability to promote budding of the mature virus from the cell surface. Using high resolution small angle X-ray scattering we show that M2 can restructure lipid membranes into bicontinuous cubic phases which are rich in negative Gaussian curvature (NGC). The active generation of negative Gaussian membrane curvature by M2 is essential to influenza virus budding. M2 has been observed to colocalize with the region of high NGC at the neck of a bud. The structural requirements for scission are even more stringent than those for budding, as the neck must be considerably smaller than the virus during ‘pinch off’. Consistent with this, the amount of NGC in the induced cubic phases suggests that M2 proteins can generate high curvatures comparable to those on a neck with size 10x smaller than a spherical influenza virus. Similar experiments on variant proteins containing different M2 domains show that the cytoplasmic amphipathic helix is necessary and sufficient for NGC generation. Mutations to the helix which reduce its amphiphilicity and are known to diminish budding attenuated NGC generation. An M2 construct comprising the membrane interactive domains, the transmembrane helix and the cytoplasmic helix, displayed enhanced ability to generate NGC, suggesting that other domains cooperatively promote membrane curvature. These studies establish the importance of M2-induced negative Gaussian curvature during budding and suggest that antagonizing this curvature is a viable anti-influenza strategy. PMID:23962302

  3. M1/M2-macrophage phenotypes regulate renal calcium oxalate crystal development

    PubMed Central

    Taguchi, Kazumi; Okada, Atsushi; Hamamoto, Shuzo; Unno, Rei; Moritoki, Yoshinobu; Ando, Ryosuke; Mizuno, Kentaro; Tozawa, Keiichi; Kohri, Kenjiro; Yasui, Takahiro

    2016-01-01

    In our previous report, M2-macrophage (Mφs) deficient mice showed increased renal calcium oxalate (CaOx) crystal formation; however, the role of Mφs-related-cytokines and chemokines that affect kidney stone formation remains unknown. Here, we investigated the role of M1/M2s in crystal development by using in vitro and in vivo approaches. The crystal phagocytic rate of bone marrow-derived M2Mφs was higher than that of bone marrow-derived Mφs and M1Mφs and increased on co-culture with renal tubular cells (RTCs). However, the amount of crystal attachment on RTCs reduced on co-culture with M2Mφs. In six hyperoxaluric C57BL/6J mice, M1Mφ transfusion and induction by LPS and IFN-γ facilitated renal crystal formation, whereas M2Mφ transfusion and induction by IL-4 and IL-13 suppressed renal crystal formation compared with the control. These M2Mφ treatments reduced the expression of crystal-related genes, such as osteopontin and CD44, whereas M1Mφ treatment increased the expression of pro-inflammatory and adhesion-related genes such as IL-6, inducible NOS, TNF-α, C3, and VCAM-1. The expression of M2Mφ-related genes was lower whereas that of M1Mφ-related genes was higher in papillary tissue of CaOx stone formers. Overall, our results suggest that renal crystal development is facilitated by M1Mφs, but suppressed by M2Mφs. PMID:27731368

  4. Organophosphorus Pesticides Decrease M2 Muscarinic Receptor Function in Guinea Pig Airway Nerves via Indirect Mechanisms

    PubMed Central

    Proskocil, Becky J.; Bruun, Donald A.; Thompson, Charles M.; Fryer, Allison D.; Lein, Pamela J.

    2010-01-01

    Background Epidemiological studies link organophosphorus pesticide (OP) exposures to asthma, and we have shown that the OPs chlorpyrifos, diazinon and parathion cause airway hyperreactivity in guinea pigs 24 hr after a single subcutaneous injection. OP-induced airway hyperreactivity involves M2 muscarinic receptor dysfunction on airway nerves independent of acetylcholinesterase (AChE) inhibition, but how OPs inhibit neuronal M2 receptors in airways is not known. In the central nervous system, OPs interact directly with neurons to alter muscarinic receptor function or expression; therefore, in this study we tested whether the OP parathion or its oxon metabolite, paraoxon, might decrease M2 receptor function on peripheral neurons via similar direct mechanisms. Methodology/Principal Findings Intravenous administration of paraoxon, but not parathion, caused acute frequency-dependent potentiation of vagally-induced bronchoconstriction and increased electrical field stimulation (EFS)-induced contractions in isolated trachea independent of AChE inhibition. However, paraoxon had no effect on vagally-induced bradycardia in intact guinea pigs or EFS-induced contractions in isolated ileum, suggesting mechanisms other than pharmacologic antagonism of M2 receptors. Paraoxon did not alter M2 receptor expression in cultured cells at the mRNA or protein level as determined by quantitative RT-PCR and radio-ligand binding assays, respectively. Additionally, a biotin-labeled fluorophosphonate, which was used as a probe to identify molecular targets phosphorylated by OPs, did not phosphorylate proteins in guinea pig cardiac membranes that were recognized by M2 receptor antibodies. Conclusions/Significance These data indicate that neither direct pharmacologic antagonism nor downregulated expression of M2 receptors contributes to OP inhibition of M2 function in airway nerves, adding to the growing evidence of non-cholinergic mechanisms of OP neurotoxicity. PMID:20479945

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

    PubMed Central

    Obuchowski, Michał; Nidzworski, Dawid

    2016-01-01

    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. PMID:27902762

  6. Immunization with the MAEBL M2 Domain Protects against Lethal Plasmodium yoelii Infection

    PubMed Central

    Leite, Juliana A.; Bargieri, Daniel Y.; Carvalho, Bruna O.; Albrecht, Letusa; Lopes, Stefanie C. P.; Kayano, Ana Carolina A. V.; Farias, Alessandro S.; Chia, Wan Ni; Claser, Carla; Malleret, Benoit; Russell, Bruce; Castiñeiras, Catarina; Santos, Leonilda M. B.; Brocchi, Marcelo; Wunderlich, Gerhard; Soares, Irene S.; Rodrigues, Mauricio M.; Rénia, Laurent

    2015-01-01

    Malaria remains a world-threatening disease largely because of the lack of a long-lasting and fully effective vaccine. MAEBL is a type 1 transmembrane molecule with a chimeric cysteine-rich ectodomain homologous to regions of the Duffy binding-like erythrocyte binding protein and apical membrane antigen 1 (AMA1) antigens. Although MAEBL does not appear to be essential for the survival of blood-stage forms, ectodomains M1 and M2, homologous to AMA1, seem to be involved in parasite attachment to erythrocytes, especially M2. MAEBL is necessary for sporozoite infection of mosquito salivary glands and is expressed in liver stages. Here, the Plasmodium yoelii MAEBL-M2 domain was expressed in a prokaryotic vector. C57BL/6J mice were immunized with doses of P. yoelii recombinant protein rPyM2-MAEBL. High levels of antibodies, with balanced IgG1 and IgG2c subclasses, were achieved. rPyM2-MAEBL antisera were capable of recognizing the native antigen. Anti-MAEBL antibodies recognized different MAEBL fragments expressed in CHO cells, showing stronger IgM and IgG responses to the M2 domain and repeat region, respectively. After a challenge with P. yoelii YM (lethal strain)-infected erythrocytes (IE), up to 90% of the immunized animals survived and a reduction of parasitemia was observed. Moreover, splenocytes harvested from immunized animals proliferated in a dose-dependent manner in the presence of rPyM2-MAEBL. Protection was highly dependent on CD4+, but not CD8+, T cells toward Th1. rPyM2-MAEBL antisera were also able to significantly inhibit parasite development, as observed in ex vivo P. yoelii erythrocyte invasion assays. Collectively, these findings support the use of MAEBL as a vaccine candidate and open perspectives to understand the mechanisms involved in protection. PMID:26169268

  7. A novel M2e based flu vaccine formulation for dogs.

    PubMed

    Leclerc, Denis; Rivest, Marie; Babin, Cindy; López-Macias, Constantino; Savard, Pierre

    2013-01-01

    The USA 2004 influenza virus outbreak H3N8 in dogs heralded the emergence of a new disease in this species. A new inactivated H3N8 vaccine was developed to control the spread of the disease but, as in humans and swine, it is anticipated that the virus will mutate shift and drift in the dog population. Therefore, there is a need for a vaccine that can trigger a broad protection to prevent the spread of the virus and the emergence of new strains. The universal M2e peptide is identical in almost all the H3N8 influenza strains sequenced to date and known to infect dogs. This epitope is therefore a good choice for development of a vaccine to provide broad protection. Malva mosaic virus (MaMV) nanoparticles were chosen as a vaccine platform to improve the stability of the M2e peptide and increase its immunogenicity in animals. The addition of an adjuvant (OmpC) purified from Salmonella typhi membrane in the vaccine formulation increased the immune response directed to the M2e peptide significantly and enlarged the protection to include the heterosubtypic strain of influenza in a mouse model. An optimal vaccine formulation was also shown to be immunogenic in dogs. The MaMV vaccine platform triggered an improved immune response directed towards the universal M2e peptide. The adjuvant OmpC increased the immune response to the M2e peptide and protection to a heterosubtypic influenza strain that harbors a different M2e peptide in a mouse model. Antibodies generated by the vaccine formulation showed cross-reactivity with M2e peptides derived from influenza strains H9N2, H5N1 and H1N1. The vaccine formulation shows a potential for commercialization of a new M2e based vaccine in dogs.

  8. A Novel M2e Based Flu Vaccine Formulation for Dogs

    PubMed Central

    Leclerc, Denis; Rivest, Marie; Babin, Cindy; López-Macias, Constantino; Savard, Pierre

    2013-01-01

    Background The USA 2004 influenza virus outbreak H3N8 in dogs heralded the emergence of a new disease in this species. A new inactivated H3N8 vaccine was developed to control the spread of the disease but, as in humans and swine, it is anticipated that the virus will mutate shift and drift in the dog population. Therefore, there is a need for a vaccine that can trigger a broad protection to prevent the spread of the virus and the emergence of new strains. Methodology and Principal Findings The universal M2e peptide is identical in almost all the H3N8 influenza strains sequenced to date and known to infect dogs. This epitope is therefore a good choice for development of a vaccine to provide broad protection. Malva mosaic virus (MaMV) nanoparticles were chosen as a vaccine platform to improve the stability of the M2e peptide and increase its immunogenicity in animals. The addition of an adjuvant (OmpC) purified from Salmonella typhi membrane in the vaccine formulation increased the immune response directed to the M2e peptide significantly and enlarged the protection to include the heterosubtypic strain of influenza in a mouse model. An optimal vaccine formulation was also shown to be immunogenic in dogs. Conclusions and Significance The MaMV vaccine platform triggered an improved immune response directed towards the universal M2e peptide. The adjuvant OmpC increased the immune response to the M2e peptide and protection to a heterosubtypic influenza strain that harbors a different M2e peptide in a mouse model. Antibodies generated by the vaccine formulation showed cross-reactivity with M2e peptides derived from influenza strains H9N2, H5N1 and H1N1. The vaccine formulation shows a potential for commercialization of a new M2e based vaccine in dogs. PMID:24098576

  9. [Combination Chemotherapy Using Oxaliplatin plus S-1 for Well-Advanced Gastric Cancer].

    PubMed

    Saito, Hiroyuki; Suematsu, Yuki; Yamagishi, Shunsuke; Takahashi, Miyuki; Nakayama, Mao; Fukabori, Michiko; Morita, Akihiko; Wakabayashi, Kazuhiko; Itoh, Yutaka

    2016-11-01

    We studied the clinical efficacy of pre-operative combination chemotherapy using S-1 plus oxaliplatin for advanced gastric cancer. Four patients hadclinical Stage IV disease, 1 patient had clinical Stage III C disease, 2 patients had clinical Stage III B disease, and 1 patient had clinical Stage III A disease. The patients received 2-8 courses of oxaliplatin(130mg/m2)on day 1, andS -1 on days 1-14 every 3 weeks. The response rate was 56%(5 PR, 1 PD, and2 SD), andthe disease control rate was 88%. Toxicities were Grade 2 anemia, Grade 1 peripheral neuropathy, Grade 1 fatigue, and anorexia. Five of the 8 patients underwent R0 surgery after SOX chemotherapy, and no severe complications occurred. Histological responses were Grade 3 for 2 cases, Grade 2 for 2 cases, andGrad e 1a for 1 case. The SOX regimen showeda high objective tumor response, andis one of the promising regimens in the neoadjuvant setting for well-advanced gastric cancer.

  10. Efficacy and safety of oxaliplatin, bevacizumab and oral S-1 for advanced recurrent colorectal cancer.

    PubMed

    Suzuki, Shuji; Shimazaki, Jiro; Morishita, Keiichi; Koike, Nobusada; Harada, Nobuhiko; Hayashi, Tsuneo; Suzuki, Mamoru

    2016-10-01

    The aim of this study was to evaluate the efficacy and safety of co-administration of oral S-1 and oxaliplatin (SOX) in combination with bevacizumab (bev) in patients with advanced recurrent colorectal cancer. A retrospective study of 36 patients with advanced recurrent colorectal cancer was performed, of whom 27 received first-line and 9 received second-line SOX+bev chemotherapy between 2010 and 2013 at the Hachioji Digestive Disease Hospital (Hachioji, Japan). The SOX+bev regimen consisted of administration of intravenous oxaliplatin (85 mg/m(2)) on days 1 and 14, bevacizumab (5 mg/kg) on day 1, and co-administration of oral S-1 twice daily on days 1-14. The drug regimen was repeated every 4 weeks. SOX+bev treatment was associated with a response rate of 45.2%, a disease control rate of 71%, and a median progression-free survival (PFS) and overall survival (OS) of 9.9 and 21.9 months, respectively. Patients who received first-line chemotherapy benefited from treatment in terms of prolonged PFS (13.8 months) and OS (28.2 months). Grade 3/4 adverse events were infrequent and included anaemia, thrombocytopenia, anorexia, diarrhea, sensory neuropathy, increased aspartate aminotransferase level and skin rash. In conclusion, SOX+bev therapy was found to be feasible and safe for patients with advanced and recurrent colorectal cancer.

  11. Colorectal cancer screening by non-invasive metabolic biomarker fecal tumor M2-PK.

    PubMed

    Tonus, Carolin; Neupert, Gero; Sellinger, Markus

    2006-11-21

    To evaluate the utility of the innovative fecal tumor M2-Pyruvate kinase (M2-PK) test in our daily clinical routine, as a marker for the pre-selection of patients who should subsequently undergo colonoscopy for the diagnosis or exclusion of colorectal cancer. Fecal tumor M2-PK was measured in stool samples of 96 study participants (33 patients with colorectal cancer, 21 patients with rectal carcinoma and 42 controls) who all underwent total colonoscopy. In 39 of 42 individuals in the control group, fecal tumor M2-PK was below 4.0 kU/L (93% specificity). Colorectal tumors were accompanied by a highly significant increase (P < 0.001) in fecal tumor M2-PK levels (median: colon carcinoma, 23.1 kU/L; rectal carcinoma, 6.9 kU/L; colorectal carcinoma, 14.7 kU/L), which correlated with Duke's staging and T-classification. The overall sensitivity was 78% for colorectal cancer, increasing from 60% for stage T1 to 100% for stage T4 and from 60% for Duke's A to 90% for Duke's D tumors. Fecal tumor M2-PK is an appropriately sensitive tool to pre-select those patients requiring colonoscopy for the further diagnostic confirmation or exclusion of colorectal cancer.

  12. Colorectal cancer screening by non-invasive metabolic biomarker fecal tumor M2-PK

    PubMed Central

    Tonus, Carolin; Neupert, Gero; Sellinger, Markus

    2006-01-01

    AIM: To evaluate the utility of the innovative fecal tumor M2-Pyruvate kinase (M2-PK) test in our daily clinical routine, as a marker for the pre-selection of patients who should subsequently undergo colonoscopy for the diagnosis or exclusion of colorectal cancer. METHODS: Fecal tumor M2-PK was measured in stool samples of 96 study participants (33 patients with colorectal cancer, 21 patients with rectal carcinoma and 42 controls) who all underwent total colonoscopy. RESULTS: In 39 of 42 individuals in the control group, fecal tumor M2-PK was below 4.0 kU/L (93% specificity). Colorectal tumors were accompanied by a highly significant increase (P < 0.001) in fecal tumor M2-PK levels (median: colon carcinoma, 23.1 kU/L; rectal carcinoma, 6.9 kU/L; colorectal carcinoma, 14.7 kU/L), which correlated with Duke’s staging and T-classification. The overall sensitivity was 78% for colorectal cancer, increasing from 60% for stage T1 to 100% for stage T4 and from 60% for Duke’s A to 90% for Duke’s D tumors. CONCLUSION: Fecal tumor M2-PK is an appropriately sensitive tool to pre-select those patients requiring colonoscopy for the further diagnostic confirmation or exclusion of colorectal cancer. PMID:17109496

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

    PubMed Central

    Chimal-Ramírez, G. Karina; Espinoza-Sánchez, Nancy Adriana; Chávez-Sánchez, Luis; Arriaga-Pizano, Lourdes

    2016-01-01

    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. PMID:27376091

  14. Influenza M2 envelope protein augments avian influenza hemagglutinin pseudotyping of lentiviral vectors.

    PubMed

    McKay, T; Patel, M; Pickles, R J; Johnson, L G; Olsen, J C

    2006-04-01

    Lentivirus-based gene transfer has the potential to efficiently deliver DNA-based therapies into non-dividing epithelial cells of the airway for the treatment of lung diseases such as cystic fibrosis. However, significant barriers both to lung-specific gene transfer and to production of lentivirus vectors must be overcome before these vectors can be routinely used for applications to the lung. In this study, we investigated whether the ability to produce lentiviral vectors pseudotyped with fowl plague virus hemagglutinin (HA) could be improved by co-expression of influenza virus M2 in vector-producing cells. We found that M2 expression led to a 10-30-fold increase in production of HA-pseudotyped lentivirus vectors based upon equine infectious anemia virus (EIAV) or human immunodeficiency virus type 1 (HIV-1). Experiments using the M2 inhibitor amantadine and a drug-resistant mutant of M2 established that the ion channel activity of M2 was important for M2-dependent augmentation of vector production. Furthermore, the neuraminidase activity necessary for particle release from producer cells could also be incorporated into producer cells by co-expression of influenza NA cDNA. Lentiviral vectors pseudotyped with influenza envelope proteins were able to efficiently transduce via the apical membrane of polarized mouse tracheal cultures in vitro as well as mouse tracheal epithelia in vivo.

  15. Muscarinic cholinergic receptor (M2) plays a crucial role in the development of myopia in mice.

    PubMed

    Barathi, Veluchamy A; Kwan, Jia Lin; Tan, Queenie S W; Weon, Sung Rhan; Seet, Li Fong; Goh, Liang Kee; Vithana, Eranga N; Beuerman, Roger W

    2013-09-01

    Myopia is a huge public health problem worldwide, reaching the highest incidence in Asia. Identification of susceptible genes is crucial for understanding the biological basis of myopia. In this paper, we have identified and characterized a functional myopia-associated gene using a specific mouse-knockout model. Mice lacking the muscarinic cholinergic receptor gene (M2; also known as Chrm2) were less susceptible to lens-induced myopia compared with wild-type mice, which showed significantly increased axial length and vitreous chamber depth when undergoing experimental induction of myopia. The key findings of this present study are that the sclera of M2 mutant mice has higher expression of collagen type I and lower expression of collagen type V than do wild-type mice and mice that are mutant for other muscarinic subtypes, and, therefore, M2 mutant mice were resistant to the development of experimental myopia. Pharmacological blockade of M2 muscarinic receptor proteins retarded myopia progression in the mouse. These results suggest for the first time a role of M2 in growth-related changes in extracellular matrix genes during myopia development in a mammalian model. M2 receptor antagonists might thus provide a targeted therapeutic approach to the management of this refractive error.

  16. Ozone-induced loss of neuronal M2 muscarinic receptor function is prevented by cyclophosphamide.

    PubMed

    Gambone, L M; Elbon, C L; Fryer, A D

    1994-09-01

    We tested the hypothesis that inflammatory cells mediate the loss of neuronal M2 muscarinic receptors in the lung after ozone exposure. Pathogen-free guinea pigs treated with cyclophosphamide (30 mg.kg-1.day-1 i.p. for 7 days) before exposure to ozone were compared with untreated ozone-exposed animals. This dose of cyclophosphamide significantly reduced leukocytes in peripheral blood and bronchoalveolar lavage fluid. Twenty-four hours after ozone, muscarinic receptor function was tested in anesthetized animals. In air-exposed guinea pigs, vagally induced bronchoconstriction was attenuated by the muscarinic agonist pilocarpine (0.1-100 micrograms/kg i.v.) and potentiated by the selective M2 antagonist gallamine (0.1-10 mg/kg i.v.), indicating that the neuronal M2 muscarinic receptors were functioning. These responses were significantly reduced after ozone, indicating loss of neuronal M2 muscarinic receptor function. However, in those animals treated with cyclophosphamide, M2 muscarinic receptor function was not altered by ozone. These data suggest that ozone-induced loss of neuronal muscarinic receptor function is mediated via inflammatory cells and that the link between ozone-induced hyperresponsiveness and inflammation may be the neuronal M2 muscarinic receptor.

  17. Muscarinic cholinergic receptor (M2) plays a crucial role in the development of myopia in mice

    PubMed Central

    Barathi, Veluchamy A.; Kwan, Jia Lin; Tan, Queenie S. W.; Weon, Sung Rhan; Seet, Li Fong; Goh, Liang Kee; Vithana, Eranga N.; Beuerman, Roger W.

    2013-01-01

    SUMMARY Myopia is a huge public health problem worldwide, reaching the highest incidence in Asia. Identification of susceptible genes is crucial for understanding the biological basis of myopia. In this paper, we have identified and characterized a functional myopia-associated gene using a specific mouse-knockout model. Mice lacking the muscarinic cholinergic receptor gene (M2; also known as Chrm2) were less susceptible to lens-induced myopia compared with wild-type mice, which showed significantly increased axial length and vitreous chamber depth when undergoing experimental induction of myopia. The key findings of this present study are that the sclera of M2 mutant mice has higher expression of collagen type I and lower expression of collagen type V than do wild-type mice and mice that are mutant for other muscarinic subtypes, and, therefore, M2 mutant mice were resistant to the development of experimental myopia. Pharmacological blockade of M2 muscarinic receptor proteins retarded myopia progression in the mouse. These results suggest for the first time a role of M2 in growth-related changes in extracellular matrix genes during myopia development in a mammalian model. M2 receptor antagonists might thus provide a targeted therapeutic approach to the management of this refractive error. PMID:23649821

  18. Opposite Effects of M1 and M2 Macrophage Subtypes on Lung Cancer Progression.

    PubMed

    Yuan, Ang; Hsiao, Yi-Jing; Chen, Hsuan-Yu; Chen, Huei-Wen; Ho, Chao-Chi; Chen, Yu-Yun; Liu, Yi-Chia; Hong, Tsai-Hsia; Yu, Sung-Liang; Chen, Jeremy J W; Yang, Pan-Chyr

    2015-09-24

    Macrophages in a tumor microenvironment have been characterized as M1- and M2-polarized subtypes. Here, we discovered the different macrophages' impacts on lung cancer cell A549. The M2a/M2c subtypes promoted A549 invasion and xenograft tumor growth. The M1 subtype suppressed angiogenesis. M1 enhanced the sensitivity of A549 to cisplatin and decreased the tube formation activity and cell viability of A549 cells by inducing apoptosis and senescence. Different macrophage subtypes regulated genes involved in the immune response, cytoskeletal remodeling, coagulation, cell adhesion, and apoptosis pathways in A549 cells, which was a pattern that correlated with the altered behaviors of the A549 cells. Furthermore, we found that the identified M1/M2 gene signatures were significantly correlated with the extended overall survival of lung cancer patients. These results suggest that M1/M2 gene expression signature may be used as a prognostic indicator for lung cancer patients, and M1/M2 polarization may be a target of investigation of immune-modulating therapies for lung cancer in the future.

  19. Phase I study of orally administered S-1 in combination with epirubicin and oxaliplatin in patients with advanced solid tumors and chemotherapy-naïve advanced or metastatic esophagogastric cancer.

    PubMed

    Moehler, Markus; Mahlberg, Rolf; Heinemann, Volker; Obermannová, Radka; Kubala, Eugen; Melichar, Bohuslav; Weinmann, Arndt; Scigalla, Paul; Tesařová, Marietta; Janda, Petr; Hédouin-Biville, Fabienne; Mansoor, Wasat

    2017-03-01

    This phase I study investigated the safety and the maximum tolerated dose (MTD) of the oral fluoropyrimidine S-1 when combined with epirubicin and oxaliplatin (EOS). Patients aged ≥18 years with advanced or metastatic solid tumors were enrolled in a 3 + 3 design with S-1 dose escalation (two planned cohorts) performed according to the occurrence of dose-limiting toxicity (DLT). On day 1 of each 21-day cycle, patients received epirubicin 50 mg/m(2) followed by oxaliplatin 130 mg/m(2) (maximum 8 cycles) and then S-1 [20 mg/m(2) (cohort 1) or 25 mg/m(2) (cohort 2), twice daily]: first dose, evening of day 1; subsequent administration on days 2-14, twice daily; last dose, morning of day 15 (unlimited number of S-1 cycles). After protocol amendment, enrollment in a third cohort was restricted to patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer. DLT was reported for two of the five patients in cohort 2, defining 20 mg/m(2) twice daily as the MTD of S-1 combined with epirubicin and oxaliplatin in heavily pretreated patients. Thirteen patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer were subsequently enrolled and treated at an S-1 dose level of 25 mg/m(2) twice daily; no DLTs were reported; median overall survival was 13.1 months. Of the 11 evaluable patients, three (27 %) had partial responses and seven (64 %) had stable disease. The safety profile was in line with expectations. The promising activity of EOS (S-1 dose level, 25 mg/m(2) twice daily) and acceptable safety profile support further clinical development of this combination for the first-line treatment of patients with advanced or metastatic esophagogastric cancer.

  20. STS-112 S1 Truss Payload arrives at KSC

    NASA Technical Reports Server (NTRS)

    1999-01-01

    KENNEDY SPACE CENTER, FLA. -- Inside the Operations and Checkout Building, a strongback is lowered toward the S1 truss below it in order to lift the truss from the Guppy cargo carrier that protected it during flight and transfer. Manufactured by the Boeing Co. in Huntington Beach, Calif., this component of the International Space Station is the first starboard (right-side) truss segment, whose main job is providing structural support for the orbiting research facility's radiator panels that cool the Space Station's complex power system. The S1 truss segment also will house communications systems, external experiment positions and other subsystems. Primarily constructed of aluminum, the truss segment is 45 feet long, 15 feet wide and 6 feet tall. When full y outfitted, it will weigh 31,137 pounds. The truss is slated for flight in 2001

  1. STS-112 S1 Truss Payload arrives at KSC

    NASA Technical Reports Server (NTRS)

    1999-01-01

    KENNEDY SPACE CENTER, FLA. -- Inside the Operations and Checkout Building, a strongback lifts the S1 truss from the Guppy cargo carrier that protected it during flight and transfer. Manufactured by the Boeing Co. in Huntington Beach, Calif., this component of the International Space Station is the first starboard (right-side) truss segment, whose main job is providing structural support for the orbiting research facility's radiator panels that cool the Space Station's complex power system. The S1 truss se gment also will house communications systems, external experiment positions and other subsystems. Primarily constructed of aluminum, the truss segment is 45 feet long, 15 feet wide and 6 feet tall. When fully outfitted, it will weigh 31,137 pounds. The tr uss is slated for flight in 2001

  2. STS-112 S1 Truss Payload arrives at KSC

    NASA Technical Reports Server (NTRS)

    1999-01-01

    KENNEDY SPACE CENTER, FLA. -- A KSC transporter moves the Guppy cargo carrier encasing the S1 truss into the Operations and Checkout Building. Manufactured by the Boeing Co. in Huntington Beach, Calif., this component of the International Space Station is the first starboard (right-side) truss segment, whose main job is providing structural support for the orbiting research facility's radiator panels that cool the Space Station's complex power system. The S1 truss segment also will house communications systems, external experiment positions and other subsystems. Primarily constructed of aluminum, the truss segment is 45 feet long, 15 feet wide and 6 feet tall. When fully outfitted, it will weigh 31,137 pounds. The truss is slated for flight in 2001.

  3. STS-112 S1 Truss Payload arrives at KSC

    NASA Technical Reports Server (NTRS)

    1999-01-01

    KENNEDY SPACE CENTER, FLA. -- Inside the Operations and Checkout Building, the top of the Guppy cargo carrier is lifted off the S1 truss (background). Manufactured by the Boeing Co. in Huntington Beach, Calif., this component of the International Space Station is the first starboard (right-side) truss segment, whose main job is providing structural support for the orbiting research facility's radiator panels that cool the Space Station's complex power system. The S1 truss segment also will house communica tions systems, external experiment positions and other subsystems. Primarily constructed of aluminum, the truss segment is 45 feet long, 15 feet wide and 6 feet tall. When fully outfitted, it will weigh 31,137 pounds. The truss is slated for flight in 200 1

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

    PubMed

    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. EVA 1 - MS Wolf and Sellers on S1 truss

    NASA Image and Video Library

    2002-10-10

    STS112-E-05123 (10 October 2002) --- Astronaut David A. Wolf, STS-112 mission specialist, anchored to the end of the Canadarm2, works on the Starboard One (S1) Truss, newly installed on the International Space Station (ISS). Astronaut Piers J. Sellers (partially obscured), mission specialist, worked in tandem with Wolf during the spacewalk. STS-112’s first session of extravehicular activity (EVA) lasted 7 hours and 1 minute.

  6. EVA 1 - MS Wolf on S1 truss

    NASA Image and Video Library

    2002-10-10

    STS112-E-05118 (10 October 2002) --- Astronaut David A. Wolf, STS-112 mission specialist, works on the Starboard One (S1) Truss, newly installed on the International Space Station (ISS). Astronaut Piers J. Sellers (out of frame), mission specialist, worked in tandem with Wolf during the spacewalk. STS-112’s first session of extravehicular activity (EVA) lasted 7 hours and 1 minute.

  7. The Global S_1 Tide in Earth's Nutation

    NASA Astrophysics Data System (ADS)

    Schindelegger, Michael; Einšpigel, David; Salstein, David; Böhm, Johannes

    2016-05-01

    Diurnal S_1 tidal oscillations in the coupled atmosphere-ocean system induce small perturbations of Earth's prograde annual nutation, but matching geophysical model estimates of this Sun-synchronous rotation signal with the observed effect in geodetic Very Long Baseline Interferometry (VLBI) data has thus far been elusive. The present study assesses the problem from a geophysical model perspective, using four modern-day atmospheric assimilation systems and a consistently forced barotropic ocean model that dissipates its energy excess in the global abyssal ocean through a parameterized tidal conversion scheme. The use of contemporary meteorological data does, however, not guarantee accurate nutation estimates per se; two of the probed datasets produce atmosphere-ocean-driven S_1 terms that deviate by more than 30 μ as (microarcseconds) from the VLBI-observed harmonic of -16.2+i113.4 μ as. Partial deficiencies of these models in the diurnal band are also borne out by a validation of the air pressure tide against barometric in situ estimates as well as comparisons of simulated sea surface elevations with a global network of S_1 tide gauge determinations. Credence is lent to the global S_1 tide derived from the Modern-Era Retrospective Analysis for Research and Applications (MERRA) and the operational model of the European Centre for Medium-Range Weather Forecasts (ECMWF). When averaged over a temporal range of 2004 to 2013, their nutation contributions are estimated to be -8.0+i106.0 μ as (MERRA) and -9.4+i121.8 μ as (ECMWF operational), thus being virtually equivalent with the VLBI estimate. This remarkably close agreement will likely aid forthcoming nutation theories in their unambiguous a priori account of Earth's prograde annual celestial motion.

  8. Prediction of M2 tidal surface currents by a global baroclinic ocean model and evaluation using observed drifter trajectories

    NASA Astrophysics Data System (ADS)

    Kodaira, Tsubasa; Thompson, Keith R.; Bernier, Natacha B.

    2016-08-01

    Global M2 tidal surface currents are predicted using a global baroclinic ocean model with horizontal grid spacing of 1/12° and 19 z-levels in the vertical. After first showing the predicted tidal elevations are in reasonable agreement with observations made by bottom pressure recorders and altimeters, the predicted tidal surface currents are evaluated by comparing them with independent estimates based on observed drifter trajectories. Both predicted and observed tidal surface currents can exceed 0.1 m s-1 in the deep ocean. Internal tides are shown to make a significant contribution to the predicted tidal surface currents. Phase locking of the surface and internal tides causes spatial changes in the predicted tidal surface currents that vary with approximately the same wavenumber as that of the lowest mode internal tide. Qualitatively similar, small-scale variations are also detected in the observed estimates but the variations do not line up exactly with the predictions. Possible explanations for the mismatch are given. The seasonal variation of M2 tidal surface currents, and the energy conversion rate from surface to internal tides, is also predicted by initializing, and restoring, the model to an observed seasonal climatology of temperature and salinity. Compared to tidal elevation, the seasonal change of tidal surface current can be large (order 10% for each hemisphere). It is caused by seasonal variations in the vertical structure of the baroclinic modes and the energy conversion rate. In the vicinity of major bathymetric features, the seasonal variation of second and higher order modes can be much larger (up to 50%).

  9. Angular momentum budget of the radiational S1 ocean tide

    NASA Astrophysics Data System (ADS)

    Schindelegger, Michael; Dobslaw, Henryk; Poropat, Lea; Salstein, David; Böhm, Johannes

    2016-04-01

    The balance of diurnal S1 oceanic angular momentum (OAM) variations through torques at the sea surface and the bottom topography is validated using both a barotropic and a baroclinic numerical tide model. This analysis discloses the extent to which atmosphere-driven S1 forward simulations are reliable for use in studies of high-frequency polar motion and changes in length-of-day. Viscous and dissipative torques associated with wind stress, bottom friction, as well as internal tidal energy conversion are shown to be small, and they are overshadowed by gravitational and pressure-related interaction forces. In particular, the zonal OAM variability of S1 is almost completely balanced by the water pressure torque on the local bathymetry, whereas in the prograde equatorial case also the air pressure torque on the seafloor as well as ellipsoidal contributions from the non-spherical atmosphere and solid Earth must be taken into account. Overall, the OAM budget is well closed in both the axial and the equatorial directions, thus allowing for an identification of the main diurnal angular momentum sinks in the ocean. The physical interaction forces are found to be largest at shelf breaks and continental slopes in low latitudes, with the most dominant contribution coming from the Indonesian archipelago.

  10. Search for ammonia in comet C/2012 S1 (ISON)

    NASA Astrophysics Data System (ADS)

    Faggi, S.; Codella, C.; Tozzi, G. P.; Comoretto, G.; Crovisier, J.; Nesti, R.; Panella, D.; Boissier, J.; Brucato, J. R.; Bolli, P.; Massi, F.; Tofani, G.

    2015-12-01

    Comets are uniquely pristine bodies providing unique insights about the formation of our Solar System. In this work, we focus on a dynamically new comet as it enters the inner Solar System for the first time after residing for billion of years in the Oort Cloud. Such comets are particularly important because they are thought to be not differentiated by solar radiation and they are supposed to have a large quantity of organic matter close to the surface. Here we report the results of a search for NH3(1,1) emission at 23.7 GHz towards comet C/2012 S1 (ISON) using a new dual-feed K band receiver mounted on the Medicina 32-m antenna. We observed the comet close to its perihelion, from 25 to 29 November 2013, when its heliocentric distance changed from 0.25 AU to 0.03 AU. We derive an upper limit of Q(NH3) of about 2.5×1029 mol s-1 on 26 November, that is consistent with the last peak of water production rate of ∼2×1030 mol s-1 within the last few days before the perihelion.

  11. The global S1 tide and Earth's nutation

    NASA Astrophysics Data System (ADS)

    Schindelegger, M.; Böhm, J.; Salstein, D. A.

    2015-08-01

    Diurnal S1 tidal atmospheric oscillations induced by the cyclic heating of air masses through solar radiation elicit a small contribution to Earth's prograde annual nutation at a level of 100 μas (microarcseconds). Previously published estimates of this Sun-synchronous perturbation based on angular momentum series from global geophysical fluid models have however diverged, and within the present conventional nutation theory, the effect has been instead accounted for in an empirical manner based on analyzing residual spectra of observed celestial pole offsets. This study constitutes a first, tentative reassessment of the S1 signal in nutation by resorting to modern-day atmospheric reanalyses as well as available hydrodynamic solutions for diurnal oceanic angular momentum changes that are driven by daily air pressure variations at the water surface. We elucidate the global character of the S1 tide with particular regard to Earth rotation variations and investigate to which extent atmospheric and oceanic excitation terms from various sources can be superimposed. The combined influence of the principal diurnal tide on Earth's nutation, associated with both atmosphere and ocean dynamics, is found to yield a sound agreement with its observational evidence from geodetic VLBI (Very Long Baseline Interferometry) measurements.

  12. Osmo-, Thermo- and Ethanol- Tolerances of Saccharomyces cerevisiae S1

    PubMed Central

    Balakumar, Sandrasegarampillai; Arasaratnam, Vasanthy

    2012-01-01

    Saccharomyces cerevisiae S1, which is a locally isolated and improved strain showed viability at 40, 45 and 50°C and produced ethanol at 40, 43 and 45°C. When the cells were given heat shock at 45°C for 30min and grown at 40°C, 100% viability was observed for 60h, and addition of 200gL−1 ethanol has led to complete cell death at 30h. Heat shock given at 45°C (for 30min) has improved the tolerance to temperature induced ethanol shock leading to 37% viability at 30h. When the cells were subjected to ethanol (200gL−1 for 30 min) and osmotic shock (sorbitol 300gL−1), trehalose contents in the cells were increased. The heat shocked cells showed better viability in presence of added ethanol. Soy flour supplementation has improved the viability of S. cerevisiae S1 to 80% in presence of 100gL−1 added ethanol and to 60% in presence of 300gL−1sorbitol. In presence of sorbitol (200gL−1) and ethanol (50gL−1) at 40°C, 46% viability was retained by S. cerevisiae S1 at 48h and it was improved to 80% by soy flour supplementation. PMID:24031814

  13. Internalization and down-regulation of human muscarinic acetylcholine receptor m2 subtypes. Role of third intracellular m2 loop and G protein-coupled receptor kinase 2.

    PubMed

    Tsuga, H; Kameyama, K; Haga, T; Honma, T; Lameh, J; Sadée, W

    1998-02-27

    Internalization and down-regulation of human muscarinic acetylcholine m2 receptors (hm2 receptors) and a hm2 receptor mutant lacking a central part of the third intracellular loop (I3-del m2 receptor) were examined in Chinese hamster ovary (CHO-K1) cells stably expressing these receptors and G protein-coupled receptor kinase 2 (GRK2). Agonist-induced internalization of up to 80-90% of hm2 receptors was demonstrated by measuring loss of [3H]N-methylscopolamine binding sites from the cell surface, and transfer of [3H]quinuclidinyl benzilate binding sites from the plasma membrane into the light-vesicle fractions separated by sucrose density gradient centrifugation. Additionally, translocation of hm2 receptors with endocytic vesicles were visualized by immunofluorescence confocal microscopy. Agonist-induced down-regulation of up to 60-70% of hm2 receptors was demonstrated by determining the loss of [3H]quinuclidinyl benzilate binding sites in the cells. The half-time (t1/2) of internalization and down-regulation in the presence of 10(-4) M carbamylcholine was estimated to be 9.5 min and 2.3 h, respectively. The rates of both internalization and down-regulation of hm2 receptors in the presence of 10(-6) M or lower concentrations of carbamylcholine were markedly increased by coexpression of GRK2. Agonist-induced internalization of I3-del m2 receptors was barely detectable upon incubation of cells for 1 h, but agonist-induced down-regulation of up to 40-50% of I3-del m2 receptors occurred upon incubation with 10(-4) M carbamylcholine for 16 h. However, the rate of down-regulation was lower compared with wild type receptors (t1/2 = 9.9 versus 2.3 h). These results indicate that rapid internalization of hm2 receptors is facilitated by their phosphorylation with GRK2 and does not occur in the absence of the third intracellular loop, but down-regulation of hm2 receptors may occur through both GRK2-facilitating pathway and third intracellular loop-independent pathways.

  14. Interleukin-1β Mediates Virus-Induced M2 Muscarinic Receptor Dysfunction and Airway Hyperreactivity

    PubMed Central

    Rynko, Abby E.; Fryer, Allison D.

    2014-01-01

    Respiratory viral infections are associated with the majority of asthma attacks. Inhibitory M2 receptors on parasympathetic nerves, which normally limit acetylcholine (ACh) release, are dysfunctional after respiratory viral infection. Because IL-1β is up-regulated during respiratory viral infections, we investigated whether IL-1β mediates M2 receptor dysfunction during parainfluenza virus infection. Virus-infected guinea pigs were pretreated with the IL-1β antagonist anakinra. In the absence of anakinra, viral infection increased bronchoconstriction in response to vagal stimulation but not to intravenous ACh, and neuronal M2 muscarinic receptors were dysfunctional. Pretreatment with anakinra prevented virus-induced increased bronchoconstriction and M2 receptor dysfunction. Anakinra did not change smooth muscle M3 muscarinic receptor response to ACh, lung viral loads, or blood and bronchoalveolar lavage leukocyte populations. Respiratory virus infection decreased M2 receptor mRNA expression in parasympathetic ganglia extracted from infected animals, and this was prevented by blocking IL-1β or TNF-α. Treatment of SK-N-SH neuroblastoma cells or primary cultures of guinea pig parasympathetic neurons with IL-1β directly decreased M2 receptor mRNA, and this was not synergistic with TNF-α treatment. Treating guinea pig trachea segment with TNF-α or IL-1β in vitro increased tracheal contractions in response to activation of airway nerves by electrical field stimulation. Blocking IL-1β during TNF-α treatment prevented this hyperresponsiveness. These data show that virus-induced hyperreactivity and M2 dysfunction involves IL-1β and TNF-α, likely in sequence with TNF-α causing production of IL-1β. PMID:24735073

  15. Lipopolysaccharide preconditioning facilitates M2 activation of resident microglia after spinal cord injury.

    PubMed

    Hayakawa, Kentaro; Okazaki, Rentaro; Morioka, Kazuhito; Nakamura, Kozo; Tanaka, Sakae; Ogata, Toru

    2014-12-01

    The inflammatory response following spinal cord injury (SCI) has both harmful and beneficial effects; however, it can be modulated for therapeutic benefit. Endotoxin/lipopolysaccharide (LPS) preconditioning, a well-established method for modifying the immune reaction, has been shown to attenuate damage induced by stroke and brain trauma in rodent models. Although such effects likely are conveyed by tissue-repairing functions of the inflammatory response, the mechanisms that control the effects have not yet been elucidated. The present study preconditioned C57BL6/J mice with 0.05 mg/kg of LPS 48 hr before inducing contusion SCI to investigate the effect of LPS preconditioning on the activation of macrophages/microglia. We found that LPS preconditioning promotes the polarization of M1/M2 macrophages/microglia toward an M2 phenotype in the injured spinal cord on quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemical analyses. Flow cytometric analyses reveal that LPS preconditioning facilitates M2 activation in resident microglia but not in infiltrating macrophages. Augmented M2 activation was accompanied by vascularization around the injured lesion, resulting in improvement in both tissue reorganization and functional recovery. Furthermore, we found that M2 activation induced by LPS preconditioning is regulated by interleukin-10 gene expression, which was preceded by the transcriptional activation of interferon regulatory factor (IRF)-3, as demonstrated by Western blotting and an IRF-3 binding assay. Altogether, our findings demonstrate that LPS preconditioning has a therapeutic effect on SCI through the modulation of M1/M2 polarization of resident microglia. The present study suggests that controlling M1/M2 polarization through endotoxin signal transduction could become a promising therapeutic strategy for various central nervous system diseases. © 2014 Wiley Periodicals, Inc.

  16. Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages.

    PubMed

    Satoh, Takashi; Kidoya, Hiroyasu; Naito, Hisamichi; Yamamoto, Masahiro; Takemura, Naoki; Nakagawa, Katsuhiro; Yoshioka, Yoshichika; Morii, Eiichi; Takakura, Nobuyuki; Takeuchi, Osamu; Akira, Shizuo

    2013-03-28

    Macrophages consist of at least two subgroups, M1 and M2 (refs 1-3). Whereas M1 macrophages are proinflammatory and have a central role in host defence against bacterial and viral infections, M2 macrophages are associated with responses to anti-inflammatory reactions, helminth infection, tissue remodelling, fibrosis and tumour progression. Trib1 is an adaptor protein involved in protein degradation by interacting with COP1 ubiquitin ligase. Genome-wide association studies in humans have implicated TRIB1 in lipid metabolism. Here we show that Trib1 is critical for the differentiation of F4/80(+)MR(+) tissue-resident macrophages--that share characteristics with M2 macrophages (which we term M2-like macrophages)--and eosinophils but not for the differentiation of M1 myeloid cells. Trib1 deficiency results in a severe reduction of M2-like macrophages in various organs, including bone marrow, spleen, lung and adipose tissues. Aberrant expression of C/EBPα in Trib1-deficient bone marrow cells is responsible for the defects in macrophage differentiation. Unexpectedly, mice lacking Trib1 in haematopoietic cells show diminished adipose tissue mass accompanied by evidence of increased lipolysis, even when fed a normal diet. Supplementation of M2-like macrophages rescues the pathophysiology, indicating that a lack of these macrophages is the cause of lipolysis. In response to a high-fat diet, mice lacking Trib1 in haematopoietic cells develop hypertriglyceridaemia and insulin resistance, together with increased proinflammatory cytokine gene induction. Collectively, these results demonstrate that Trib1 is critical for adipose tissue maintenance and suppression of metabolic disorders by controlling the differentiation of tissue-resident M2-like macrophages.

  17. Expression patterns of ubiquitin conjugating enzyme UbcM2 during mouse embryonic development.

    PubMed

    Yanjiang, Xing; Hongjuan, He; Tiantian, Gu; Yan, Zhang; Zhijun, Huang; Qiong, Wu

    2012-01-01

    Ubiquitin conjugating enzyme UbcM2 (Ubiquitin-conjugating enzymes from Mice, the number reveals the identification order) has been implicated in many critical processes, such like growth-inhibiting, mediating cell proliferation and regulation of some transcription factor, but the expression profile during mouse embryo development remains unclear. Hereby, during mid-later embryonic stage, the expression patterns of UbcM2 were examined using in situ hybridization and quantitative real-time PCR (qRT-PCR). The signals were significantly intense in central nervous system and skeletal system, weak in tongue, heart, lung, liver, and kidney. In the central nervous system, UbcM2 was principally expressed in thalamus, external germinal layer of cerebellum (EGL), mitral cell layer of olfactory bulb, hippocampus, marginal zone and ventricular zone of cerebral cortex, and spinal cord. In the skeletal system, UbcM2 was primarily expressed in proliferating cartilage. Furthermore, qRT-PCR analysis displayed that the expression of UbcM2 was ubiquitous at E15.5, most prominent in brain, weaker in lung liver and kidney, accompanied by the lowest level in tongue and heart. During brain development, the expression level of UbcM2 first ascended and then decreased from E12.5 to E18.5, the peak of which sustained starting at E14.5 until E16.5. Together, these results suggest that UbcM2 may play potential roles in the development of mouse diverse tissues and organs, particularly in the development of brain and skeleton.

  18. M2 macrophages induce EMT through the TGF-β/Smad2 signaling pathway.

    PubMed

    Zhu, Liangying; Fu, Xiao; Chen, Xiang; Han, Xiaodong; Dong, Ping

    2017-09-01

    IPF is characterized by fibroblast accumulation, collagen deposition, and ECM remodeling, with myofibroblasts believed to be the effector cell type. Myofibroblasts develop due to EMT of lung alveolar epithelial cells, which can be induced by TGF-β. M2 macrophages, a macrophage subpopulation, secrete large amounts of TGF-β. To clarify the relationship between IPF, EMT, TGF-β, and M2 macrophages, a bleomycin-induced pulmonary fibrosis mouse model was used. Seventeen days after mice were treated with bleomycin, the successful establishment of a pulmonary fibrosis model was confirmed by HE stain and Masson's trichrome stain. We found evidence in support of EMT, such as elevated protein levels of α-SMA in lung tissue and decreased levels of E-cadherin and CK-18. Additionally, increased TGF-β levels and TGF-β/Smad2 signaling activation was observed. Macrophages were recruited to pulmonary alveoli. Alveolar macrophages were phenotyped and identified as M2 macrophages, with up-regulated CD206 on the cell surfaces. For in vitro studies, we treated RAW 264.7 cells with IL-4 for 24 h, and the cells were then utilized as M2 macrophages. TGF-β levels increased significantly in the culture supernatant. Forty-eight hours after lung epithelial cells (MLE-12) were co-cultured with the M2 macrophages, the expression of α-SMA increased, and E-cadherin and CK-18 decreased. When a TGF-β receptor inhibitor, LY2109761 was used, the EMT induced by M2 macrophages was blocked. In conclusion, we demonstrated that M2 macrophages induce EMT through the TGF-β/Smad2 signaling pathway. © 2017 International Federation for Cell Biology.

  19. Health-related quality of life in a randomised phase III study of gemcitabine plus S-1, S-1 alone and gemcitabine alone for locally advanced or metastatic pancreatic cancer: GEST study.

    PubMed

    Hagiwara, Yasuhiro; Ohashi, Yasuo; Okusaka, Takuji; Ueno, Hideki; Ioka, Tatsuya; Boku, Narikazu; Egawa, Shinichi; Hatori, Takashi; Furuse, Junji; Mizumoto, Kazuhiro; Ohkawa, Shinichi; Yamaguchi, Taketo; Yamao, Kenji; Funakoshi, Akihiro; Cheng, Ann-Lii; Kihara, Kiyohiro; Sato, Atsushi; Tanaka, Masao

    2017-01-01

    This study was performed to compare health-related quality of life (HRQOL) of gemcitabine plus S-1 (GS), S-1 alone and gemcitabine alone as first-line chemotherapy for locally advanced or metastatic pancreatic cancer in the GEST (Gemcitabine and TS-1 Trial) study and to assess the impacts of adverse events and tumour response on HRQOL. Patients were randomly assigned to receive gemcitabine alone (1000 mg/m(2) weekly for 3 of 4 weeks), S-1 alone (80, 100 or 120 mg/day twice daily for 4 of 6 weeks) or GS (gemcitabine at 1000 mg/m(2) weekly plus S-1 at 60, 80 or 100 mg/day twice daily for 2 of 3 weeks). HRQOL was assessed using the EuroQoL-5D (EQ-5D) questionnaire at baseline and weeks 6, 12, 24, 48 and 72. EQ-5D scores, quality-adjusted life months (QALMs), quality-adjusted progression-free months (QAPFMs) and time until definitive HRQOL deterioration (TUDD) were compared among the three groups. The impacts of adverse events and tumour response on EQ-5D scores were analysed. Including EQ-5D scores after death as 0, the mean profile was significantly better in the GS than gemcitabine group (difference, 0.069; p=0.003), but not the S-1 group (difference, -0.011; p=0.613). The mean profiles until death were similar in the three groups. QALMs, QAPFMs and TUDD were significantly longer in the GS than gemcitabine group (p<0.001, p<0.001 and p=0.004, respectively), but not the S-1 group (p=0.563, p=0.741 and p=0.701, respectively). Fatigue, anorexia and tumour response were significantly associated with changes in EQ-5D scores. GS achieved better HRQOL than gemcitabine alone, resulting a good balance between overall survival and HRQOL benefits. S-1 alone provides HRQOL similar to that provided by gemcitabine alone. Preventing fatigue and anorexia and maintaining better response would improve HRQOL.

  20. Switch maintenance chemotherapy using S-1 with or without bevacizumab in patients with advanced non-small cell lung cancer: a phase II study.

    PubMed

    Niho, Seiji; Ohe, Yuichiro; Ohmatsu, Hironobu; Umemura, Shigeki; Matsumoto, Shingo; Yoh, Kiyotaka; Goto, Koichi

    2017-06-01

    We conducted this single-institute; prospective, non-randomized parallel two-arm phase II study to evaluate the efficacy and safety of switch maintenance chemotherapy with S-1 after induction therapy with a platinum-based regimen in patients with advanced non-small cell lung cancer (NSCLC). Patients not showing disease progression after induction platinum-based chemotherapy received S-1 at the dose of 40mg/m(2) twice daily for 14 consecutive days, every three weeks, with or without bevacizumab (Bev) at the dose of 15mg/kg. In cases where the induction chemotherapy regimen contained Bev, Bev was used as continuation maintenance chemotherapy where appropriate. The efficacy/toxicity of switch maintenance chemotherapy with S-1 and S-1+Bev was evaluated separately. The primary end point of this study was the treatment success rate at three months after the start of S-1 treatment. Between July 2010 and January 2014, 79 patients were enrolled, of which 78 were found to be eligible for inclusion in this study. The treatment success rate at three months was 28.2% (90% confidence interval (CI), 7.1-17.1%) in the S-1 group and 64.1% (90% CI, 50.0-76.8%) in the S-1+Bev group. The primary endpoint was met in the S-1+Bev group. The median PFS and OS were 2.6 months and 11.0 months in the S-1 group, and 4.6 months and 19.9 months in the S-1+Bev group, respectively. The most common grade three toxicity was neutropenia (10% incidence in the S-1+Bev group). There were no cases of febrile neutropenia. Switch maintenance chemotherapy with S-1 in combination with continuation maintenance chemotherapy with bevacizumab yielded modest efficacy with mild and acceptable toxicities. Copyright © 2017. Published by Elsevier B.V.

  1. Interaction of integrin β4 with S1P receptors in S1P- and HGF-induced endothelial barrier enhancement.

    PubMed

    Ni, Xiuqin; Epshtein, Yulia; Chen, Weiguo; Zhou, Tingting; Xie, Lishi; Garcia, Joe G N; Jacobson, Jeffrey R

    2014-06-01

    We previously reported sphingosine 1-phosphate (S1P) and hepatocyte growth factor (HGF) augment endothelial cell (EC) barrier function and attenuate murine acute lung inury (ALI). While the mechanisms underlying these effects are not fully understood, S1P and HGF both transactivate the S1P receptor, S1PR1 and integrin β4 (ITGB4) at membrane caveolin-enriched microdomains (CEMs). In the current study, we investigated the roles of S1PR2 and S1PR3 in S1P/HGF-mediated EC signaling and their associations with ITGB4. Our studies confirmed ITGB4 and S1PR2/3 are recruited to CEMs in human lung EC in response to either S1P (1 µM, 5 min) or HGF (25 ng/ml, 5 min). Co-immunoprecipitation experiments identified an S1P/HGF-mediated interaction of ITGB4 with both S1PR2 and S1PR3. We then employed an in situ proximity ligation assay (PLA) to confirm a direct ITGB4-S1PR3 association induced by S1P/HGF although a direct association was not detectable between S1PR2 and ITGB4. S1PR1 knockdown (siRNA), however, abrogated S1P/HGF-induced ITGB4-S1PR2 associations while there was no effect on ITGB4-S1PR3 associations. Moreover, PLA confirmed a direct association between S1PR1 and S1PR2 induced by S1P and HGF. Finally, silencing of S1PR2 significantly attenuated S1P/HGF-induced EC barrier enhancement as measured by transendothelial resistance while silencing of S1PR3 significantly augmented S1P/HGF-induced barrier enhancement. These results confirm an important role for S1PR2 and S1PR3 in S1P/HGF-mediated EC barrier responses that are associated with their complex formation with ITGB4. Our findings elucidate novel mechanisms of EC barrier regulation that may ultimately lead to new therapeutic targets for disorders characterized by increased vascular permeability including ALI.

  2. Phase I study of 3-weekly combination chemotherapy using epirubicin, oxaliplatin, and S-1 (EOS) in patients with previously untreated advanced gastric cancer.

    PubMed

    Sym, Sun Jin; Hong, Junsik; Jung, Minkyu; Park, Jinny; Cho, Eun Kyung; Lee, Woon Ki; Chung, Min; Kim, Hyung-Sik; Lee, Jae Hoon; Shin, Dong Bok

    2012-08-01

    This study was performed to determine the recommended dose (RD) and dose-limiting toxicity (DLT) associated with epirubicin, oxaliplatin, and S-1 (EOS) combination therapy in patients with previously untreated advanced gastric cancer (AGC). Previously untreated patients with histologically proven metastatic AGC, with an ECOG performance status of 0-2, were enrolled in this study. A fixed dose of epirubicin (50 mg/m(2)) and oxaliplatin (130 mg/m(2)) was intravenously administered on day 1 of treatment, followed by oral S-1 administration twice daily on days 1-14. The S-1 dose was escalated according to the following schedule: level I, 35 mg/m(2); level II, 40 mg/m(2); level III, 45 mg/m(2); Level IV, 50 mg/m(2). Each cycle was repeated every 21 days. DLTs were evaluated during the first two cycles of treatment. Nineteen patients with a median age of 53 years (range, 40-71 years) were enrolled in this study. One case of DLT (grade 4 neutropenia lasting more than 5 days) developed from among the six dose level II patients, while 2 DLTs (grade 3 diarrhea and nausea) were observed among the 4 dose level III patients. Based on these results, dose level II was determined as the RD. Of the 13 patients with measurable lesions, eight achieved partial response, three showed stable disease, and the objective response rate was 61.5 % (95 % confidence interval (CI), 13.3-66.6 %). The median progression-free survival and overall survival of all patients was 6.8 months (95 % CI, 1.4-9.5 months) and 13.3 months (95 % CI, 1.9-24.6 months), respectively. The RD of the EOS regimen in patients with previously untreated AGC was 50 mg/m(2) of epirubicin and 130 mg/m(2) of oxaliplatin on day 1, with administration of 40 mg/m(2) of S-1 twice a day on days 1-14 for each 21-day cycle. The EOS regimen described produced promising results.

  3. Differences in forward angular light scattering distributions between M1 and M2 macrophages

    NASA Astrophysics Data System (ADS)

    Halaney, David L.; Zahedivash, Aydin; Phipps, Jennifer E.; Wang, Tianyi; Dwelle, Jordan; Saux, Claude Jourdan Le; Asmis, Reto; Milner, Thomas E.; Feldman, Marc D.

    2015-11-01

    The ability to distinguish macrophage subtypes noninvasively could have diagnostic potential in cancer, atherosclerosis, and diabetes, where polarized M1 and M2 macrophages play critical and often opposing roles. Current methods to distinguish macrophage subtypes rely on tissue biopsy. Optical imaging techniques based on light scattering are of interest as they can be translated into biopsy-free strategies. Because mitochondria are relatively strong subcellular light scattering centers, and M2 macrophages are known to have enhanced mitochondrial biogenesis compared to M1, we hypothesized that M1 and M2 macrophages may have different angular light scattering profiles. To test this, we developed an in vitro angle-resolved forward light scattering measurement system. We found that M1 and M2 macrophage monolayers scatter relatively unequal amounts of light in the forward direction between 1.6 deg and 3.2 deg with M2 forward scattering significantly more light than M1 at increasing angles. The ratio of forward scattering can be used to identify the polarization state of macrophage populations in culture.

  4. Differences in forward angular light scattering distributions between M1 and M2 macrophages

    PubMed Central

    Halaney, David L.; Zahedivash, Aydin; Phipps, Jennifer E.; Wang, Tianyi; Dwelle, Jordan; Saux, Claude Jourdan Le; Asmis, Reto; Milner, Thomas E.; Feldman, Marc D.

    2015-01-01

    Abstract. The ability to distinguish macrophage subtypes noninvasively could have diagnostic potential in cancer, atherosclerosis, and diabetes, where polarized M1 and M2 macrophages play critical and often opposing roles. Current methods to distinguish macrophage subtypes rely on tissue biopsy. Optical imaging techniques based on light scattering are of interest as they can be translated into biopsy-free strategies. Because mitochondria are relatively strong subcellular light scattering centers, and M2 macrophages are known to have enhanced mitochondrial biogenesis compared to M1, we hypothesized that M1 and M2 macrophages may have different angular light scattering profiles. To test this, we developed an in vitro angle-resolved forward light scattering measurement system. We found that M1 and M2 macrophage monolayers scatter relatively unequal amounts of light in the forward direction between 1.6 deg and 3.2 deg with M2 forward scattering significantly more light than M1 at increasing angles. The ratio of forward scattering can be used to identify the polarization state of macrophage populations in culture. PMID:26538329

  5. Beam quality M 2 factor matrix for non-circular symmetric laser beams

    NASA Astrophysics Data System (ADS)

    Du, Yongzhao; Fu, Yuqing; Zheng, Chaoying

    2017-02-01

    It is standard to use Mx2 and My2 to characterize the beam quality of a non-circular symmetrical beam on its x-axis and y-axis orientation. However, we knew that the values of Mx2 and My2 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, a new beam quality characterization method, the M 2 factor matrix, is developed. It not only contains the beam quality terms, Mx2 and My2 , to characterize the beam quality along x-axis and y-axis orientation for the non-symmetric beam, but also introduces two additional cross terms, M xy and M yx , which are used to characterize the location relationship between the principal axis of the test beam and coordinate system in experiment. Moreover, M 2 factor matrix can be measured with a similar procedure to the traditional M 2 factor whose measurement instructions are described in ISO11146 by adding some additional image and signal processing procedure. The measurement principle and method is present and the experiment system for beam quality M 2 factor matrix is built to demonstrate the performance of M 2 factor matrix with real experiments.

  6. Structural environment built by AKAP12+ colon mesenchymal cells drives M2 macrophages during inflammation recovery

    PubMed Central

    Yang, Jun-Mo; Lee, Hye Shin; Seo, Ji Hae; Park, Ji-Hyeon; Gelman, Irwin H.; Lo, Eng H.; Kim, Kyu-Won

    2017-01-01

    Macrophages exhibit phenotypic plasticity, as they have the ability to switch their functional phenotypes during inflammation and recovery. Simultaneously, the mechanical environment actively changes. However, how these dynamic alterations affect the macrophage phenotype is unknown. Here, we observed that the extracellular matrix (ECM) constructed by AKAP12+ colon mesenchymal cells (CMCs) generated M2 macrophages by regulating their shape during recovery. Notably, rounded macrophages were present in the linear and loose ECM of inflamed colons and polarized to the M1 phenotype. In contrast, ramified macrophages emerged in the contracted ECM of recovering colons and mainly expressed M2 macrophage markers. These contracted structures were not observed in the inflamed colons of AKAP12 knockout (KO) mice. Consequently, the proportion of M2 macrophages in inflamed colons was lower in AKAP12 KO mice than in WT mice. In addition, clinical symptoms and histological damage were more severe in AKAP12 KO mice than in WT mice. In experimentally remodeled collagen gels, WT CMCs drove the formation of a more compacted structure than AKAP12 KO CMCs, which promoted the polarization of macrophages toward an M2 phenotype. These results demonstrated that tissue contraction during recovery provides macrophages with the physical cues that drive M2 polarization. PMID:28205544

  7. Large-Scale Mini-Magnetosphere Plasma Propulsion (M2P2) Experiments

    NASA Technical Reports Server (NTRS)

    Winglee, R. M.; Slough, J.; Ziemba, T.; Euripides, P.; Adrian, M. L.; Gallagher, D.; Craven, P.; Tomlinson, W.; Cravens, J.; Burch, J.; hide

    2001-01-01

    Mini-Magnetosphere Plasma Propulsion (M2P2) is an innovative plasma propulsion system that has the potential to propel spacecraft at unprecedented speeds of 50 to 80 km per second with a low-power requirement of approx. 1 kW per 100 kg of payload and approx. 1 kg of neutral gas [fuel] consumption per day of acceleration. Acceleration periods from several days to a few months are envisioned. High specific impulse and efficiency are achieved through coupling of the spacecraft to the 400 km per second solar wind through an artificial magnetosphere. The mini-magnetosphere or inflated magnetic bubble is produced by the injection of cold dense plasma into a spacecraft-generated magnetic field envelope. Magnetic bubble inflation is driven by electromagnetic processes thereby avoiding the material and deployment problems faced by mechanical solar sail designs, Here, we present the theoretical design of M2P2 as well as initial results from experimental testing of an M2P2 prototype demonstrating: 1) inflation of the dipole magnetic field geometry through the internal injection of cold plasma; and 2) deflection of and artificial solar wind by the prototype M2P2 system. In addition, we present plans for direct laboratory measurement of thrust imparted to a prototype M2P2 by an artificial solar wind during the summer of 2001.

  8. Large-Scale Mini-Magnetosphere Plasma Propulsion (M2P2) Experiments

    NASA Technical Reports Server (NTRS)

    Winglee, R. M.; Slough, J.; Ziemba, T.; Euripides, P.; Gallagher, D.; Craven, P.; Adrian, M. L.; Tomlinson, W.; Cravens, J.; Burch, J.; hide

    2001-01-01

    Mini-Magnetosphere Plasma Propulsion (M2P2) is an innovative plasma propulsion system that has the potential to propel spacecraft at unprecedented speeds of 50 to 80 km/s, with a low power requirement of approx. 1 kW per 100 kg of payload and -1 kg of neutral gas [fuel] consumption per day of acceleration. Acceleration periods from several days to a few months are envisioned. High specific impulse and efficiency are achieved through coupling of the spacecraft to the 400 km/s. solar wind through an artificial magnetosphere. The mini-magnetosphere or inflated magnetic bubble is produced by the injection of cold dense plasma into a spacecraft-generated magnetic field envelope. Magnetic bubble inflation is driven by electromagnetic processes thereby avoiding the material and deployment problems faced by mechanical solar sail designs. Here, we present the theoretical design of M2P2 as well as initial results from experimental testing of an M2P2 prototype demonstrating: 1) inflation of the dipole magnetic field geometry through the internal injection of cold plasma; and 2) deflection of and artificial solar wind by the prototype M2P2 system. In addition, we present plans for direct laboratory measurement of thrust imparted to a prototype M2P2 by an artificial solar wind during the summer of 2001.

  9. Modelling packing interactions in parallel helix bundles: pentameric bundles of nicotinic receptor M2 helices.

    PubMed

    Sankararamakrishnan, R; Sansom, M S

    1995-11-01

    The transbilayer pore of the nicotinic acetylcholine receptor (nAChR) is formed by a pentameric bundle of M2 helices. Models of pentameric bundles of M2 helices have been generated using simulated annealing via restrained molecular dynamics. The influence of: (a) the initial C alpha template; and (b) screening of sidechain electrostatic interactions on the geometry of the resultant M2 helix bundles is explored. Parallel M2 helices, in the absence of sidechain electrostatic interactions, pack in accordance with simple ridges-in-grooves considerations. This results in a helix crossing angle of ca. +12 degrees, corresponding to a left-handed coiled coil structure for the bundle as a whole. Tilting of M2 helices away from the central pore axis at their C-termini and/or inclusion of sidechain electrostatic interactions may perturb such ridges-in-grooves packing. In the most extreme cases right-handed coiled coils are formed. An interplay between inter-helix H-bonding and helix bundle geometry is revealed. The effects of changes in electrostatic screening on the dimensions of the pore mouth are described and the significance of these changes in the context of models for the nAChR pore domain is discussed.

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

    PubMed Central

    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

  11. Ozone-induced airway hyperresponsiveness and loss of neuronal M2 muscarinic receptor function.

    PubMed

    Schultheis, A H; Bassett, D J; Fryer, A D

    1994-03-01

    The effect of acute ozone exposure on the function of efferent parasympathetic nerves, M3 muscarinic receptors on airway smooth muscle, and inhibitory M2 muscarinic receptors on the parasympathetic nerves was studied. Immediately after exposure to 2.0 ppm ozone for 4 h, guinea pigs became hyperresponsive to electrical stimulation of the vagus nerves. The normal airway response to intravenous cholinergic agonists at this time demonstrates normal M3 receptor function. M2 muscarinic receptors on the nerves, which normally inhibit release of acetylcholine, were dysfunctional after ozone exposure, as demonstrated by the failure of the muscarinic agonist pilocarpine to inhibit, and the failure of the M2 antagonist gallamine to potentiate, vagally mediated bronchoconstriction. Thus, loss of inhibitory M2 muscarinic receptor function after ozone exposure potentiates release of acetylcholine from the vagus nerves, increasing vagally mediated bronchoconstriction. By 14 days, postozone responses to vagal nerve stimulation were not different from those of air-exposed animals and the function of the neuronal M2 muscarinic receptor was normal, confirming that ozone-induced hyperresponsiveness is reversible.

  12. Structural environment built by AKAP12+ colon mesenchymal cells drives M2 macrophages during inflammation recovery.

    PubMed

    Yang, Jun-Mo; Lee, Hye Shin; Seo, Ji Hae; Park, Ji-Hyeon; Gelman, Irwin H; Lo, Eng H; Kim, Kyu-Won

    2017-02-16

    Macrophages exhibit phenotypic plasticity, as they have the ability to switch their functional phenotypes during inflammation and recovery. Simultaneously, the mechanical environment actively changes. However, how these dynamic alterations affect the macrophage phenotype is unknown. Here, we observed that the extracellular matrix (ECM) constructed by AKAP12+ colon mesenchymal cells (CMCs) generated M2 macrophages by regulating their shape during recovery. Notably, rounded macrophages were present in the linear and loose ECM of inflamed colons and polarized to the M1 phenotype. In contrast, ramified macrophages emerged in the contracted ECM of recovering colons and mainly expressed M2 macrophage markers. These contracted structures were not observed in the inflamed colons of AKAP12 knockout (KO) mice. Consequently, the proportion of M2 macrophages in inflamed colons was lower in AKAP12 KO mice than in WT mice. In addition, clinical symptoms and histological damage were more severe in AKAP12 KO mice than in WT mice. In experimentally remodeled collagen gels, WT CMCs drove the formation of a more compacted structure than AKAP12 KO CMCs, which promoted the polarization of macrophages toward an M2 phenotype. These results demonstrated that tissue contraction during recovery provides macrophages with the physical cues that drive M2 polarization.

  13. Free-Energy Profiles for Ions in the Influenza M2-TMD Channel

    PubMed Central

    Mustafa, Morad; Henderson, Douglas J.; Busath, David D.

    2009-01-01

    M2 transmembrane domain channel (M2-TMD) permeation properties are studied using molecular dynamics simulations of M2-TMD (1NYJ) embedded in a lipid bilayer (DMPC) with 1 mol/kg NaCl or KCl saline solution. This study allows examination of spontaneous cation and anion entry into the selectivity filter. Three titration states of the M2-TMD tetramer are modeled for which the four His37 residues, forming the selectivity filter, are net uncharged, +2 charged, or +3 charged. M2-TMD structural properties from our simulations are compared with the properties of other models extracted from NMR and X-ray studies. During 10 ns simulations, chloride ions rarely occupy the positively-charged selectivity filter, whereas from umbrella sampling simulations, Cl− has a lower free-energy barrier in the selectivity-filter region than either Na+ or NH4+, and NH4+ has a lower free-energy barrier than Na+. For Na+ and Cl−, the free-energy barriers are less than 5 kcal/mol, suggesting that the 1NYJ conformation would probably not be exquisitely proton selective. We also point out a rotameric configuration of Trp41 that could fully occlude the channel. PMID:19296508

  14. Differences in forward angular light scattering distributions between M1 and M2 macrophages.

    PubMed

    Halaney, David L; Zahedivash, Aydin; Phipps, Jennifer E; Wang, Tianyi; Dwelle, Jordan; Saux, Claude Jourdan Le; Asmis, Reto; Milner, Thomas E; Feldman, Marc D

    2015-11-01

    The ability to distinguish macrophage subtypes noninvasively could have diagnostic potential in cancer, atherosclerosis, and diabetes, where polarized M1 and M2 macrophages play critical and often opposing roles. Current methods to distinguish macrophage subtypes rely on tissue biopsy. Optical imaging techniques based on light scattering are of interest as they can be translated into biopsy-free strategies. Because mitochondria are relatively strong subcellular light scattering centers, and M2 macrophages are known to have enhanced mitochondrial biogenesis compared to M1, we hypothesized that M1 and M2 macrophages may have different angular light scattering profiles. To test this, we developed an in vitro angle-resolved forward light scattering measurement system. We found that M1 and M2 macrophage monolayers scatter relatively unequal amounts of light in the forward direction between 1.6 deg and 3.2 deg with M2 forward scattering significantly more light than M1 at increasing angles. The ratio of forward scattering can be used to identify the polarization state of macrophage populations in culture.

  15. [[sup 3]H]QNB displays in vivo selectivity for the m2 subtype

    SciTech Connect

    Gitler, M.S.; De La Cruz, R.; Zeeberg, B.R. ); Reba, R.C. Univ. of Chicago Hospital, Chicago, IL )

    1994-01-01

    Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1, subtype neuroreceptors in the posterior parietal cortex of the human brain. Emission tomographic study of the loss of m2 receptors in AD is limited by the fact that there is currently no available m2-selective radioligand which can penetrate the blood-brain barrier. [[sup 3]H](R)-3-quinuclidinylbenzilate ([[sup 3]H]QNB) is commonly used for performing in vitro studies of the muscarinic acetylcholine receptor (mAChR), either with membrane homogenates or with autoradiographic slices, in which [[sup 3]H]QNB is nonsubtype-selective. We report here the results of in vivo studies, using both carrier-free and low specific activity [[sup 3]H]QNB, which show that [[sup 3]H]QNB exhibits a substantial in vivo m2-selectivity. Previously reported in vivo (R)-3-quinuclidinyl (R)-4-iodobenzilate ((R,R)-[[sup 125]I]lQNB) binding appears to be nonsubtype-selective. Apparently the bulky iodine substitution in the 4 position reduces the subtype selectivity of QNB. It is possible that a less bulky fluorine substitution might permit retention of the selectivity exhibited by QNB itself. We conclude that a suitably radiolabeled derivative of QNB, possibly labeled with [sup 18]F, may be of potential use in positron emission tomographic (PET) study of the loss of m2 receptors in AD. 39 refs., 8 figs., 2 tab.

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

    PubMed

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

    2015-06-22

    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 (374)KKKPPPS(380) servers as a sorting signal for the clathrin-independent internalization of M2 mAChR. Switching (374)KKKPPPS(380) 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, (361)VARKIVKMTKQPA(373), which is normally masked in the presence of the downstream sequence (374)KKKPPPS(380). Taken together, our data indicate that endocytosis and postendocytic sorting of GPCRs that undergo CIE could be sequence-dependent.

  17. ICAM-1 suppresses tumor metastasis by inhibiting macrophage M2 polarization through blockade of efferocytosis

    PubMed Central

    Yang, M; Liu, J; Piao, C; Shao, J; Du, J

    2015-01-01

    Efficient clearance of apoptotic cells (efferocytosis) can profoundly influence tumor-specific immunity. Tumor-associated macrophages are M2-polarized macrophages that promote key processes in tumor progression. Efferocytosis stimulates M2 macrophage polarization and contributes to cancer metastasis, but the signaling mechanism underlying this process is unclear. Intercellular cell adhesion molecule-1 (ICAM-1) is a transmembrane glycoprotein member of the immunoglobulin superfamily, which has been implicated in mediating cell–cell interaction and outside-in cell signaling during the immune response. We report that ICAM-1 expression is inversely associated with macrophage infiltration and the metastasis index in human colon tumors by combining Oncomine database analysis and immunohistochemistry for ICAM-1. Using a colon cancer liver metastasis model in ICAM-1-deficient (ICAM-1−/−) mice and their wild-type littermates, we found that loss of ICAM-1 accelerated liver metastasis of colon carcinoma cells. Moreover, ICAM-1 deficiency increased M2 macrophage polarization during tumor progression. We further demonstrated that ICAM-1 deficiency in macrophages led to promotion of efferocytosis of apoptotic tumor cells through activation of the phosphatidylinositol 3 kinase/Akt signaling pathway. More importantly, coculture of ICAM-1−/− macrophages with apoptotic cancer cells resulted in an increase of M2-like macrophages, which was blocked by an efferocytosis inhibitor. Our findings demonstrate a novel role for ICAM-1 in suppressing M2 macrophage polarization via downregulation of efferocytosis in the tumor microenvironment, thereby inhibiting metastatic tumor progression. PMID:26068788

  18. Endoplasmic Reticulum Stress Controls M2 Macrophage Differentiation and Foam Cell Formation*

    PubMed Central

    Oh, Jisu; Riek, Amy E.; Weng, Sherry; Petty, Marvin; Kim, David; Colonna, Marco; Cella, Marina; Bernal-Mizrachi, Carlos

    2012-01-01

    Macrophages are essential in atherosclerosis progression, but regulation of the M1 versus M2 phenotype and their role in cholesterol deposition are unclear. We demonstrate that endoplasmic reticulum (ER) stress is a key regulator of macrophage differentiation and cholesterol deposition. Macrophages from diabetic patients were classically or alternatively stimulated and then exposed to oxidized LDL. Alternative stimulation into M2 macrophages lead to increased foam cell formation by inducing scavenger receptor CD36 and SR-A1 expression. ER stress induced by alternative stimulation was necessary to generate the M2 phenotype through JNK activation and increased PPARγ expression. The absence of CD36 or SR-A1 signaling independently of modified cholesterol uptake decreased ER stress and prevented the M2 differentiation typically induced by alternative stimulation. Moreover, suppression of ER stress shifted differentiated M2 macrophages toward an M1 phenotype and subsequently suppressed foam cell formation by increasing HDL- and apoA-1-induced cholesterol efflux indicating suppression of macrophage ER stress as a potential therapy for atherosclerosis. PMID:22356914

  19. Large-Scale Mini-Magnetosphere Plasma Propulsion (M2P2) Experiments

    NASA Technical Reports Server (NTRS)

    Winglee, R. M.; Slough, J.; Ziemba, T.; Euripides, P.; Adrian, M. L.; Gallagher, D.; Craven, P.; Tomlinson, W.; Cravens, J.; Burch, J.; Whitaker, Ann F. (Technical Monitor)

    2001-01-01

    Mini-Magnetosphere Plasma Propulsion (M2P2) is an innovative plasma propulsion system that has the potential to propel spacecraft at unprecedented speeds of 50 to 80 km per second with a low-power requirement of approx. 1 kW per 100 kg of payload and approx. 1 kg of neutral gas [fuel] consumption per day of acceleration. Acceleration periods from several days to a few months are envisioned. High specific impulse and efficiency are achieved through coupling of the spacecraft to the 400 km per second solar wind through an artificial magnetosphere. The mini-magnetosphere or inflated magnetic bubble is produced by the injection of cold dense plasma into a spacecraft-generated magnetic field envelope. Magnetic bubble inflation is driven by electromagnetic processes thereby avoiding the material and deployment problems faced by mechanical solar sail designs, Here, we present the theoretical design of M2P2 as well as initial results from experimental testing of an M2P2 prototype demonstrating: 1) inflation of the dipole magnetic field geometry through the internal injection of cold plasma; and 2) deflection of and artificial solar wind by the prototype M2P2 system. In addition, we present plans for direct laboratory measurement of thrust imparted to a prototype M2P2 by an artificial solar wind during the summer of 2001.

  20. Large-Scale Mini-Magnetosphere Plasma Propulsion (M2P2) Experiments

    NASA Technical Reports Server (NTRS)

    Winglee, R. M.; Slough, J.; Ziemba, T.; Euripides, P.; Gallagher, D.; Craven, P.; Adrian, M. L.; Tomlinson, W.; Cravens, J.; Burch, J.; Rose, M. Franklin (Technical Monitor)

    2001-01-01

    Mini-Magnetosphere Plasma Propulsion (M2P2) is an innovative plasma propulsion system that has the potential to propel spacecraft at unprecedented speeds of 50 to 80 km/s, with a low power requirement of approx. 1 kW per 100 kg of payload and -1 kg of neutral gas [fuel] consumption per day of acceleration. Acceleration periods from several days to a few months are envisioned. High specific impulse and efficiency are achieved through coupling of the spacecraft to the 400 km/s. solar wind through an artificial magnetosphere. The mini-magnetosphere or inflated magnetic bubble is produced by the injection of cold dense plasma into a spacecraft-generated magnetic field envelope. Magnetic bubble inflation is driven by electromagnetic processes thereby avoiding the material and deployment problems faced by mechanical solar sail designs. Here, we present the theoretical design of M2P2 as well as initial results from experimental testing of an M2P2 prototype demonstrating: 1) inflation of the dipole magnetic field geometry through the internal injection of cold plasma; and 2) deflection of and artificial solar wind by the prototype M2P2 system. In addition, we present plans for direct laboratory measurement of thrust imparted to a prototype M2P2 by an artificial solar wind during the summer of 2001.

  1. RGS4 regulates partial agonism of the M2 muscarinic receptor-activated K+ currents

    PubMed Central

    Chen, I-Shan; Furutani, Kazuharu; Inanobe, Atsushi; Kurachi, Yoshihisa

    2014-01-01

    Partial agonists are used clinically to avoid overstimulation of receptor-mediated signalling, as they produce a submaximal response even at 100% receptor occupancy. The submaximal efficacy of partial agonists is due to conformational change of the agonist–receptor complex, which reduces effector activation. In addition to signalling activators, several regulators help control intracellular signal transductions. However, it remains unclear whether these signalling regulators contribute to partial agonism. Here we show that regulator of G-protein signalling (RGS) 4 is a determinant for partial agonism of the M2 muscarinic receptor (M2R). In rat atrial myocytes, pilocarpine evoked smaller G-protein-gated K+ inwardly rectifying (KG) currents than those evoked by ACh. In a Xenopus oocyte expression system, pilocarpine acted as a partial agonist in the presence of RGS4 as it did in atrial myocytes, while it acted like a full agonist in the absence of RGS4. Functional couplings within the agonist–receptor complex/G-protein/RGS4 system controlled the efficacy of pilocarpine relative to ACh. The pilocarpine–M2R complex suppressed G-protein-mediated activation of KG currents via RGS4. Our results demonstrate that partial agonism of M2R is regulated by the RGS4-mediated inhibition of G-protein signalling. This finding helps us to understand the molecular components and mechanism underlying the partial agonism of M2R-mediated physiological responses. PMID:24421355

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

    PubMed

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

    2016-10-28

    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 briefly introduce the current state of knowledge regarding macrophage function and nomenclature. Next, we discuss the use of controlled release strategies to tune the balance between the M1 and M2 phenotypes in the context of tissue engineering applications. We discuss recent literature related to the release of anti-inflammatory molecules (including nucleic acids) and the sequential release of cytokines to promote a timely M1-M2 shift. In addition, we describe the use of macrophages as controlled release agents upon stimulation by physical and/or mechanical cues provided by scaffolds. Moreover, we discuss current and future applications of "smart" implantable scaffolds capable of controlling the cascade of biochemical events related to healing and vascularization. Finally, we provide our opinion on the current challenges and the future research directions to improve our understanding of the M1-M2 macrophage balance and properly exploit it in tissue engineering and regenerative medicine applications. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Lama glama αS1-casein: Identification of new polymorphisms in the CSN1S1 gene.

    PubMed

    Pauciullo, A; Gauly, M; Cosenza, G; Wagner, H; Erhardt, G

    2017-02-01

    South American camelids have been poorly genetically investigated and little information is available in llamas (Lama glama) regarding the diversity of the caseins at the protein and gene level. Exon skipping and duplication events previously reported in the αS1-casein gene (CSN1S1) led us to investigate the genetic variability at this locus. Seventy-two positive clones for the αS1-casein transcripts were analyzed and randomly sequenced. The comparative analysis of the sequences revealed 2 transitions, c.366A>G and c.690T>C, at the 10th nucleotide of exon 12 and 94 bp of exon 19, respectively. These SNP are responsible for 2 amino acid changes, Ile→Val in position 86 and Tyr→His in position 194 of the mature protein. Both polymorphisms clarify the genetic events behind the protein variants A and B. This result was confirmed by isoelectric focusing analysis of llama milk samples. Quick methods based on PCR-RFLP and allele-specific PCR were set up for allelic discrimination in a population of 128 animals. Based on genotyping results, 4 haplotypes were observed and the estimated frequencies indicated B as the most common haplotype (0.629) in the investigated population. These data add knowledge to the genetic variability of a species little investigated, and open opportunity for new investigation in the field of milk protein for South American camelids, including the possibility, in the future, to select alleles with favorable characteristics.

  4. Holographic cosmology from a system of M2-M5 branes

    NASA Astrophysics Data System (ADS)

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

    2016-05-01

    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.

  5. Water-mediated conformational transitions in nicotinic receptor M2 helix bundles: a molecular dynamics study.

    PubMed

    Sankararamakrishnan, R; Sansom, M S

    1995-12-27

    The ion channel of the nicotinic acetylcholine receptor is a water-filled pore formed by five M2 helix segments, one from each subunit. Molecular dynamics simulations on bundles of five M2 alpha 7 helices surrounding a central column of water and with caps of water molecules at either end of the pore have been used to explore the effects of intrapore water on helix packing. Interactions of water molecules with the N-terminal polar sidechains lead to a conformational transition from right- to left-handed supercoils during these stimulations. These studies reveal that the pore formed by the bundle of M2 helices is flexible. A structural role is proposed for water molecules in determining the geometry of bundles of isolated pore-forming helices.

  6. A model of the closed form of the nicotinic acetylcholine receptor m2 channel pore.

    PubMed

    Kim, Sanguk; Chamberlain, Aaron K; Bowie, James U

    2004-08-01

    The nicotinic acetylcholine receptor is a neurotransmitter-gated ion channel in the postsynaptic membrane. It is composed of five homologous subunits, each of which contributes one transmembrane helix--the M2 helix--to create the channel pore. The M2 helix from the delta subunit is capable of forming a channel by itself. Although a model of the receptor was recently proposed based on a low-resolution, cryo-electron microscopy density map, we found that the model does not explain much of the other available experimental data. Here we propose a new model of the M2 channel derived solely from helix packing and symmetry constraints. This model agrees well with experimental results from solid-state NMR, chemical reactivity, and mutagenesis experiments. The model depicts the channel pore, the channel gate, and the residues responsible for cation specificity.

  7. A Novel Voltage Sensor in the Orthosteric Binding Site of the M2 Muscarinic Receptor.

    PubMed

    Barchad-Avitzur, Ofra; Priest, Michael F; Dekel, Noa; Bezanilla, Francisco; Parnas, Hanna; Ben-Chaim, Yair

    2016-10-04

    G protein-coupled receptors (GPCRs) mediate many signal transduction processes in the body. The discovery that these receptors are voltage-sensitive has changed our understanding of their behavior. The M2 muscarinic acetylcholine receptor (M2R) was found to exhibit depolarization-induced charge movement-associated currents, implying that this prototypical GPCR possesses a voltage sensor. However, the typical domain that serves as a voltage sensor in voltage-gated channels is not present in GPCRs, making the search for the voltage sensor in the latter challenging. Here, we examine the M2R and describe a voltage sensor that is comprised of tyrosine residues. This voltage sensor is crucial for the voltage dependence of agonist binding to the receptor. The tyrosine-based voltage sensor discovered here constitutes a noncanonical by which membrane proteins may sense voltage. Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.

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

    SciTech Connect

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

    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.

  9. The M2&M3 positioning control systems of a 2.5m telescope

    NASA Astrophysics Data System (ADS)

    Ye, Yu; Pei, Chong; Zhang, Zhiyong; Gu, Bozhong

    2012-09-01

    The 2.5m optical/infrared telescope is an F/8 telescope comprising one Cassegrain foci, two Nasmyth foci and two student Nasmyth foci. This paper presents a brief description of the physical structure, conceptual design, hardware implementing measure and software structure in the positioning control system of M2&M3. The graphical user interface application (Qt) is adopted to design the software. During the full working range the M2 focus and decenter achieve the positioning repeatability is better than +/-4μm and the M2 tilt is better than 10 μrad. The M3 angular positioning and locking accuracy is better than 10 arcsec and repeatability is better than 2 arcsec RMS.

  10. M2-F1 in flight being towed by a C-47

    NASA Technical Reports Server (NTRS)

    1964-01-01

    The M2-F1 Lifting Body is seen here being towed behind a C-47 at the Flight Research Center (later redesignated the Dryden Flight Research Center), Edwards, California. In this rear view, the M2-F1 is flying above and to one side of the C-47. This was done to avoid wake turbulence from the towplane. Lacking wings, the M2-F1 used an unusual configuration for its control surfaces. It had two rudders on the fins, two elevons (called 'elephant ears') mounted on the outsides of the fins, and two body flaps on the upper rear fuselage. 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. These initial tests produced enough flight data about the M2-F1 to proceed with flights behind the C-47 tow plane at greater altitudes. The C-47 took the craft to an altitude of 12,000 where free flights back to Rogers Dry Lake began. Pilot for the first series of flights of the M2-F1 was NASA research pilot Milt Thompson. Typical glide flights with the M2-F1 lasted about two minutes and reached speeds of 110 to l20 mph. More than 400 ground tows and 77 aircraft tow flights were carried out with the M2-F1. The success of Dryden's M2-F1 program led to NASA's development and construction of two heavyweight lifting bodies based on studies at NASA's Ames and

  11. Membrane remodeling by the M2 amphipathic helix drives influenza virus membrane scission

    PubMed Central

    Martyna, Agnieszka; Bahsoun, Basma; Badham, Matthew D.; Srinivasan, Saipraveen; Howard, Mark J.; Rossman, Jeremy S.

    2017-01-01

    Membrane scission is a crucial step in all budding processes, from endocytosis to viral budding. Many proteins have been associated with scission, though the underlying molecular details of how scission is accomplished often remain unknown. Here, we investigate the process of M2-mediated membrane scission during the budding of influenza viruses. Residues 50–61 of the viral M2 protein bind membrane and form an amphipathic α-helix (AH). Membrane binding requires hydrophobic interactions with the lipid tails but not charged interactions with the lipid headgroups. Upon binding, the M2AH induces membrane curvature and lipid ordering, constricting and destabilizing the membrane neck, causing scission. We further show that AHs in the cellular proteins Arf1 and Epsin1 behave in a similar manner. Together, they represent a class of membrane-induced AH domains that alter membrane curvature and fluidity, mediating the scission of constricted membrane necks in multiple biological pathways. PMID:28317901

  12. Purinergic signaling during macrophage differentiation results in M2 alternative activated macrophages.

    PubMed

    Barberà-Cremades, Maria; Baroja-Mazo, Alberto; Pelegrín, Pablo

    2016-02-01

    Macrophages represent a highly heterogenic cell population of the innate immune system, with important roles in the initiation and resolution of the inflammatory response. Purinergic signaling regulates both M1 and M2 macrophage function at different levels by controlling the secretion of cytokines, phagocytosis, and the production of reactive oxygen species. We found that extracellular nucleotides arrest macrophage differentiation from bone marrow precursors via adenosine and P2 receptors. This results in a mature macrophage with increased expression of M2, but not M1, genes. Similar to adenosine and ATP, macrophage growth arrested with LPS treatment resulted in an increase of the M2-related marker Ym1. Recombinant Ym1 was able to affect macrophage proliferation and could, potentially, be involved in the arrest of macrophage growth during hematopoiesis. © Society for Leukocyte Biology.

  13. M2IS (modular miniature imaging sensor) for law enforcement applications

    NASA Astrophysics Data System (ADS)

    Pruitt, Gerald R.; Shaffer, Stephen

    2001-02-01

    Raytheon Electronics Systems, under contract from the DARPA Advanced Technology Office, has designed, fabricated and delivered the Modular Miniature Imaging Sensor (M2IS). M2IS is a rifle- or tripod-mountable system that integrates a high-performance multispectral sensor with an eyesafe laser rangefinder and a digital compass. A cooled 480 X 640 InSb focal plane array and dual-FOV reflective optics provide capability to acquire and identify targets at ranges of several kilometers. The LRF and compass facilitate reporting target location. M2IP provides the law enforcement officer an integrated surveillance and targeting system that consumes less than 6.5 W and weighs less than 7.5 lbs. This paper describes measured performance and capabilities of the system.

  14. Most general spherically symmetric M2-branes and type-IIB strings

    SciTech Connect

    Wang Zhaolong; Lue, H.

    2009-09-15

    We obtain the most general spherically symmetric M2-branes and type-IIB strings, with R{sup 1,2}xSO(8) and R{sup 1,1}xSO(8) isometries, respectively. We find that there are 12 different classes of M2-branes, and we study their curvature properties. In particular, we obtain new smooth M2-brane wormholes that connect two asymptotic regions: one is flat and the other can be either flat or AdS{sub 4}xS{sup 7}. We find that these wormholes are traversable with certain timelike trajectories. We also obtain the most general Ricci-flat solutions in five dimensions with R{sup 1,1}xSO(3) isometries.

  15. Attaining Doppler Precision of 3 M s-1

    NASA Astrophysics Data System (ADS)

    Butler, R. P.; Marcy, G. W.; Williams, E.; McCarthy, C.; Dosanjh, P.; Vogt, S. S.

    1996-06-01

    Current spectroscopic techniques yield Doppler-shift errors of 10 to 50 m s^-1, barely adequate to detect reflex velocities caused by Jupiter-like and lower-mass planets. We describe a technique which yields relative radial velocity errors of 3 m s^-1. This technique makes use of a fast echelle spectrograph at resolution of R=62,000 and a large format CCD which acquires the entire visible and near IR spectrum in each exposure. Starlight is sent through an iodine absorption cell placed at the spectrometer entrance slit. The resulting superimposed iodine lines provide a fiducial wavelength scale against which to measure radial velocity shifts. The shapes of iodine lines convey the PSF of the spectrometer to account for changes in spectrometer optics and illumination on all times scales. We construct a model of each observed spectrum by multiplying a stellar spectrum with an iodine spectrum and convolving the result with the spectrometer PSF. The free parameters of the model include the wavelength scale, spectrometer PSF, and stellar Doppler shift. All model parameters are derived anew for each exposure and the synthesis is done on a grid of CCD sub-pixels, using spline functions as interpolation predictors. We present Doppler tests of the Sun, Tau Ceti, and 107 Psc, observed with the Lick and Keck echelles. All exhibit apparent errors of about 3 m s^-1, maintained on time scales of minutes to a year. This precision agrees with the theoretically predicted errors that stem primarily from photon statistics. (SECTION: Astronomical Instrumentation)

  16. Highly selective and potent agonists of sphingosine-1-phosphate 1 (S1P1) receptor.

    PubMed

    Vachal, Petr; Toth, Leslie M; Hale, Jeffrey J; Yan, Lin; Mills, Sander G; Chrebet, Gary L; Koehane, Carol A; Hajdu, Richard; Milligan, James A; Rosenbach, Mark J; Mandala, Suzanne

    2006-07-15

    Novel series of sphingosine-1-phosphate (S1P) receptor agonists were developed through a systematic SAR aimed to achieve high selectivity for a single member of the S1P family of receptors, S1P1. The optimized structure represents a highly S1P1-selective and efficacious agonist: S1P1/S1P2, S1P1/S1P3, S1P1/S1P4>10,000-fold, S1P1/S1P5>600-fold, while EC50 (S1P1) <0.2 nM. In vivo experiments are consistent with S1P1 receptor agonism alone being sufficient for achieving desired lymphocyte-lowering effect.

  17. Spangolite: an s = 1/2 maple leaf lattice antiferromagnet?

    NASA Astrophysics Data System (ADS)

    Fennell, T.; Piatek, J. O.; Stephenson, R. A.; Nilsen, G. J.; Rønnow, H. M.

    2011-04-01

    Spangolite, Cu6Al(SO4)(OH)12Cl·3H2O, is a hydrated layered copper sulfate mineral. The Cu2 + ions of each layer form a systematically depleted triangular lattice which approximates a maple leaf lattice. We present details of the crystal structure, which suggest that in spangolite this lattice actually comprises two species of edge linked trimers with different exchange parameters. However, magnetic susceptibility measurements show that despite the structural trimers, the magnetic properties are dominated by dimerization. The high temperature magnetic moment is strongly reduced below that expected for the six s = 1/2 in the unit cell.

  18. M2b macrophage polarization accompanied with reduction of long noncoding RNA GAS5.

    PubMed

    Ito, Ichiaki; Asai, Akira; Suzuki, Sumihiro; Kobayashi, Makiko; Suzuki, Fujio

    2017-11-04

    Macrophages (Mϕ) are highly plastic and change their functional phenotypes depending on microenvironmental signals. Recent studies have shown that microRNAs are involved in the polarization of Mϕ. In this study, we demonstrated that the phenotype of M2bMϕ [CCL1(+) IL-10(+) LIGHT(+)] switches to other phenotypes with interchangeability attained through the increased expression of growth arrest-specific 5 RNA (GAS5 RNA), a long noncoding RNA. GAS5 RNA has been described as a silencer of the CCL1 gene. Various phenotypes of Mϕ were prepared from bone marrow-derived Mϕ (BMDMϕ) after stimulation with IFNγ [M(IFNγ)/M1Mϕ], IL-4 [M(IL-4)/M2aMϕ], LPS and immobilized IgG [M(LPS + IC)/M2bMϕ], and IL-10 [M(IL-10)/M2cMϕ]. BMDMϕ cultured with medium [M(no)/quiescent Mϕ] were used as a control. As compared to Μ(no), M(IFNγ), M(IL-4) and M(IL-10), the reduced level of GAS5 RNA was shown in M(LPS + IC). CCL1 and LIGHT mRNAs (typical biomarkers of M2bMϕ) were not expressed by M(LPS + IC) transduced with a GAS5 gene using lentiviral vector. The reduction of GAS5 RNA in M(LPS + IC) was mediated by the activation of nonsense-mediated RNA decay (NMD) pathway. BMDMϕ overexpressed with GAS5 RNA after GAS5 gene transduction did not polarize to M2bMϕ even though they were stimulated with LPS and IC in combination. These results indicate that the reduction of GAS5 RNA influenced by the NMD pathway activation leads to the Mϕ polarization stimulated with LPS and IC in combination. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Mechanism of the Pseudoirreversible Binding of Amantadine to the M2 Proton Channel.

    PubMed

    Llabrés, Salomé; Juárez-Jiménez, Jordi; Masetti, Matteo; Leiva, Rosana; Vázquez, Santiago; Gazzarrini, Sabrina; Moroni, Anna; Cavalli, Andrea; Luque, F Javier

    2016-11-30

    The M2 proton channel of influenza A virus is an integral membrane protein involved in the acidification of the viral interior, a step necessary for the release of the viral genetic material and replication of new virions. The aim of this study is to explore the mechanism of drug (un)binding to the M2 channel in order to gain insight into the structural and energetic features relevant for the development of novel inhibitors. To this end, we have investigated the binding of amantadine (Amt) to the wild type (wt) M2 channel and its V27A variant using multiple independent molecular dynamics simulations, exploratory conventional metadynamics, and multiple-walkers well-tempered metadynamics calculations. The results allow us to propose a sequential mechanism for the (un)binding of Amt to the wt M2 channel, which involves the adoption of a transiently populated intermediate (up state) leading to the thermodynamically favored down binding mode in the channel pore. Furthermore, they suggest that chloride anions play a relevant role in stabilizing the down binding mode of Amt to the wt channel, giving rise to a kinetic trapping that explains the experimentally observed pseudoirreversible inhibition of the wt channel by Amt. We propose that this trapping mechanism underlies the inhibitory activity of potent M2 channel blockers, as supported by the experimental confirmation of the irreversible binding of a pyrrolidine analogue from electrophysiological current assays. Finally, the results reveal that the thermodynamics and kinetics of Amt (un)binding is very sensitive to the V27A mutation, providing a quantitative rationale to the drastic decrease in inhibitory potency against the V27A variant. Overall, these findings pave the way to explore the inhibitory activity of Amt-related analogues in mutated M2 channel variants, providing guidelines for the design of novel inhibitors against resistant virus strains.

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

    NASA Image and Video Library

    1966-02-28

    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.

  1. Fast M2 measurement for fiber beams based on modal analysis.

    PubMed

    Flamm, Daniel; Schulze, Christian; Brüning, Robert; Schmidt, Oliver A; Kaiser, Thomas; Schröter, Siegmund; Duparré, Michael

    2012-03-01

    We report on a fast and experimentally easy technique for measuring the beam propagation ratio M(2) of light guided by optical fibers. A holographic filter enables us to determine amplitudes and phases of the excited fiber eigenmodes. The coherent superposition of modes allows the reconstruction of the optical field. With this information at hand, we are able to simulate the free-space propagation of the beam and to perform a virtual caustic measurement. Associated beam propagation ratios M(2) accurately agree with ISO-standard measurements. © 2012 Optical Society of America

  2. Open M2-branes with flux and the modified Basu-Harvey equation

    NASA Astrophysics Data System (ADS)

    Chu, Chong-Sun; Sehmbi, Gurdeep S.

    2011-04-01

    The supersymmetric actions of closed multiple M2 branes with flux for the Bagger-Lambert (BL) and ABJM theories have been constructed recently by Lambert and Richmond (2009 J. High Energy Phys. JHEP10(2009)084). In this paper, we extend the construction to the case of open M2-branes with flux and derive the boundary conditions. This allows us to derive the modified Basu-Harvey equation in the presence of flux. As an example, we consider the Lorentzian BL model. A new feature of the fuzzy funnel solution describing a D2-D4 intersection is obtained as a result of the flux.

  3. Production, chemical and isotopic separation of the178m2Hf high-spin isomer

    NASA Astrophysics Data System (ADS)

    Oganessian, Yu. Ts.; Hussonnois, M.; Brianôcon, Ch.; Karamian, S. A.; Szeglowski, Z.; Ledu, D.; Meunier, R.; Constantinescu, M.; Kim, J. B.; Constantinescu, O.

    1997-05-01

    The 178m2Hf with its long-lived (T1/2=31 y), high-spin Iπ = 16+, isomeric state, is a challenge for new and exotic nuclear physics studies. The 178m2Hf isomer has been produced in microweight quantities using the 176Yb(α,2n) nuclear reaction, by irradiation with a high-intensity beam using the U-200 cyclotron in Dubna. Radiochemistry and mass separation methods have been developed, with the aim to separate and purify the produced Hf material. Thin targets of isomeric hafnium-178 on carbon backings have been prepared and used in experiments with neutron, proton and deuteron beams.

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

    USGS Publications Warehouse

    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

  5. Desensitization and internalization of the m2 muscarinic acetylcholine receptor are directed by independent mechanisms.

    PubMed

    Pals-Rylaarsdam, R; Xu, Y; Witt-Enderby, P; Benovic, J L; Hosey, M M

    1995-12-01

    The phenomenon of acute desensitization of G-protein-coupled receptors has been associated with several events, including receptor phosphorylation, loss of high affinity agonist binding, receptor:G-protein uncoupling, and receptor internalization. However, the biochemical events underlying these processes are not fully understood, and their contributions to the loss of signaling remain correlative. In addition, the nature of the kinases and the receptor domains which are involved in modulation of activity have only begun to be investigated. In order to directly measure the role of G-protein-coupled receptor kinases (GRKs) in the desensitization of the m2 muscarinic acetylcholine receptor (m2 mAChR), a dominant-negative allele of GRK2 was used to inhibit receptor phosphorylation by endogenous GRK activity in a human embryonic kidney cell line. The dominant-negative GRK2K220R reduced agonist-dependent phosphorylation of the m2 mAChR by approximately 50% and prevented acute desensitization of the receptor as measured by the ability of the m2 mAChR to attenuate adenylyl cyclase activity. In contrast, the agonist-induced internalization of the m2 mAChR was unaffected by the GRK2K220R construct. Further evidence linking receptor phosphorylation to acute receptor desensitization was obtained when two deletions of the third intracellular loop were made which created m2 mAChRs that did not become phosphorylated in an agonist-dependent manner and did not desensitize. However, the mutant mAChRs retained the ability to internalize. These data provide the first direct evidence that GRK-mediated receptor phosphorylation is necessary for m2 mAChR desensitization; the likely sites of in vivo phosphorylation are in the central portion of the third intracellular loop (amino acids 282-323). These results also indicate that internalization of the m2 receptor is not a key event in desensitization and is mediated by mechanisms distinct from GRK phosphorylation of the receptor.

  6. Spontaneous mobility of GABAA receptor M2 extracellular half relative to noncompetitive antagonist action.

    PubMed

    Chen, Ligong; Durkin, Kathleen A; Casida, John E

    2006-12-15

    The gamma-aminobutyric acid type A receptor beta(3) homopentamer is spontaneously open and highly sensitive to many noncompetitive antagonists(NCAs) and Zn(2+). Our earlier study of the M2 cytoplasmic half (-1' to 10') established a model in which NCAs bind at pore-lining residues Ala(2)', Thr(6)', and Leu(9)'. To further define transmembrane 2 (M2) structure relative to NCA action, we extended the Cys scanning to the extra cellular half of the beta(3) homopentamer (11' to 20'). Spontaneous disulfides formed with T13'C, L18'C, and E20'C from M2/M2 cross-linking and with I14'C (weak), H17'C, and R19'Con bridging M2/M3 intersubunits, based on single (M2 Cys only) and dual (M2 Cys plus M3 C289S) mutations. Induced disulfides also formed with T16'C, but there were few or none with M11'C, T12'C, and N15'C. These findings show conformational flexibility/mobility in the M2 extracellular half 17' to 20' region interpreted as a deformed beta-like conformation in the open channel. The NCA radioligands used were [(3)H]1-(4-ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane ([(3)H]EBOB) and [(3)H]3,3-bis-trifluoromethylbicyclo[2.2.1]heptane-2,2-dicarbonitrile with essentially the same results. NCA binding was disrupted by individual Cys substitutions at 13',14',16',17', and 19'. The inactivity of T13'C/T13'S may have been due to disturbance of the channel gate; I14'S and T16'S showed much better binding activity than their Cys counterparts, and the low activities of H17'C and R19'C were reversed by dithiothreitol. Zn(2+) potency for inhibition of [(3)H]EBOB binding was lowered 346-fold by the mutation H17'A. We propose that NCAs enter their binding site both directly, through the channel pore, and indirectly, through the water cavity of adjacent subunits.

  7. Spontaneous thermal motion of the GABA(A) receptor M2 channel-lining segments.

    PubMed

    Bera, Amal K; Akabas, Myles H

    2005-10-21

    The gamma-aminobutyric acid type A (GABA(A)) receptor channel opening involves translational and rotational motions of the five channel-lining, M2 transmembrane segments. The M2 segment's extracellular half is loosely packed and undergoes significant thermal motion. To characterize the extent of the M2 segment's motion, we used disulfide trapping experiments between pairs of engineered cysteines. In alpha1beta1 gamma2S receptors the single gamma subunit is flanked by an alpha and beta subunit. The gamma2 M2-14' position is located in the alpha-gamma subunit interface. Gamma2 13' faces the channel lumen. We expressed either the gamma2 14' or the gamma2 13' cysteine substitution mutants with alpha1 cysteine substitution mutants between 12' and 16' and wild-type beta1. Disulfide bonds formed spontaneously between gamma2 14'C and both alpha1 15'C and alpha1 16'C and also between gamma2 13'C and alpha1 13'C. Oxidation by copper phenanthroline induced disulfide bond formation between gamma2 14'C and alpha1 13'C. Disulfide bond formation rates with gamma2 14'C were similar in the presence and absence of GABA, although the rate with alpha1 13'C was slower than with the other two positions. In a homology model based on the acetylcholine receptor structure, alphaM2 would need to rotate in opposite directions by approximately 80 degrees to bring alpha1 13' and alpha1 15' into close proximity with gamma2 14'. Alternatively, translational motion of alphaM2 would reduce the extent of rotational motion necessary to bring these two alpha subunit residues into close proximity with the gamma2 14' position. These experiments demonstrate that in the closed state the M2 segments undergo continuous spontaneous motion in the region near the extracellular end of the channel gate. Opening the gate may involve similar but concerted motions of the M2 segments.

  8. Pharmacokinetics of PEGylated recombinant human endostatin (M2ES) in rats

    PubMed Central

    Li, Zuo-gang; Jia, Lin; Guo, Li-fang; Yu, Min; Sun, Xu; Nie, Wen; Fu, Yan; Rao, Chun-ming; Wang, Jun-zhi; Luo, Yong-zhang

    2015-01-01

    Aim: M2ES is PEGylated recombinant human endostatin. In this study we investigated the pharmacokinetics, tissue distribution, and excretion of M2ES in rats. Methods: 125I-radiolabeled M2ES was administered to rats by intravenous bolus injection at 3 mg/kg. The pharmacokinetics, tissue distribution and excretion of M2ES were investigated using the trichloroacetic acid (TCA) precipitation method. Results: The serum M2ES concentration-time curve after a single intravenous dose of 3 mg/kg in rats was fitted with a non-compartment model. The pharmacokinetic parameters were evaluated as follows: Cmax=28.3 μg·equ/mL, t1/2=71.5 h, AUC(0–∞)=174.6 μg·equ·h/mL, Cl=17.2 mL·h−1·kg−1, MRT=57.6 h, and Vss=989.8 mL/kg for the total radioactivity; Cmax=30.3 μg·equ/mL, t1/2=60.1 h, AUC(0–∞)=146.2 μg·equ·h/mL, Cl=20.6 mL·h−1·kg−1, MRT=47.4 h, and Vss=974.6 mL/kg for the TCA precipitate radioactivity. M2ES was rapidly and widely distributed in various tissues and showed substantial deposition in kidney, adrenal gland, lung, spleen, bladder and liver. The radioactivity recovered in the urine and feces by 432 h post-dose was 71.3% and 8.3%, respectively. Only 0.98% of radioactivity was excreted in the bile by 24 h post-dose. Conclusion: PEG modification substantially prolongs the circulation time of recombinant human endostatin and effectively improves its pharmacokinetic behavior. M2ES is extensively distributed in most tissues of rats, including kidney, adrenal gland, lung, spleen, bladder and liver. Urinary excretion was the major elimination route for M2ES. PMID:26027657

  9. Ixmyelocel-T, an expanded multicellular therapy, contains a unique population of M2-like macrophages

    PubMed Central

    2013-01-01

    Introduction M2 macrophages promote tissue repair and regeneration through various mechanisms including immunomodulation and scavenging of tissue debris. Delivering increased numbers of these cells to ischemic tissues may limit tissue injury and promote repair. Ixmyelocel-T is an expanded, autologous multicellular therapy cultured from bone-marrow mononuclear cells (BMMNCs). The purpose of this study was to characterize further a unique expanded population of M2-like macrophages, generated in ixmyelocel-T therapy. Methods Approximately 50 ml of whole bone marrow was obtained from healthy donors and shipped overnight. BMMNCs were produced by using density-gradient separation and cultured for approximately 12 days to generate ixmyelocel-T. CD14+ cells were isolated from ixmyelocel-T with positive selection for analysis. Cell-surface phenotype was examined with flow cytometry and immunofluorescence, and expression of cytokines and chemokines was analyzed with enzyme-linked immunosorbent assay (ELISA). Quantitative real-time PCR was used to analyze expression of genes in BMMNCs, ixmyelocel-T, the CD14+ population from ixmyelocel-T, and M1 and M2 macrophages. Ixmyelocel-T was cultured with apoptotic BMMNCs, and then visualized under fluorescence microscopy to assess efferocytosis. Results Macrophages in ixmyelocel-T therapy expressed surface markers of M2 macrophages, CD206, and CD163. These cells were also found to express several M2 markers, and few to no M1 markers. After stimulation with lipopolysaccharide (LPS), they showed minimal secretion of the proinflammatory cytokines interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-α) compared with M1 and M2 macrophages. Ixmyelocel-T macrophages efficiently ingested apoptotic BMMNCs. Conclusions Ixmyelocel-T therapy contains a unique population of M2-like macrophages that are characterized by expression of M2 markers, decreased secretion of proinflammatory cytokines after inflammatory stimuli, and efficient

  10. Influenza Hemagglutinin and M2 ion channel priming by trypsin: Killing two birds with one stone.

    PubMed

    Chlanda, Petr

    2017-09-01

    Influenza A virus membrane fusion and disassembly, prerequisite processes for viral infectivity, depend on acidic pH. In a recent study, Zhirnov et al. reported an important finding-that influenza virions are not permeable to protons unless the hemagglutinin (HA) fusion protein is primed by trypsin cleavage. This raises the question of whether in the viral context the M2 ion channel requires priming prior to its activation by low pH. Here, it is hypothesized that both HA and M2 ion channel direct priming by trypsin is required for their sensitization by low pH. Published by Elsevier Inc.

  11. Increased function of inhibitory neuronal M2 muscarinic receptors in diabetic rat lungs

    PubMed Central

    Belmonte, Kristen E; Jacoby, David B; Fryer, Allison D

    1997-01-01

    The function of inhibitory neuronal M2 muscarinic receptors in diabetic rat lungs was investigated. Neuronal M2 muscarinic receptors inhibit acetylcholine release from parasympathetic nerves. Thus, stimulation of neuronal M2 muscarinic receptors with muscarinic agonists, such as pilocarpine, inhibits acetylcholine release and vagally induced bronchoconstriction. In contrast, blockade of neuronal M2 muscarinic receptors with selective M2 muscarinic antagonists, such as AF-DX 116, potentiates acetylcholine release and vagally induced bronchoconstriction. Rats were made diabetic by streptozotocin (65 mg kg−1, i.v.). After 7–14 days the rats were anaesthetized with urethane (1.5 g kg−1, i.p.), tracheostomized, vagotomized, ventilated and paralysed with suxamethonium (30 mg kg−1, i.v.). Some 7 day diabetic rats were treated with low doses of long acting (NPH) insulin (2 units day−1, s.c.) for 7 days before experimentation. This dose of insulin was not sufficient to restore normoglycaemia in diabetic rats. Thus, insulin-treated diabetic rats remained hyperglycaemic. Distal electrical stimulation (5–70 Hz, 6 s, 40 V, 0.4 ms) of the vagi caused bronchoconstriction, measured as an increase in inflation pressure and bradycardia. In diabetic rats, vagally induced bronchoconstriction was significantly depressed vs controls. In contrast, bronchoconstriction caused by i.v. acetylcholine was similar in diabetic and control animals. The function of neuronal M2 muscarinic receptors was tested with the muscarinic agonist pilocarpine (0.001–100.0 μg kg−1, i.v.) and the antagonist AF-DX 116 (0.01–3.0 mg kg−1, i.v.). Pilocarpine inhibited vagally-induced bronchoconstriction (30 Hz, 20–40 V, 0.4 ms at 6 s) and AF-DX 116 potentiated vagally-induced bronchoconstriction (20 Hz, 20–40 V, 0.4 ms at 6 s) to a significantly greater degree in diabetic rats compared to controls. Both frequency-dependent vagally

  12. Complete genome sequence of Rhodospirillum rubrum type strain (S1).

    PubMed

    Munk, A Christine; Copeland, Alex; Lucas, Susan; Lapidus, Alla; Del Rio, Tijana Glavina; Barry, Kerrie; Detter, John C; Hammon, Nancy; Israni, Sanjay; Pitluck, Sam; Brettin, Thomas; Bruce, David; Han, Cliff; Tapia, Roxanne; Gilna, Paul; Schmutz, Jeremy; Larimer, Frank; Land, Miriam; Kyrpides, Nikos C; Mavromatis, Konstantinos; Richardson, Paul; Rohde, Manfred; Göker, Markus; Klenk, Hans-Peter; Zhang, Yaoping; Roberts, Gary P; Reslewic, Susan; Schwartz, David C

    2011-07-01

    Rhodospirillum rubrum (Esmarch 1887) Molisch 1907 is the type species of the genus Rhodospirillum, which is the type genus of the family Rhodospirillaceae in the class Alphaproteobacteria. The species is of special interest because it is an anoxygenic phototroph that produces extracellular elemental sulfur (instead of oxygen) while harvesting light. It contains one of the most simple photosynthetic systems currently known, lacking light harvesting complex 2. Strain S1(T) can grow on carbon monoxide as sole energy source. With currently over 1,750 PubMed entries, R. rubrum is one of the most intensively studied microbial species, in particular for physiological and genetic studies. Next to R. centenum strain SW, the genome sequence of strain S1(T) is only the second genome of a member of the genus Rhodospirillum to be published, but the first type strain genome from the genus. The 4,352,825 bp long chromosome and 53,732 bp plasmid with a total of 3,850 protein-coding and 83 RNA genes were sequenced as part of the DOE Joint Genome Institute Program DOEM 2002.

  13. STS-112 S1 Truss Payload arrives at KSC

    NASA Technical Reports Server (NTRS)

    1999-01-01

    KENNEDY SPACE CENTER, FLA. -- NASA's Super Guppy airplane, with the International Space Station's (ISS) S1 truss aboard, arrives at KSC's Shuttle Landing Facility from Marshall Space Flight Center. Manufactured by the Boeing Co. in Huntington Beach, Calif ., this component of the ISS is the first starboard (right-side) truss segment, whose main job is providing structural support for the orbiting research facility's radiator panels that cool the Space Station's complex power system. The S1 truss segment al so will house communications systems, external experiment positions and other subsystems. Primarily constructed of aluminum, the truss segment is 45 feet long, 15 feet wide and 6 feet tall. When fully outfitted, it will weigh 31,137 pounds. The truss is s lated for flight in 2001. The Super Guppy, with its 25-foot diameter fuselage designed to handle oversized loads, is well prepared to transport the truss and other ISS segments. Loading the Guppy is easy because of the unique 'fold-away' nose of the aircr aft that opens 110 degrees for cargo loading. A system of rails in the cargo compartment, used with either Guppy pallets or fixtures designed for specific cargo, makes cargo loading simple and efficient. Rollers mounted in the rails allow pallets or fixtu res to be moved by an electric winch mounted beneath the cargo floor. Automatic hydraulic lock pins in each rail secure the pallet for flight. The truss is to be moved to the Operations and Checkout Building

  14. STS-112 S1 Truss Payload arrives at KSC

    NASA Technical Reports Server (NTRS)

    1999-01-01

    KENNEDY SPACE CENTER, FLA. -- At the Shuttle Landing Facility, the S1 truss, a segment of the International Space Station, is moved away from the Super Guppy that brought it to KSC from Marshall Space Flight Center. Manufactured by the Boeing Co. in Hunti ngton Beach, Calif., this component of the ISS is the first starboard (right-side) truss segment, whose main job is providing structural support for the orbiting research facility's radiator panels that cool the Space Station's complex power system. The S 1 truss segment also will house communications systems, external experiment positions and other subsystems. Primarily constructed of aluminum, the truss segment is 45 feet long, 15 feet wide and 6 feet tall. When fully outfitted, it will weigh 31,137 poun ds. The truss is slated for flight in 2001. The Super Guppy, with its 25-foot diameter fuselage designed to handle oversized loads, is well prepared to transport the truss and other ISS segments. Loading the Guppy is easy because of the unique 'fold-away' nose of the aircraft that opens 110 degrees for cargo loading. A system of rails in the cargo compartment, used with either Guppy pallets or fixtures designed for specific cargo, makes cargo loading simple and efficient. Rollers mounted in the rails allow pallets or fixtures to be moved by an electric winch mounted beneath the cargo floor. Automatic hydraulic lock pins in each rail secure the pallet for flight. The truss is being transferred to the Operations and Checkout Building.

  15. STS-112 S1 Truss Payload arrives at KSC

    NASA Technical Reports Server (NTRS)

    1999-01-01

    KENNEDY SPACE CENTER, FLA. -- Escort vehicles prepare to leave the Shuttle Landing Facility with the S1 truss (at right) on its trek to the Operations and Checkout Building. Manufactured by the Boeing Co. in Huntington Beach, Calif., this component of the ISS is the first starboard (right-side) truss segment, whose main job is providing structural support for the orbiting research facility's radiator panels that cool the Space Station's complex power system. The S1 truss segment also will house communications systems, external experiment positions and other subsystems. Primarily constructed of aluminum, the truss segment is 45 feet long, 15 feet wide and 6 feet tall. When fully outfitted, it will weigh 31,137 pounds. The truss is slated for flight in 2001. The truss arrived at KSC aboard NASA's Super Guppy, seen in the background. The aircraft is uniquely built with a 25-foot diameter fuselage designed to handle oversized loads and a 'fold-away' nose that opens 110 degrees for cargo loading. A system of rails in the cargo compartment, used with either Guppy pallets or fixtures designed for specific cargo, makes cargo loading simple and efficient. Rollers mounted in the rails allow pallets or fixtures to be moved by an electric winch mounted beneath the cargo floor. Automatic hydraulic lock pins in each rail secure the pallet for flight

  16. STS-112 S1 Truss Payload arrives at KSC

    NASA Technical Reports Server (NTRS)

    1999-01-01

    KENNEDY SPACE CENTER, FLA. -- At KSC's Shuttle Landing Facility, NASA's Super Guppy opens to reveal its cargo, the International Space Station's (ISS) S1 truss. Manufactured by the Boeing Co. in Huntington Beach, Calif., this component of the ISS is the f irst starboard (right-side) truss segment, whose main job is providing structural support for the orbiting research facility's radiator panels that cool the Space Station's complex power system. The S1 truss segment also will house communications systems, external experiment positions and other subsystems. Primarily constructed of aluminum, the truss segment is 45 feet long, 15 feet wide and 6 feet tall. When fully outfitted, it will weigh 31,137 pounds. The truss is slated for flight in 2001. The Super G uppy, with its 25-foot diameter fuselage designed to handle oversized loads, is well prepared to transport the truss and other ISS segments. Loading the Guppy is easy because of the unique 'fold-away' nose of the aircraft that opens 110 degrees for cargo loading. A system of rails in the cargo compartment, used with either Guppy pallets or fixtures designed for specific cargo, makes cargo loading simple and efficient. Rollers mounted in the rails allow pallets or fixtures to be moved by an electric winch mounted beneath the cargo floor. Automatic hydraulic lock pins in each rail secure the pallet for flight. The truss is to be transferred to the Operations and Checkout Building

  17. STS-112 S1 Truss Payload arrives at KSC

    NASA Technical Reports Server (NTRS)

    1999-01-01

    KENNEDY SPACE CENTER, FLA. -- NASA's Super Guppy airplane, with the International Space Station's (ISS) S1 truss aboard, rolls to a stop at KSC's Shuttle Landing Facility. Manufactured by the Boeing Co. in Huntington Beach, Calif., this component of the I SS is the first starboard (right-side) truss segment, whose main job is providing structural support for the orbiting research facility's radiator panels that cool the Space Station's complex power system. The S1 truss segment also will house communicatio ns systems, external experiment positions and other subsystems. Primarily constructed of aluminum, the truss segment is 45 feet long, 15 feet wide and 6 feet tall. When fully outfitted, it will weigh 31,137 pounds. The truss is slated for flight in 2001. The Super Guppy, with its 25-foot diameter fuselage designed to handle oversized loads, is well prepared to transport the truss and other ISS segments. Loading the Guppy is easy because of the unique 'fold-away' nose of the aircraft that opens 110 degrees for cargo loading. A system of rails in the cargo compartment, used with either Guppy pallets or fixtures designed for specific cargo, makes cargo loading simple and efficient. Rollers mounted in the rails allow pallets or fixtures to be moved by an elec tric winch mounted beneath the cargo floor. Automatic hydraulic lock pins in each rail secure the pallet for flight. The truss is to be transferred to the Operations and Checkout Building

  18. STS-112 S1 Truss Payload arrives at KSC

    NASA Technical Reports Server (NTRS)

    1999-01-01

    KENNEDY SPACE CENTER, FLA. -- At the Shuttle Landing Facility, the newly arrived S1 truss, a segment of the International Space Station (ISS), is offloaded from NASA's Super Guppy aircraft. Manufactured by the Boeing Co. in Huntington Beach, Calif., this component of the ISS is the first starboard (right-side) truss segment, whose main job is providing structural support for the orbiting research facility's radiator panels that cool the Space Station's complex power system. The S1 truss segment also will house communications systems, external experiment positions and other subsystems. Primarily constructed of aluminum, the truss segment is 45 feet long, 15 feet wide and 6 feet tall. When fully outfitted, it will weigh 31,137 pounds. The truss is slated fo r flight in 2001. The Super Guppy, with its 25-foot diameter fuselage designed to handle oversized loads, is well prepared to transport the truss and other ISS segments. Loading the Guppy is easy because of the unique 'fold-away' nose of the aircraft that opens 110 degrees for cargo loading. A system of rails in the cargo compartment, used with either Guppy pallets or fixtures designed for specific cargo, makes cargo loading simple and efficient. Rollers mounted in the rails allow pallets or fixtures to b e moved by an electric winch mounted beneath the cargo floor. Automatic hydraulic lock pins in each rail secure the pallet for flight. The truss is being transferred to the Operations and Checkout Building.

  19. STS-112 S1 Truss Payload arrives at KSC

    NASA Technical Reports Server (NTRS)

    1999-01-01

    KENNEDY SPACE CENTER, FLA. -- At the Shuttle Landing Facility, workers attach cranes to the S1 truss, a segment of the International Space Station, to lift the truss to a payload transporter for its transfer to the Operations and Checkout Building. Manufa ctured by the Boeing Co. in Huntington Beach, Calif., this component of the ISS is the first starboard (right-side) truss segment, whose main job is providing structural support for the orbiting research facility's radiator panels that cool the Space Station's complex power system. The S1 truss segment also will house communications systems, external experiment positions and other subsystems. Primarily constructed of aluminum, the truss segment is 45 feet long, 15 feet wide and 6 feet tall. When fully out fitted, it will weigh 31,137 pounds. The truss is slated for flight in 2001. The truss arrived at KSC aboard NASA's Super Guppy, with a 25-foot diameter fuselage designed to handle oversized loads. Loading the Guppy is easy because of the unique 'fold-away' nose of the aircraft that opens 110 degrees for cargo loading. A system of rails in the cargo compartment, used with either Guppy pallets or fixtures designed for specific cargo, makes cargo loading simple and efficient. Rollers mounted in the rails al low pallets or fixtures to be moved by an electric winch mounted beneath the cargo floor. Automatic hydraulic lock pins in each rail secure the pallet for flight

  20. Transport of coenzyme M (2-mercaptoethanesulfonic acid) and methylcoenzyme M [(2-methylthio)ethanesulfonic acid] in Methanococcus voltae: identification of specific and general uptake systems.

    PubMed Central

    Dybas, M; Konisky, J

    1989-01-01

    A transport system for coenzyme M (2-mercaptoethanesulfonic acid [HS-CoM]) and methylcoenzyme M [(2-(methylthio)ethanesulfonic acid (CH3-S-CoM)] in Methanococcus voltae required energy, showed saturation kinetics, and concentrated both forms of coenzyme M against a concentration gradient. Transport required hydrogen and carbon dioxide for maximal uptake. CH3-S-CoM uptake was inhibited by N-ethylmaleimide and monensin. Both HS-CoM and CH3-S-CoM uptake showed sodium dependence. In wild-type M. voltae, HS-CoM uptake was concentration dependent, with a Vmax of 960 pmol/min per mg of protein and an apparent Km of 61 microM. Uptake of CH3-S-CoM showed a Vmax of 88 pmol/min per mg of protein and a Km of 53 microM. A mutant of M. voltae resistant to the coenzyme M analog 2-bromoethanesulfonic acid (BES) showed no uptake of CH3-S-CoM but accumulated HS-CoM at the wild-type rate. While the higher-affinity uptake system was specific for HS-CoM, the lower-affinity system mediated uptake of HS-CoM, CH3-S-CoM, and BES. Analysis of the intracellular coenzyme M pools in metabolizing cells showed an intracellular HS-CoM concentration of 14.8 mM and CH3-S-CoM concentration of 0.21 mM. PMID:2509421

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

    NASA Technical Reports Server (NTRS)

    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

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

    NASA Technical Reports Server (NTRS)

    1963-01-01

    Following the first M2-F1 airtow flight on 16 August 1963, the Flight Research Center used the vehicle for both research flights and to check out new lifting-body pilots. These included Bruce Peterson, Don Mallick, Fred Haise, and Bill Dana from NASA. Air Force pilots who flew the M2-F1 included Chuck Yeager, Jerry Gentry, Joe Engle, Jim Wood, and Don Sorlie, although Wood, Haise, and Engle only flew on car tows. In the three years between the first and last flights of the M2-F1, it made about 400 car tows and 77 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

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

    NASA Technical Reports Server (NTRS)

    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

  4. Resonance Conversion as the Effective Way of Triggering the 178m2Hf Isomer Energy

    NASA Astrophysics Data System (ADS)

    Feodor, Karpeshin F.; Trzhaskovskaya, M. B.; Zhang, Jing-Bo

    2006-08-01

    Experiments on photo-induced de-excitation triggering of 178m2Hf are revisited. We present an alternative and more effective way of triggering by exploiting the resonance internal conversion. Full theoretical description of a possible channel is presented. It is therefore revisited the impact itself produced by those experiments.

  5. A survey on M2M systems for mHealth: a wireless communications perspective.

    PubMed

    Kartsakli, Elli; Lalos, Aris S; Antonopoulos, Angelos; Tennina, Stefano; Renzo, Marco Di; Alonso, Luis; Verikoukis, Christos

    2014-09-26

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

    NASA Astrophysics Data System (ADS)

    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.

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

    PubMed Central

    Kartsakli, Elli; Lalos, Aris S.; Antonopoulos, Angelos; Tennina, Stefano; Di Renzo, Marco; Alonso, Luis; Verikoukis, Christos

    2014-01-01

    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 of Wireless 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. PMID:25264958

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

    NASA Technical Reports Server (NTRS)

    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

  9. M2-polarized macrophages contribute to neovasculogenesis, leading to relapse of oral cancer following radiation

    PubMed Central

    Okubo, Makiko; Kioi, Mitomu; Nakashima, Hideyuki; Sugiura, Kei; Mitsudo, Kenji; Aoki, Ichiro; Taniguchi, Hideki; Tohnai, Iwai

    2016-01-01

    Despite the fact that radiation is one of the standard therapies in the treatment of patients with oral cancer, tumours can recur even in the early stages of the disease, negatively impacting prognosis and quality of life. We previously found that CD11b+ bone marrow-derived cells (BMDCs) were recruited into human glioblastoma multiforme (GBM), leading to re-organization of the vasculature and tumour regrowth. However, it is not yet known how these cells contribute to tumour vascularization. In the present study, we investigated the role of infiltrating CD11b+ myeloid cells in the vascularization and recurrence of oral squamous cell carcinoma (OSCC). In a xenograft mouse model, local irradiation caused vascular damage and hypoxia in the tumour and increased infiltration of CD11b+ myeloid cells. These infiltrating cells showed characteristics of M2 macrophages (M2Mφs) and are associated with the promotion of vascularization. M2Mφs promoted tumour progression in recurrence after irradiation compared to non-irradiated tumours. In addition, we found that CD11b+ myeloid cells, as well as CD206+ M2Mφs, are increased during recurrence after radiotherapy in human OSCC specimens. Our findings may lead to the development of potential clinical biomarkers or treatment targets in irradiated OSCC patients. PMID:27271009

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

    PubMed

    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

    2012-01-25

    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.

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

    SciTech Connect

    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

    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.

  12. Embryonic stem cell-derived M2-like macrophages delay cutaneous wound healing.

    PubMed

    Dreymueller, Daniela; Denecke, Bernd; Ludwig, Andreas; Jahnen-Dechent, Willi

    2013-01-01

    In adults, repair of deeply injured skin wounds results in the formation of scar tissue, whereas in embryos wounds heal almost scar-free. Macrophages are important mediators of wound healing and secrete cytokines and tissue remodeling enzymes. In contrast to host defense mediated by inflammatory M1 macrophages, wound healing and tissue repair involve regulatory M2/M2-like macrophages. Embryonic/fetal macrophages are M2-like, and this may promote scar-free wound healing. In the present study, we asked whether atopical application of ex vivo generated, embryonic stem cell-derived macrophages (ESDM) improve wound healing in mice. ESDM were tested side by side with bone marrow-derived macrophages (BMDM). Compared to BMDM, ESDM resembled a less inflammatory and more M2-like macrophage subtype as indicated by their reduced responsiveness to lipopolysaccharide, reduced expression of Toll-like receptors, and reduced bacterial phagocytosis. Despite this anti-inflammatory phenotype in cell culture, ESDM prolonged the healing of deep skin wounds even more than BMDM. Healed wounds had more scar formation compared to wounds receiving BMDM or cell-free treatment. Our data indicate that atopical application of ex vivo generated macrophages is not a suitable cell therapy of dermal wounds. © 2012 by the Wound Healing Society.

  13. M2 polarization of macrophages facilitates arsenic-induced cell transformation of lung epithelial cells.

    PubMed

    Cui, Jiajun; Xu, Wenhua; Chen, Jian; Li, Hui; Dai, Lu; Frank, Jacqueline A; Peng, Shaojun; Wang, Siying; Chen, Gang

    2017-03-28

    The alterations in microenvironment upon chronic arsenic exposure may contribute to arsenic-induced lung carcinogenesis. Immune cells, such as macrophages, play an important role in mediating the microenvironment in the lungs. Macrophages carry out their functions after activation. There are two activation status for macrophages: classical (M1) or alternative (M2); the latter is associated with tumorigenesis. Our previous work showed that long-term arsenic exposure induces transformation of lung epithelial cells. However, the crosstalk between epithelial cells and macrophages upon arsenic exposure has not been investigated. In this study, using a co-culture system in which human lung epithelial cells are cultured with macrophages, we determined that long-term arsenic exposure polarizes macrophages towards M2 status through ROS generation. Co-culture with epithelial cells further enhanced the polarization of macrophages as well as transformation of epithelial cells, while blocking macrophage M2 polarization decreased the transformation. In addition, macrophage M2 polarization decreased autophagy activity, which may account for increased cell transformation of epithelial cells with co-culture of macrophages.

  14. Universal M2 ectodomain-based influenza A vaccines: preclinical and clinical developments

    PubMed Central

    Schotsaert, Michael; De Filette, Marina; Fiers, Walter; Saelens, Xavier

    2009-01-01

    Influenza vaccines used today are strain specific and need to be adapted every year to try and match the antigenicity of the virus strains that are predicted to cause the next epidemic. The strain specificity of the next pandemic is unpredictable. An attractive alternative approach would be to use a vaccine that matches multiple influenza virus strains, including multiple subtypes. In this review, we focus on the development and clinical potential of a vaccine that is based on the conserved ectodomain of matrix protein 2 (M2) of influenza A virus. Since 1999, a number of studies have demonstrated protection against influenza A virus challenge in animal models using chemical or genetic M2 external domain (M2e) fusion constructs. More recently, Phase I clinical studies have been conducted with M2e vaccine candidates, demonstrating their safety and immunogenicity in humans. Ultimately, and possibly in the near future, efficacy studies in humans should provide proof that this novel vaccine concept can mitigate epidemic and even pandemic influenza A virus infections. PMID:19348565

  15. M2 polarization of macrophages facilitates arsenic-induced cell transformation of lung epithelial cells

    PubMed Central

    Li, Hui; Dai, Lu; Frank, Jacqueline A.; Peng, Shaojun; Wang, Siying; Chen, Gang

    2017-01-01

    The alterations in microenvironment upon chronic arsenic exposure may contribute to arsenic-induced lung carcinogenesis. Immune cells, such as macrophages, play an important role in mediating the microenvironment in the lungs. Macrophages carry out their functions after activation. There are two activation status for macrophages: classical (M1) or alternative (M2); the latter is associated with tumorigenesis. Our previous work showed that long-term arsenic exposure induces transformation of lung epithelial cells. However, the crosstalk between epithelial cells and macrophages upon arsenic exposure has not been investigated. In this study, using a co-culture system in which human lung epithelial cells are cultured with macrophages, we determined that long-term arsenic exposure polarizes macrophages towards M2 status through ROS generation. Co-culture with epithelial cells further enhanced the polarization of macrophages as well as transformation of epithelial cells, while blocking macrophage M2 polarization decreased the transformation. In addition, macrophage M2 polarization decreased autophagy activity, which may account for increased cell transformation of epithelial cells with co-culture of macrophages. PMID:28423485

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

    NASA Technical Reports Server (NTRS)

    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

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

    NASA Technical Reports Server (NTRS)

    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

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

    NASA Technical Reports Server (NTRS)

    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

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

    NASA Technical Reports Server (NTRS)

    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

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

    PubMed

    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).

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

    PubMed Central

    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 7th 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. PMID:26203332

  2. Adenosine augments IL-10-induced STAT3 signaling in M2c macrophages.

    PubMed

    Koscsó, Balázs; Csóka, Balázs; Kókai, Endre; Németh, Zoltán H; Pacher, Pál; Virág, László; Leibovich, S Joseph; Haskó, György

    2013-12-01

    The alternatively activated macrophage phenotype induced by IL-10 is called M2c. Adenosine is an endogenous purine nucleoside that accumulates in the extracellular space in response to metabolic disturbances, hypoxia, inflammation, physical damage, or apoptosis. As adenosine is known to regulate classically activated M1 and IL4- and IL-13-activated M2a macrophages, the goal of the present study was to explore its effects on M2c macrophages. We found that adenosine augmented the IL-10-induced expression of TIMP-1 and arginase-1 by the mouse macrophage cell line RAW 264.7 and by mouse BMDMs. The effects of AR stimulation on IL-10-induced TIMP-1 or arginase-1 expression were lacking in A2BAR KO macrophages. The role of A2BAR on TIMP-1 production of RAW 264.7 cells was confirmed with specific agonist BAY606583 and antagonist PSB0788. AR stimulation augmented IL-10-induced STAT3 phosphorylation in macrophages, and pharmacological inhibition or silencing of STAT3 using siRNA reduced the stimulatory effect of AR stimulation on TIMP-1 production. In contrast to its stimulatory effect on IL-10-induced STAT3 activation, adenosine inhibited IL-6-induced STAT3 phosphorylation and SAA3 expression. In conclusion, adenosine enhances IL-10-induced STAT3 signaling and M2c macrophage activation.

  3. M2C precipitates in isothermal tempering of high Co-Ni secondary hardening steel

    NASA Astrophysics Data System (ADS)

    Yoo, Choong Hwa; Lee, Hyuck Mo; Chan, Jin W.; Morris, John W.

    1996-11-01

    The effects of isothermal tempering on the coarsening behavior of hexagonal M2C precipitates and the secondary hardening reaction in ultrahigh-strength AerMet 100 steel were investigated. The tempering temperatures were 468 °C, 482 °C, and 510 °C, and the tempering time spanned the range from 1 to 400 hours. Experimental studies of the coarsening behavior of the carbides were made by utilizing transmission electron microscopy (TEM), scanning electron microscopy (SEM), and X-ray diffractometry (XRD). The hardness at the secondary hardening peak was about HRc 55. The average length and diameter of M2C carbides were 4 to 8 nm and 1.5 to 2.5 nm, respectively, at all three tempering temperatures; hence, the aspect ratio was almost 3, an equilibrium value in this case. The size of the M2C carbides increased monotonically with time, but the growth kinetics did not exactly follow the classical coarsening behavior. The amount of precipitated austenite increased with tempering time and temperature. M2C precipitates were still relatively fine even after 200 hours of tempering. This feature seemed to be closely related to the high hardness maintained after prolonged tempering.

  4. Abundance, distribution, mobility and oligomeric state of M2 muscarinic acetylcholine receptors in live cardiac muscle

    PubMed Central

    Nenasheva, Tatiana A.; Neary, Marianne; Mashanov, Gregory I.; Birdsall, Nigel J.M.; Breckenridge, Ross A.; Molloy, Justin E.

    2013-01-01

    M2 muscarinic acetylcholine receptors modulate cardiac rhythm via regulation of the inward potassium current. To increase our understanding of M2 receptor physiology we used Total Internal Reflection Fluorescence Microscopy to visualize individual receptors at the plasma membrane of transformed CHOM2 cells, a cardiac cell line (HL-1), primary cardiomyocytes and tissue slices from pre- and post-natal mice. Receptor expression levels between individual cells in dissociated cardiomyocytes and heart slices were highly variable and only 10% of murine cardiomyocytes expressed muscarinic receptors. M2 receptors were evenly distributed across individual cells and their density in freshly isolated embryonic cardiomyocytes was ~ 1 μm− 2, increasing at birth (to ~ 3 μm− 2) and decreasing back to ~ 1 μm− 2 after birth. M2 receptors were primarily monomeric but formed reversible dimers. They diffused freely at the plasma membrane, moving approximately 4-times faster in heart slices than in cultured cardiomyocytes. Knowledge of receptor density and mobility has allowed receptor collision rate to be modeled by Monte Carlo simulations. Our estimated encounter rate of 5–10 collisions per second, may explain the latency between acetylcholine application and GIRK channel opening. PMID:23357106

  5. Muscarinic M2 receptors in acetylcholine-isoproterenol functional antagonism in human isolated bronchus.

    PubMed

    Sarria, Benjamin; Naline, Emmanuel; Zhang, Yong; Cortijo, Julio; Molimard, Mathieu; Moreau, Joelle; Therond, Patrice; Advenier, Charles; Morcillo, Esteban J

    2002-11-01

    The muscarinic functional antagonism of isoproterenol relaxation and the contribution of muscarinic M2 receptors were examined in human isolated bronchus. In intact tissues, acetylcholine (ACh) precontraction decreased isoproterenol potency and maximal relaxation (-log EC50 shift = -1.49 +/- 0.16 and E(max) inhibition for 100 microM ACh = 30%) more than the same levels of histamine contraction. The M2 receptor-selective antagonist methoctramine (1 microM) reduced this antagonism in ACh- but not histamine-contracted tissues. Similar results were obtained for forskolin-induced relaxation. After selective inactivation of M3 receptors with 4-diphenylacetoxy-N-(2-chloroethyl)piperadine hydrochloric acid (30 nM), demonstrated by abolition of contractile and inositol phosphate responses to ACh, muscarinic recontractile responses were obtained in U-46619-precontracted tissues fully relaxed with isoproterenol. Methoctramine antagonized recontraction, with pK(B) (6.9) higher than in intact tissues (5.4), suggesting participation of M2 receptors. In M3-inactivated tissues, methoctramine augmented the isoproterenol relaxant potency in U-46619-contracted bronchus and reversed the ACh-induced inhibition of isoproterenol cAMP accumulation. These results indicate that M2 receptors cause indirect contraction of human bronchus by reversing sympathetically mediated relaxation and contribute to cholinergic functional antagonism.

  6. Polarization of M2 macrophages requires Lamtor1 that integrates cytokine and amino-acid signals.

    PubMed

    Kimura, Tetsuya; Nada, Shigeyuki; Takegahara, Noriko; Okuno, Tatsusada; Nojima, Satoshi; Kang, Sujin; Ito, Daisuke; Morimoto, Keiko; Hosokawa, Takashi; Hayama, Yoshitomo; Mitsui, Yuichi; Sakurai, Natsuki; Sarashina-Kida, Hana; Nishide, Masayuki; Maeda, Yohei; Takamatsu, Hyota; Okuzaki, Daisuke; Yamada, Masaki; Okada, Masato; Kumanogoh, Atsushi

    2016-10-12

    Macrophages play crucial roles in host defence and tissue homoeostasis, processes in which both environmental stimuli and intracellularly generated metabolites influence activation of macrophages. Activated macrophages are classified into M1 and M2 macrophages. It remains unclear how intracellular nutrition sufficiency, especially for amino acid, influences on macrophage activation. Here we show that a lysosomal adaptor protein Lamtor1, which forms an amino-acid sensing complex with lysosomal vacuolar-type H(+)-ATPase (v-ATPase), and is the scaffold for amino acid-activated mTORC1 (mechanistic target of rapamycin complex 1), is critically required for M2 polarization. Lamtor1 deficiency, amino-acid starvation, or inhibition of v-ATPase and mTOR result in defective M2 polarization and enhanced M1 polarization. Furthermore, we identified liver X receptor (LXR) as the downstream target of Lamtor1 and mTORC1. Production of 25-hydroxycholesterol is dependent on Lamtor1 and mTORC1. Our findings demonstrate that Lamtor1 plays an essential role in M2 polarization, coupling immunity and metabolism.

  7. First principles study of CrH and CrM2H

    NASA Astrophysics Data System (ADS)

    Kanagaprabha, S.; Santhosh, M.; Rajeswarapalanichamy, R.; Iyakutti, K.

    2013-06-01

    First principles calculation were performed using Tight-binding LMTO method with Local density approximation (LDA) and Atomic sphere approximation (ASA) to understand the electronic properties of CrH. A pressure induced structural phase transition from cubic to hexagonal structure of CrH is predicted. The stability of CrM2H is analyzed.

  8. Predominance of M2-polarized macrophages in bladder cancer affects angiogenesis, tumor grade and invasiveness.

    PubMed

    Takeuchi, Hisashi; Tanaka, Michio; Tanaka, Ayako; Tsunemi, Akisa; Yamamoto, Hidenobu

    2016-05-01

    Tumor-associated macrophages (TAMs) often assume an immunoregulatory M2 phenotype. Thus, the aim of the present study was to clarify the correlation of vascularity and TAMs, in particular the M2 phenotype in the stroma and tumor areas, with the clinical and pathological outcomes of patients with bladder cancer. The TAM counts and microvessel counts (MVCs) were determined immunohistochemically in 21 patients with bladder cancer. The number of infiltrating TAMs was measured using immunohistochemistry with anti-cluster of differentiation (CD)68 and anti-CD163 antibodies, to identify a macrophage lineage marker and an M2-polarized-specific cell surface receptor, respectively. CD68(+) and CD163(+) macrophages were evaluated in the stroma and tumor areas, and areas with a high density of infiltrating cell spots were counted. MVCs were determined using immunohistochemistry with anti-CD34 antibodies. The results revealed that the higher ratio of CD163(+)/CD68(+) macrophages in the stroma, tumor and total tumor tissues were correlated with a higher stage and grade (P<0.05). In addition, the low ratio of CD68(+)/CD34(+) microvessels was correlated with a higher stage (P<0.05). There was also a positive correlation between TAMs and MVC (r(2)=0.25; P<0.05). These results suggest that the TAM polarized M2 phenotype affects microvessels, pathological outcome, tumor grade and invasiveness.

  9. Chronic hepatitis C infection–induced liver fibrogenesis is associated with M2 macrophage activation

    PubMed Central

    Bility, Moses T.; Nio, Kouki; Li, Feng; McGivern, David R.; Lemon, Stanley M.; Feeney, Eoin R.; Chung, Raymond T.; Su, Lishan

    2016-01-01

    The immuno-pathogenic mechanisms of chronic hepatitis C virus (HCV) infection remain to be elucidated and pose a major hurdle in treating or preventing chronic HCV-induced advanced liver diseases such as cirrhosis. Macrophages are a major component of the inflammatory milieu in chronic HCV–induced liver disease, and are generally derived from circulating inflammatory monocytes; however very little is known about their role in liver diseases. To investigate the activation and role of macrophages in chronic HCV–induced liver fibrosis, we utilized a recently developed humanized mouse model with autologous human immune and liver cells, human liver and blood samples and cell culture models of monocyte/macrophage and/or hepatic stellate cell activation. We showed that M2 macrophage activation was associated with liver fibrosis during chronic HCV infection in the livers of both humanized mice and patients, and direct-acting antiviral therapy attenuated M2 macrophage activation and associated liver fibrosis. We demonstrated that supernatant from HCV-infected liver cells activated human monocytes/macrophages with M2-like phenotypes. Importantly, HCV-activated monocytes/macrophages promoted hepatic stellate cell activation. These results suggest a critical role for M2 macrophage induction in chronic HCV-associated immune dysregulation and liver fibrosis. PMID:28000758

  10. Polarization of M2 macrophages requires Lamtor1 that integrates cytokine and amino-acid signals

    PubMed Central

    Kimura, Tetsuya; Nada, Shigeyuki; Takegahara, Noriko; Okuno, Tatsusada; Nojima, Satoshi; Kang, Sujin; Ito, Daisuke; Morimoto, Keiko; Hosokawa, Takashi; Hayama, Yoshitomo; Mitsui, Yuichi; Sakurai, Natsuki; Sarashina-Kida, Hana; Nishide, Masayuki; Maeda, Yohei; Takamatsu, Hyota; Okuzaki, Daisuke; Yamada, Masaki; Okada, Masato; Kumanogoh, Atsushi

    2016-01-01

    Macrophages play crucial roles in host defence and tissue homoeostasis, processes in which both environmental stimuli and intracellularly generated metabolites influence activation of macrophages. Activated macrophages are classified into M1 and M2 macrophages. It remains unclear how intracellular nutrition sufficiency, especially for amino acid, influences on macrophage activation. Here we show that a lysosomal adaptor protein Lamtor1, which forms an amino-acid sensing complex with lysosomal vacuolar-type H+-ATPase (v-ATPase), and is the scaffold for amino acid-activated mTORC1 (mechanistic target of rapamycin complex 1), is critically required for M2 polarization. Lamtor1 deficiency, amino-acid starvation, or inhibition of v-ATPase and mTOR result in defective M2 polarization and enhanced M1 polarization. Furthermore, we identified liver X receptor (LXR) as the downstream target of Lamtor1 and mTORC1. Production of 25-hydroxycholesterol is dependent on Lamtor1 and mTORC1. Our findings demonstrate that Lamtor1 plays an essential role in M2 polarization, coupling immunity and metabolism. PMID:27731330

  11. Chronic hepatitis C infection-induced liver fibrogenesis is associated with M2 macrophage activation.

    PubMed

    Bility, Moses T; Nio, Kouki; Li, Feng; McGivern, David R; Lemon, Stanley M; Feeney, Eoin R; Chung, Raymond T; Su, Lishan

    2016-12-21

    The immuno-pathogenic mechanisms of chronic hepatitis C virus (HCV) infection remain to be elucidated and pose a major hurdle in treating or preventing chronic HCV-induced advanced liver diseases such as cirrhosis. Macrophages are a major component of the inflammatory milieu in chronic HCV-induced liver disease, and are generally derived from circulating inflammatory monocytes; however very little is known about their role in liver diseases. To investigate the activation and role of macrophages in chronic HCV-induced liver fibrosis, we utilized a recently developed humanized mouse model with autologous human immune and liver cells, human liver and blood samples and cell culture models of monocyte/macrophage and/or hepatic stellate cell activation. We showed that M2 macrophage activation was associated with liver fibrosis during chronic HCV infection in the livers of both humanized mice and patients, and direct-acting antiviral therapy attenuated M2 macrophage activation and associated liver fibrosis. We demonstrated that supernatant from HCV-infected liver cells activated human monocytes/macrophages with M2-like phenotypes. Importantly, HCV-activated monocytes/macrophages promoted hepatic stellate cell activation. These results suggest a critical role for M2 macrophage induction in chronic HCV-associated immune dysregulation and liver fibrosis.

  12. Chlorogenic acid inhibits glioblastoma growth through repolarizating macrophage from M2 to M1 phenotype

    PubMed Central

    Xue, Nina; Zhou, Qin; Ji, Ming; Jin, Jing; Lai, Fangfang; Chen, Ju; Zhang, Mengtian; Jia, Jing; Yang, Huarong; Zhang, Jie; Li, Wenbin; Jiang, Jiandong; Chen, Xiaoguang

    2017-01-01

    Glioblastoma is an aggressive tumor that is associated with distinctive infiltrating microglia/macrophages populations. Previous studies demonstrated that chlorogenic acid (5-caffeoylquinic acid, CHA), a phenolic compound with low molecular weight, has an anti-tumor effect in multiple malignant tumors. In the present study, we focused on the macrophage polarization to investigate the molecular mechanisms behind the anti-glioma response of CHA in vitro and in vivo. We found that CHA treatment increased the expression of M1 markers induced by LPS/IFNγ, including iNOS, MHC II (I-A/I-E subregions) and CD11c, and reduced the expression of M2 markers Arg and CD206 induced by IL-4, resulting in promoting the production of apoptotic-like cancer cells and inhibiting the growth of tumor cells by co-culture experiments. The activations of STAT1 and STAT6, which are two crucial signaling events in M1 and M2-polarization, were significantly promoted and suppressed by CHA in macrophages, respectively. Furthermore, In G422 xenograft mice, CHA increased the proportion of CD11c-positive M1 macrophages and decreased the distribution of CD206-positive M2 macrophages in tumor tissue, consistent with the reduction of tumor weight observed in CHA-treated mice. Overall these findings indicated CHA as a potential therapeutic approach to reduce glioma growth through promoting M1-polarized macrophage and inhibiting M2 phenotypic macrophage. PMID:28045028

  13. Medroxyprogesterone acetate drives M2 macrophage differentiation toward a phenotype of decidual macrophage.

    PubMed

    Tsai, Yung-Chieh; Tseng, Joseph T; Wang, Chia-Yih; Su, Mei-Tsz; Huang, Jyun-Yuan; Kuo, Pao-Lin

    2017-09-05

    M1 macrophage differentiation plays a crucial role in enhanced inflammation during pregnancy, which may lead to pregnancy complications. Therefore, modulation of macrophage differentiation toward the M2 phenotype is desirable to ensure a successful pregnancy. Medroxyprogesterone acetate (MPA) is a potent progestin with an anti-inflammatory property, but its effect on macrophage differentiation is unknown. This study aimed to examine whether MPA can induce an M2 macrophage differentiation by using the human monocytes cell line THP-1 or primary monocytes. THP-1 cells were primed with phorbol-12-myristate-13 acetate (PMA) to initiate macrophage differentiation. By incubating with MPA, the cells (denoted as MPA-pTHP-1) underwent M2 macrophage differentiation with downregulations of CD11c, IL-1β and TNF-α, and upregulations of CD163 and IL-10; while cells incubated with progesterone (P4) did not show the M2 phenotype. Primary monocytes treated with MPA also had the same M2 phenotype. Moreover, M1 macrophages derived from IFN-γ/LPS-treated THP-1 cells, which had high levels of IL-1b and iNOS, and low levels of IL-10 and IDO, were reversed to the M2 phenotype by the MPA treatment. We also found that the MPA-pTHP-1 promoted the decidualization of endometrial stromal cells and the invasion of trophoblast cells. To mimic conditions of exposure to various pathogens, MPA-pTHP-1 cells were stimulated by different types of TLR ligands. We found they produced lower levels of IL-1β and TNF-α, as well as a higher level of IL-10, compared to untreated cells. Finally, we found the level of phosphorylated ERK in the MPA-pTHP-1 cells was increased, but its IL-10 production was suppressed by either the progesterone/glucocorticoid antagonist (Mifepristone) or MEK inhibitor (U0126). Taken together, MPA could drive monocyte differentiation toward an M2 phenotype that mimics decidual macrophages. This finding holds great potential to combat chronic endometrial inflammation

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

    NASA Technical Reports Server (NTRS)

    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

  15. Sphingosine 1-phosphate (S1P)/S1P receptor 1 signaling regulates receptor activator of NF-{kappa}B ligand (RANKL) expression in rheumatoid arthritis

    SciTech Connect

    Takeshita, Harunori; Kitano, Masayasu; Iwasaki, Tsuyoshi; Kitano, Sachie; Tsunemi, Sachi; Sato, Chieri; Sekiguchi, Masahiro; Azuma, Naoto; Miyazawa, Keiji; Hla, Timothy; Sano, Hajime

    2012-03-09

    Highlights: Black-Right-Pointing-Pointer MH7A cells and CD4{sup +} T cells expressed S1P1 and RANKL. Black-Right-Pointing-Pointer S1P increased RANKL expression in MH7A cells and CD4{sup +} T cells. Black-Right-Pointing-Pointer The effect of S1P in MH7A cells was inhibited by specific Gi/Go inhibitors. -- Abstract: Sphingosine 1-phosphate (S1P)/S1P receptor 1 (S1P1) signaling plays an important role in synovial cell proliferation and inflammatory gene expression by rheumatoid arthritis (RA) synoviocytes. The purpose of this study is to clarify the role of S1P/S1P1 signaling in the expression of receptor activator of NF-{kappa}B ligand (RANKL) in RA synoviocytes and CD4{sup +} T cells. We demonstrated MH7A cells, a human RA synovial cell line, and CD4{sup +} T cells expressed S1P1 and RANKL. Surprisingly, S1P increased RANKL expression in MH7A cells and CD4{sup +} T cells in a dose-dependent manner. Moreover, S1P enhanced RANKL expression induced by stimulation with TNF-{alpha} in MH7A cells and CD4{sup +} T cells. These effects of S1P in MH7A cells were inhibited by pretreatment with PTX, a specific Gi/Go inhibitor. These findings suggest that S1P/S1P1 signaling may play an important role in RANKL expression by MH7A cells and CD4{sup +} T cells. S1P/S1P1 signaling of RA synoviocytes is closely connected with synovial hyperplasia, inflammation, and RANKL-induced osteoclastogenesis in RA. Thus, regulation of S1P/S1P1 signaling may become a novel therapeutic target for RA.

  16. Platelet and Erythrocyte Sources of S1P Are Redundant for Vascular Development and Homeostasis, but Both Rendered Essential After Plasma S1P Depletion in Anaphylactic Shock.

    PubMed

    Gazit, Salomé L; Mariko, Boubacar; Thérond, Patrice; Decouture, Benoit; Xiong, Yuquan; Couty, Ludovic; Bonnin, Philippe; Baudrie, Véronique; Le Gall, Sylvain M; Dizier, Blandine; Zoghdani, Nesrine; Ransinan, Jessica; Hamilton, Justin R; Gaussem, Pascale; Tharaux, Pierre-Louis; Chun, Jerold; Coughlin, Shaun R; Bachelot-Loza, Christilla; Hla, Timothy; Ho-Tin-Noé, Benoit; Camerer, Eric

    2016-09-30

    Sphingosine-1-phosphate (S1P) signaling is essential for vascular development and postnatal vascular homeostasis. The relative importance of S1P sources sustaining these processes remains unclear. To address the level of redundancy in bioactive S1P provision to the developing and mature vasculature. S1P production was selectively impaired in mouse platelets, erythrocytes, endothelium, or smooth muscle cells by targeted deletion of genes encoding sphingosine kinases -1 and -2. S1P deficiency impaired aggregation and spreading of washed platelets and profoundly reduced their capacity to promote endothelial barrier function ex vivo. However, and in contrast to recent reports, neither platelets nor any other source of S1P was essential for vascular development, vascular integrity, or hemostasis/thrombosis. Yet rapid and profound depletion of plasma S1P during systemic anaphylaxis rendered both platelet- and erythrocyte-derived S1P essential for survival, with a contribution from blood endothelium observed only in the absence of circulating sources. Recovery was sensitive to aspirin in mice with but not without platelet S1P, suggesting that platelet activation and stimulus-response coupling is needed. S1P deficiency aggravated vasoplegia in this model, arguing a vital role for S1P in maintaining vascular resistance during recovery from circulatory shock. Accordingly, the S1P2 receptor mediated most of the survival benefit of S1P, whereas the endothelial S1P1 receptor was dispensable for survival despite its importance for maintaining vascular integrity. Although source redundancy normally secures essential S1P signaling in developing and mature blood vessels, profound depletion of plasma S1P renders both erythrocyte and platelet S1P pools necessary for recovery and high basal plasma S1P levels protective during anaphylactic shock. © 2016 American Heart Association, Inc.

  17. Neisseria gonorrhoeae Modulates Immunity by Polarizing Human Macrophages to a M2 Profile

    PubMed Central

    Ortiz, María Carolina; Lefimil, Claudia; Rodas, Paula I.; Vernal, Rolando; Lopez, Mercedes; Acuña-Castillo, Claudio; Imarai, Mónica; Escobar, Alejandro

    2015-01-01

    Current data suggest that Neisseria gonorrhoeae is able to suppress the protective immune response at different levels, such as B and T lymphocytes and antigen-presenting cells. The present report is focused on gonococcus evasion mechanism on macrophages (MФ) and its impact in the subsequent immune response. In response to various signals MФ may undergo classical-M1 (M1-MФ) or alternative-M2 (M2-MФ) activation. Until now there are no reports of the gonococcus effects on human MФ polarization. We assessed the phagocytic ability of monocyte-derived MФ (MDM) upon gonococcal infection by immunofluorescence and gentamicin protection experiments. Then, we evaluated cytokine profile and M1/M2 specific-surface markers on MФ challenged with N. gonorrhoeae and their proliferative effect on T cells. Our findings lead us to suggest N. gonorrhoeae stimulates a M2-MФ phenotype in which some of the M2b and none of the M1-MФ-associated markers are induced. Interestingly, N. gonorrhoeae exposure leads to upregulation of a Programmed Death Ligand 1 (PD-L1), widely known as an immunosuppressive molecule. Moreover, functional results showed that N. gonorrhoeae-treated MФ are unable to induce proliferation of human T-cells, suggesting a more likely regulatory phenotype. Taken together, our data show that N. gonorroheae interferes with MФ polarization. This study has important implications for understanding the mechanisms of clearance versus long-term persistence of N. gonorroheae infection and might be applicable for the development of new therapeutic strategies. PMID:26125939

  18. Selective M2 Macrophage Depletion Leads to Prolonged Inflammation in Surgical Wounds.

    PubMed

    Klinkert, Kerstin; Whelan, Derek; Clover, Anthony J P; Leblond, Anne-Laure; Kumar, Arun H S; Caplice, Noel M

    2017-01-01

    A prolonged inflammatory phase is seen in aberrant wound healing and in chronic wounds. Macrophages are central to wound healing. Distinct macrophage subtypes have differing roles both in initial inflammation and in later tissue repair. Broadly, these cells can be divided into M1 and M2 macrophages. M2 macrophage proliferation and differentiation is regulated by colony-stimulating factor 1 (CSF-1) signalling and can be blocked by GW2580, a competitive cFMS kinase inhibitor, thereby allowing for analysis of the effect of M2 blockade on progression of surgical wounds. Macrophage Fas-induced apoptosis (MaFIA) transgenic mice with a macrophage-specific promoter used to express green fluorescent protein (GFP) were used to allow for cell tracking. The animals were treated by oral gavage with GW2580. Surgical wounds were created and harvested after 2 weeks for analysis. GW2580-treated mice had significantly more GFP+ cells in the surgical scar than vehicle-treated animals (GW2580, 68.0 ± 3.1%; vehicle, 42.8 ± 1.7%; p < 0.001), and GW2580 treatment depleted CD206+ M2 macrophages in the scar (GW2580, 1.4%; vehicle, 19.3%; p < 0.001). Treated animals showed significantly higher numbers of neutrophils (vehicle, 18.0%; GW2580, 51.3%; p < 0.01) and M1 macrophages (vehicle, 3.8%; GW2580, 12.8%; p < 0.01) in the scar compared to vehicle-treated animals. The total collagen content in the area of the scar was decreased in animals treated with GW2580 as compared to those treated with vehicle alone (GW2580, 67.1%; vehicle, 79.9%; p < 0.005). Depletion of M2 macrophages in surgical wounds via CSF-1 signalling blockade leads to persistent inflammation, with an increase in neutrophils and M1 macrophages and attenuated collagen deposition. © 2017 S. Karger AG, Basel.

  19. Viral M2 ion channel protein: a promising target for anti-influenza drug discovery.

    PubMed

    Moorthy, N S Hari Narayana; Poongavanam, Vasanthanathan; Pratheepa, V

    2014-01-01

    Influenza virus is an important RNA virus causing pandemics (Spanish Flu (1918), Asian Flu (1957), Hong Kong Flu (1968) and Swine Flu (2009)) over the last decades. Due to the spontaneous mutations of these viral proteins, currently available antiviral and anti-influenza drugs quickly develop resistance. To account this, only limited antiinfluenza drugs have been approved for the therapeutic use. These include amantadine and rimantadine (M2 proton channel blockers), zanamivir, oseltamivir and peramivir (neuraminidase inhibitors), favipravir (polymerase inhibitor) and laninamivir. This review provides an outline on the strategies to develop novel, potent chemotherapeutic agents against M2 proton channel. Primarily, the M2 proton channel blockers elicit pharmacological activity through destabilizing the helices by blocking the proton transport across the transmembrane. The biologically important compounds discovered using the scaffolds such as bisnoradmantane, noradamantane, triazine, spiroadamantane, isoxazole, amino alcohol, azaspiro, spirene, pinanamine, etc are reported to exhibit anti-influenza activity against wild or mutant type (S31N and V27A) of M2 proton channel protein. The reported studies explained that the adamantane based compounds (amantadine and rimantadine) strongly interact with His37 (through hydrogen bonding) and Ala30, Ile33 and Gly34 residues (hydrophobic interactions). The adamantane and the non-adamantane scaffolds fit perfectly in the active site pocket present in the wild type and the charged amino groups (ammonium) create positive electrostatic potential, which blocks the transport of protons across the pore. In the mutated proteins, larger or smaller binding pocket are created by small or large mutant residues, which do not allow the molecules fit in the active site. This causes the channel to be unblocked and the protons are allowed to transfer inside the pore. The structural analysis of the M2 proton channel blockers illustrated that

  20. Chemotherapy toxicity in gynecologic cancer patients with a body surface area (BSA)>2 m2.

    PubMed

    Schwartz, Joanna; Toste, Beth; Dizon, Don S

    2009-07-01

    Although many clinicians practice empiric dose reduction to prevent toxicity, it is unknown whether obese patients given chemotherapy dosed according to actual body weight (ABW) experience excess toxicity. At our institution, cancer patients receive chemotherapy dosed by ABW unless on a protocol capping doses at a maximum body surface area (BSA). We compared toxicities and dose modifications between women with a BSA>2 m(2) on uncapped versus capped paclitaxel as part of adjuvant paclitaxel/carboplatin for gynecologic malignancy. In this retrospective study, women with a BSA>2 m(2) treated with paclitaxel (P) and carboplatin (C) for endometrial and ovarian cancer between January 1999 and July 2007 were identified using the chemotherapy database. Records were reviewed for patient age, BSA, diagnosis, stage, standardized and actual doses for each cycle, adverse drug reactions, and dosing modifications. Statistical comparisons were made using Fisher's exact test. We identified 59 women with BSA>2 m(2) on adjuvant P/C for endometrial and ovarian cancers. 50 received paclitaxel dosed by ABW and 9 received paclitaxel capped at a BSA of 2 m(2). There were no statistically significant differences in rates of toxicity or dose modification. Obese women with a BSA>2 m(2) on paclitaxel dosed by ABW do not experience excess toxicity in comparison to women on paclitaxel capped at a maximum BSA or women in published trials of adjuvant P/C. Empiric dose reduction is unnecessary and may result in suboptimal treatment of obese patients. However, as this was a retrospective review, more research is needed to make definitive recommendations on this topic.

  1. Generation and characterization of a Tet-On (rtTA-M2) transgenic rat

    PubMed Central

    2010-01-01

    Background The tetracycline-inducible gene regulation system is a powerful tool that allows temporal and dose-dependent regulation of target transgene expression in vitro and in vivo. Several tetracycline-inducible transgenic mouse models have been described with ubiquitous or tissue-specific expression of tetracycline-transactivator (tTA), reverse tetracycline-transactivator (rtTA) or Tet repressor (TetR). Here we describe a Tet-On transgenic rat that ubiquitously expresses rtTA-M2 driven by the murine ROSA 26 promoter. Results The homozygous rat line (ROSA-rtTA-M2) generated by lentiviral vector injection, has a single integration site and was derived from the offspring of a genetic mosaic founder with multiple transgene integrations. The rtTA-M2 transgene integrated into an intron of a putative gene on chromosome 2 and does not appear to affect the tissue-specificity or expression of that gene. Fibroblasts from the ROSA-rtTA-M2 rats were transduced with a TetO7/CMV-EGFP lentivirus and exhibited doxycycline dose-dependent expression of the EGFP reporter transgene, in vitro. In addition, doxycycline-inducible EGFP expression was observed, in vivo, when the TetO7/CMV-EGFP lentivirus was injected into testis, kidney and muscle tissues of ROSA-rtTA-M2 rats. Conclusions This conditional expression rat model may have application for transgenic overexpression or knockdown studies of gene function in development, disease and gene therapy. PMID:20158911

  2. Study on Phylogenetic Relationships, Variability, and Correlated Mutations in M2 Proteins of Influenza Virus A

    PubMed Central

    Le, Ly; Leluk, Jacek

    2011-01-01

    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. PMID:21829678

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

    PubMed Central

    Lenzo, Jason C.; Fong, Shao B.; Reynolds, Eric C.

    2016-01-01

    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. PMID:27383471

  4. Dietary oleic acid increases m2 macrophages in the mesenteric adipose tissue.

    PubMed

    Camell, Christina; Smith, C Wayne

    2013-01-01

    Several studies have implicated fatty-acids as inflammatory regulators, suggesting that there may be a direct role for common dietary fatty-acids in regulating innate immune cells. In humans, a single high-fat meal increases systemic cytokines and leukocytes. In mice, short term high-fat feeding increases adipose tissue (AT) leukocytes and alters the inflammatory profile of AT macrophages. We have seen that short term high fat feeding to C57BL/6J male mice increases palmitic and oleic acid within AT depots, but oleic acid increase is highest in the mesenteric AT (MAT). In vitro, oleic acid increases M2 macrophage markers (CD206, MGL1, and ARG1) in a murine macrophage cell line, while addition of palmitic acid is able to inhibit that increase. Three day supplementation of a chow diet, with oleic acid, induced an increase in M2 macrophage markers in the MAT, but not in the epididymal AT. We tested whether increases in M2 macrophages occur during short term ad lib feeding of a high fat diet, containing oleic acid. Experiments revealed two distinct populations of macrophages were altered by a three day high milk-fat diet. One population, phenotypically intermediate for F4/80, showed diet-induced increases in CD206, an anti-inflammatory marker characteristic of M2 macrophages intrinsic to the AT. Evidence for a second population, phenotypically F4/80(HI)CD11b(HI) macrophages, showed increased association with the MAT following short term feeding that is dependent on the adhesion molecule, ICAM-1. Collectively, we have shown that short term feeding of a high-fat diet changes two population of macrophages, and that dietary oleic acid is responsible for increases in M2 macrophage polarization.

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

    NASA Technical Reports Server (NTRS)

    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

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

    NASA Technical Reports Server (NTRS)

    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

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

    NASA Technical Reports Server (NTRS)

    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

  8. Magnetoelectric Behavior from S =1 /2 Asymmetric Square Cupolas

    NASA Astrophysics Data System (ADS)

    Kato, Yasuyuki; Kimura, Kenta; Miyake, Atsushi; Tokunaga, Masashi; Matsuo, Akira; Kindo, Koichi; Akaki, Mitsuru; Hagiwara, Masayuki; Sera, Masakazu; Kimura, Tsuyoshi; Motome, Yukitoshi

    2017-03-01

    Magnetoelectric properties are studied by a combined experimental and theoretical study of a quasi-two-dimensional material composed of square cupolas, Ba(TiO )Cu4(PO4 ) 4 . The magnetization is measured up to the field above the saturation, and several anomalies are observed depending on the field directions. We propose a S =1 /2 spin model with Dzyaloshinskii-Moriya interactions, which reproduces the full magnetization curves well. Elaborating the phase diagram of the model, we show that the anomalies are explained by magnetoelectric phase transitions. Our theory also accounts for the scaling of the dielectric anomaly observed in the experiments. The results elucidate the crucial role of the in-plane component of Dzyaloshinskii-Moriya interactions, which is induced by the noncoplanar buckling of a square cupola. We also predict a "hidden" phase and another magnetoelectric response, both of which appear in a nonzero magnetic field.

  9. Effect of anisotropy in the S=1 underscreened Kondo lattice

    NASA Astrophysics Data System (ADS)

    Thomas, Christopher; da Rosa Simões, Acirete S.; Lacroix, Claudine; Iglesias, José Roberto; Coqblin, Bernard

    2014-12-01

    We study the effect of crystal field anisotropy in the underscreened S=1 Kondo lattice model. Starting from the two orbital Anderson lattice model and including a local anisotropy term, we show, through Schrieffer-Wolff transformation, that local anisotropy is equivalent to an anisotropic Kondo interaction (J∥≠J⊥). The competition and coexistence between ferromagnetism and Kondo effect in this effective model is studied within a generalized mean-field approximation. Several regimes are obtained, depending on the parameters, exhibiting or not coexistence of magnetic order and Kondo effect. Particularly, we show that a re-entrant Kondo phase at low temperature can be obtained. We are also able to describe phases where the Kondo temperature is smaller than the Curie temperature (TK

  10. Confinement and power balance in the S-1 spheromak

    SciTech Connect

    Levinton, F.M.; Meyerhofer, D.D.; Mayo, R.M.; Janos, A.C.; Ono, Y.; Ueda, Y.; Yamada, M.

    1989-07-01

    The confinement and scaling features of the S-1 spheromak have been investigated using magnetic, spectroscopic, and Thomson scattering data in conjunction with numerical modeling. Results from the multipoint Thomson scattering diagnostic shows that the central beta remains constant (/beta//sub to/ /approximately/ 5%) as the plasma current density increases from 0.68--2.1 MA/m/sup 2/. The density is observed to increase slowly over this range, while the central electron temperature increases much more rapidly. Analysis of the global plasma parameters shows a decrease in the volume average beta and energy confinement as the total current is increased. The power balance has been modeled numerically with a 0-D non-equilibrium time-dependent coronal model and is consistent with the experimental observations. 20 refs., 12 figs., 2 tabs.

  11. Transitive Lie groups on S^1\\times S^{2m}

    NASA Astrophysics Data System (ADS)

    Gorbatsevich, Vladimir V.

    2007-10-01

    The structure of Lie groups acting transitively on the direct product of a circle and an even-dimensional sphere is described. For products of two spheres of dimension >1 a similar problem has already been solved by other authors. The minimal transitive Lie groups on S^1 and S^{2m} are also indicated. As an application of these results, the structure of the automorphism group of one class of geometric structures, generalized quadrangles (a special case of Tits buildings) is considered. A conjecture put forward by Kramer is proved: the automorphism group of a connected generalized quadrangle of type (1,2m) always contains a transitive subgroup that is the direct product of a compact simple Lie group and a one-dimensional Lie group. Bibliography: 16 titles.

  12. Safety and efficacy of stereotactic body radiation therapy combined with S-1 simultaneously followed by sequential S-1 as an initial treatment for locally advanced pancreatic cancer (SILAPANC) trial: study design and rationale of a phase II clinical trial

    PubMed Central

    Zhu, Xiaofei; Ju, Xiaoping; Cao, Fei; Fang, Fang; Qing, Shuiwang; Shen, Yuxin; Jia, Zhen; Cao, Yangsen; Zhang, Huojun

    2016-01-01

    Introduction Upfront surgeries are not beneficial to most patients with pancreatic cancer. Therefore, more emphasis has been placed chemoradiotherapy in locally advanced pancreatic cancer recently. Gemcitabine-based regimens or FOLFIRINOX (a chemotherapy regimen including leucovorin, 5-FU, irinotecan, oxaliplatin) has been proven as a standard chemotherapy in pancreatic cancer. However, severe toxicities may prevent the completion of chemotherapy. S-1 has showed better objective response rates, similar overall survival rates and progression-free survival rates compared with gemcitabine, revealing that S-1 may be a potential candidate in treating pancreatic cancer, especially for patients refractory to gemcitabine. Additionally, stereotactic body radiation therapy with Cyberknife could provide better efficacy than conventional radiotherapy in pancreatic cancer. Therefore, Cyberknife with S-1 simultaneously followed by sequential S-1 as an initial treatment may bring about favourable outcomes but needs further studies. Methods and analysis The S-1 as an initial treatment for locally advanced pancreatic cancer (SILAPANC) trial is a prospective, single-centre, one armed ongoing study. 190 eligible patients are required to initially receive Cyberknife with 1 cycle of S-1 simultaneously. After the concurrent chemoradiotherapy, 2 or 3 cycles of S-1 are sequentially given. Doses and fractions depend on the locations and volumes of tumours and the adjacent organs at risk. S-1 is taken orally, 2 times a day, at a dose of 80 mg/m2 for 28 days, followed by a 14-day interval. The primary objectives are overall survival and 1-year, 2-year, 3-year, 4-year and 5-year overall survival rates. The secondary objectives are cancer-specific survival, progression-free survival, time to progression, local control rates, clinical benefit rates, radiation-induced acute and late toxicities, adverse effects of chemotherapy and quality of life of patients. Besides, variables most

  13. A phase I study of S-1 with concurrent thoracic radiotherapy in elderly patients with localized advanced non-small cell lung cancer.

    PubMed

    Takigawa, Nagio; Kiura, Katsuyuki; Hotta, Katsuyuki; Hosokawa, Shinobu; Nogami, Naoyuki; Aoe, Keisuke; Gemba, Kenichi; Fujiwara, Keiichi; Harita, Shingo; Takemoto, Mitsuhiro; Himei, Kengo; Shinkai, Tetsu; Fujiwara, Yoshirou; Takata, Saburo; Tabata, Masahiro; Kanazawa, Susumu; Tanimoto, Mitsune

    2011-01-01

    S-1, an oral 5-fluorouracil derivative, is effective against advanced non-small cell lung cancer (NSCLC) with mild toxicity and synergistic effects with radiation in preclinical trials. In this phase I study, we evaluated the dose-limiting toxicity and recommended dose of S-1 for a future phase II study when administered concurrently with thoracic radiation (total dose of 60 Gy at 2 Gy per daily fraction) in elderly patients (>75 years old) with localized advanced NSCLC. S-1 was administered on days 1-14 and 29-42 at the following dosages: 60, 70, and 80 mg/m(2)/day. Twenty-two previously untreated patients were enrolled in this study. Dose-limiting toxicity included febrile neutropenia, thrombocytopenia, stomatitis, and pneumonitis. One patient had grade 5 radiation pneumonitis. No other patient experienced radiation pneumonitis or esophagitis exceeding grade 2. The recommended dose for S-1 was determined to be 80 mg/m(2)/day, which produced an overall response rate of 75% (n=12). The median progression-free survival time was 11.5 months (95% confidence interval: 7.1-15.8 months) with a median follow-up time of 27.9 months. These results indicate that concurrent treatment with S-1 and thoracic radiation is a feasible option for NSCLC in the elderly. A phase II study is currently under way.

  14. Prevalence of Extended-Spectrum β-Lactamases CTX-M-8 and CTX-M-2-Producing Salmonella Serotypes from Clinical and Nonhuman Isolates in Brazil.

    PubMed

    Fernandes, Sueli Aparecida; Camargo, Carlos Henrique; Francisco, Gabriela Rodrigues; Bueno, Maria Fernanda Campagnari; Garcia, Doroti Oliveira; Doi, Yohei; Casas, Monique Ribeiro Tiba

    2017-07-01

    We characterized extended-spectrum β-lactamases (ESBL) enzymes among Salmonella strains isolated in Brazil from 2009 to 2014. Salmonella recovered from both clinical and nonhuman (food, poultry, and environment) sources were subjected to antimicrobial susceptibility testing. β-lactamases genes were detected by polymerase chain reaction/sequencing; plasmid profiles and transferability were assessed by S1-pulsed field gel electrophoresis (PFGE). Genetic diversity was evaluated by XbaI-PFGE. Out of 630 Salmonella strains screened, 46 displayed ESBL phenotype, distributed across 11 different serotypes. blaCTX-M-8 and blaCTX-M-2 genes were detected at frequencies of 47% and 41%, respectively. blaSHV-5 and blaSHV-2 were also detected but in lower frequencies (4%, 2%). blaTEM-1 gene was detected in 22% of the strains. Most of the ESBL genes were transferable by conjugation, and the respective blaESBL gene was detected in the recipient strain, indicating the location of ESBL determinants on transferable plasmids. XbaI-PFGE revealed genomic diversity of Salmonella Typhimurium bearing blaCTX-M-2, blaCTX-M-8, blaTEM-1, and blaSHV-2 genes. Salmonella Muenchen (harboring blaCTX-M-2) and Salmonella Corvallis (blaCTX-M-8 and blaSHV-5) showed clonal relatedness within respective serotypes. Our findings underscore the occurrence of diverse ESBL genes in several Salmonella serotypes, reinforcing the need for continuous surveillance of resistance genes circulating in human and nonhuman sources.

  15. Sphingosine 1-phosphate (S1P) induces COX-2 expression and PGE2 formation via S1P receptor 2 in renal mesangial cells.

    PubMed

    Völzke, Anja; Koch, Alexander; Meyer Zu Heringdorf, Dagmar; Huwiler, Andrea; Pfeilschifter, Josef

    2014-01-01

    Understanding the mechanisms of sphingosine 1-phosphate (S1P)-induced cyclooxygenase (COX)-2 expression and prostaglandin E2 (PGE2) formation in renal mesangial cells may provide potential therapeutic targets to treat inflammatory glomerular diseases. Thus, we evaluated the S1P-dependent signaling mechanisms which are responsible for enhanced COX-2 expression and PGE2 formation in rat mesangial cells under basal conditions. Furthermore, we investigated whether these mechanisms are operative in the presence of angiotensin II (Ang II) and of the pro-inflammatory cytokine interleukin-1β (IL-1β). Treatment of rat and human mesangial cells with S1P led to concentration-dependent enhanced expression of COX-2. Pharmacological and molecular biology approaches revealed that the S1P-dependent increase of COX-2 mRNA and protein expression was mediated via activation of S1P receptor 2 (S1P2). Further, inhibition of Gi and p42/p44 MAPK signaling, both downstream of S1P2, abolished the S1P-induced COX-2 expression. In addition, S1P/S1P2-dependent upregulation of COX-2 led to significantly elevated PGE2 levels, which were further potentiated in the presence of Ang II and IL-1β. A functional consequence downstream of S1P/S1P2 signaling is mesangial cell migration that is stimulated by S1P. Interestingly, inhibition of COX-2 by celecoxib and SC-236 completely abolished the migratory response. Overall, our results demonstrate that extracellular S1P induces COX-2 expression via activation of S1P2 and subsequent Gi and p42/p44 MAPK-dependent signaling in renal mesangial cells leading to enhanced PGE2 formation and cell migration that essentially requires COX-2. Thus, targeting S1P/S1P2 signaling pathways might be a novel strategy to treat renal inflammatory diseases.

  16. Selective coupling of the S1P3 receptor subtype to S1P-mediated RhoA activation and cardioprotection.

    PubMed

    Yung, Bryan S; Brand, Cameron S; Xiang, Sunny Y; Gray, Charles B B; Means, Christopher K; Rosen, Hugh; Chun, Jerold; Purcell, Nicole H; Brown, Joan Heller; Miyamoto, Shigeki

    2017-02-01

    Sphingosine-1-phosphate (S1P), a bioactive lysophospholipid, is generated and released at sites of tissue injury in the heart and can act on S1P1, S1P2, and S1P3 receptor subtypes to affect cardiovascular responses. We established that S1P causes little phosphoinositide hydrolysis and does not induce hypertrophy indicating that it does not cause receptor coupling to Gq. We previously demonstrated that S1P confers cardioprotection against ischemia/reperfusion by activating RhoA and its downstream effector PKD. The S1P receptor subtypes and G proteins that regulate RhoA activation and downstream responses in the heart have not been determined. Using siRNA or pertussis toxin to inhibit different G proteins in NRVMs we established that S1P regulates RhoA activation through Gα13 but not Gα12, Gαq, or Gαi. Knockdown of the three major S1P receptors using siRNA demonstrated a requirement for S1P3 in RhoA activation and subsequent phosphorylation of PKD, and this was confirmed in studies using isolated hearts from S1P3 knockout (KO) mice. S1P treatment reduced infarct size induced by ischemia/reperfusion in Langendorff perfused wild-type (WT) hearts and this protection was abolished in the S1P3 KO mouse heart. CYM-51736, an S1P3-specific agonist, also decreased infarct size after ischemia/reperfusion to a degree similar to that achieved by S1P. The finding that S1P3 receptor- and Gα13-mediated RhoA activation is responsible for protection against ischemia/reperfusion suggests that selective targeting of S1P3 receptors could provide therapeutic benefits in ischemic heart disease.

  17. Regulation of human cerebro-microvascular endothelial baso-lateral adhesion and barrier function by S1P through dual involvement of S1P1 and S1P2 receptors.

    PubMed

    Wiltshire, Rachael; Nelson, Vicky; Kho, Dan Ting; Angel, Catherine E; O'Carroll, Simon J; Graham, E Scott

    2016-01-27

    Herein we show that S1P rapidly and acutely reduces the focal adhesion strength and barrier tightness of brain endothelial cells. xCELLigence biosensor technology was used to measure focal adhesion, which was reduced by S1P acutely and this response was mediated through both S1P1 and S1P2 receptors. S1P increased secretion of several pro-inflammatory mediators from brain endothelial cells. However, the magnitude of this response was small in comparison to that mediated by TNFα or IL-1β. Furthermore, S1P did not significantly increase cell-surface expression of any key cell adhesion molecules involved in leukocyte recruitment, included ICAM-1 and VCAM-1. Finally, we reveal that S1P acutely and dynamically regulates microvascular endothelial barrier tightness in a manner consistent with regulated rapid opening followed by closing and strengthening of the barrier. We hypothesise that the role of the S1P receptors in this process is not to cause barrier dysfunction, but is related to controlled opening of the endothelial junctions. This was revealed using real-time measurement of barrier integrity using ECIS ZΘ TEER technology and endothelial viability using xCELLigence technology. Finally, we show that these responses do not occur simply though the pharmacology of a single S1P receptor but involves coordinated action of S1P1 and S1P2 receptors.

  18. Regulation of human cerebro-microvascular endothelial baso-lateral adhesion and barrier function by S1P through dual involvement of S1P1 and S1P2 receptors

    PubMed Central

    Wiltshire, Rachael; Nelson, Vicky; Kho, Dan Ting; Angel, Catherine E.; O’Carroll, Simon J.; Graham, E. Scott

    2016-01-01

    Herein we show that S1P rapidly and acutely reduces the focal adhesion strength and barrier tightness of brain endothelial cells. xCELLigence biosensor technology was used to measure focal adhesion, which was reduced by S1P acutely and this response was mediated through both S1P1 and S1P2 receptors. S1P increased secretion of several pro-inflammatory mediators from brain endothelial cells. However, the magnitude of this response was small in comparison to that mediated by TNFα or IL-1β. Furthermore, S1P did not significantly increase cell-surface expression of any key cell adhesion molecules involved in leukocyte recruitment, included ICAM-1 and VCAM-1. Finally, we reveal that S1P acutely and dynamically regulates microvascular endothelial barrier tightness in a manner consistent with regulated rapid opening followed by closing and strengthening of the barrier. We hypothesise that the role of the S1P receptors in this process is not to cause barrier dysfunction, but is related to controlled opening of the endothelial junctions. This was revealed using real-time measurement of barrier integrity using ECIS ZΘ TEER technology and endothelial viability using xCELLigence technology. Finally, we show that these responses do not occur simply though the pharmacology of a single S1P receptor but involves coordinated action of S1P1 and S1P2 receptors. PMID:26813587

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

    PubMed

    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

  20. Motion-to-Energy (M2Eâ„¢) Power Generation Technology

    ScienceCinema

    Idaho National Laboratory

    2016-07-12

    INL researchers developed M2E, a new technology that converts motion to energy. M2E uses an innovative, optimized microgenerator with power management circuitry that kinetically charges mobile batteries from natural motion such as walking. To learn more,

  1. Ab initio calculations of MAX phases M2TlC (M = Ti, Zr, Hf), and M2GaN (M = Ti, V, Cr)

    NASA Astrophysics Data System (ADS)

    Khare, Sanjay; Patil, Sunil; Warner, Jacob

    2006-03-01

    MAX phases have been a subject of interest recently [cf. M. W. Barsoum Prog. Solid St. Chem. 28, 201 (2000).] because of their useful mechanical, electrical and thermal properties. Here we have studied two groups of M2AX : (i) M = Ti, V, Cr, A = Ga and X = N and (ii) M = Ti, Zr, Hf, A = Tl and X = C. We calculated the lattice parameters, bulk modulus B and local electronic density of states (LDOS) of these phases using first-principles total energy calculations. Our computed lattice structural parameters match the experimental values within 5% for all six materials. Values for B were computed to be (i) 158, 170, and 180 GPa and (ii) 125, 120, and 131 GPa for the first and second group respectively. These values suggest that Ti2TlC, Zr2TlC and Hf2TlC maybe the softest of all the MAX phases explored so far. The total density of states shows that all six materials are conducting. The major features in LDOS are i) the hybridization of the M d orbitals with X p orbitals and (ii) M d orbitals with A p orbitals.

  2. A phase I study of combination S-1 plus cisplatin chemotherapy with concurrent thoracic radiation for locally advanced non-small cell lung cancer.

    PubMed

    Chikamori, Kenichi; Kishino, Daizo; Takigawa, Nagio; Hotta, Katsuyuki; Nogami, Naoyuki; Kamei, Haruhito; Kuyama, Shoichi; Gemba, Kenichi; Takemoto, Mitsuhiro; Kanazawa, Susumu; Ueoka, Hiroshi; Segawa, Yoshihiko; Takata, Saburo; Tabata, Masahiro; Kiura, Katsuyuki; Tanimoto, Mitsune

    2009-07-01

    A combination of S-1, a newly developed oral 5-fluorouracil derivative, and cisplatin is reported to show anti-tumour activity against advanced non-small cell lung cancer (NSCLC). Because S-1 shows synergistic effects with radiation, we conducted a phase I study to evaluate the maximum tolerated doses (MTDs), recommended doses (RDs), and dose-limiting toxicities (DLTs) of cisplatin and S-1 when combined with concurrent thoracic radiation (total dose of 60 Gy with 2 Gy per daily fraction) in patients with locally advanced NSCLC. Chemotherapy consisted of two 4-week cycles of cisplatin administered on days 1 and 8, and S-1 administered on days 1-14. S-1/cisplatin dosages (mg/m(2)/day) were escalated as follows: 60/30, 60/40, 70/40, 80/40 and 80/50. Twenty-two previously untreated patients were enrolled. The MTDs and RDs for S-1/cisplatin were 80/50 and 80/40, respectively. DLTs included febrile neutropaenia, thrombocytopaenia, bacterial pneumonia and delayed second cycle of chemotherapy. No patient experienced radiation pneumonitis>grade 2 and only one patient experienced grade 3 radiation oesophagitis. The overall response rate was 86.4% with a median survival time of 24.4 months. These results indicate that combination cisplatin-S-1 chemotherapy with concurrent thoracic radiation would be a feasible treatment option and a phase II study is currently under way.

  3. S-1 and Cisplatin With or Without Nimotuzumab for Patients With Untreated Unresectable or Metastatic Gastric Cancer

    PubMed Central

    Du, Feng; Zheng, Zhaoxu; Shi, SuSheng; Jiang, Zhichao; Qu, Tao; Yuan, Xinhua; Sun, Yongkun; Song, Yan; Yang, Lin; Zhao, Jiuda; Wang, Jinwan; Chi, Yihebali

    2015-01-01

    Abstract This open-label, randomized phase II trial was performed to compare the efficacy and safety of nimotuzumab plus S-1 and cisplatin (NCS) versus S-1 and cisplatin (CS) alone in patients with untreated unresectable or metastatic gastric cancer in the first-line setting. Eligible participants were randomly assigned (1:1) to receive either NCS or CS. The treatment consisted of 3-week cycles of twice-daily S-1 40 mg/m2 (on days 1–14) and intravenous cisplatin 30 mg/m2 (on days 1, 2), with or without weekly nimotuzumab (200 mg/m2). The primary endpoint was objective response rate (ORR). The second endpoint included progression-free survival (PFS), overall survival (OS), safety and association between efficacy and tumor epidermal growth factor receptor (EGFR) expression. Between October, 2009, and February, 2012, we enrolled 62 patients in Cancer Hospital Chinese Academy of Medical Sciences (CAMS). The ORR for 31 patients allocated NCS was 54.8% compared with 58.1% for 31 patients who were allocated to receive CS alone (P = 0.798). Median PFS for patients in CS arm was significantly improved than that in NCS arm [7.2 months vs. 4.8 months HR = 2.136 (95% CI 1.193–3.826), P = 0.011]. There was also a trend toward better overall survival for patients in CS arm compared with NCS arm [14.3 months vs. 10.2 months; HR = 1.776 (95% CI 0.972–3.246), P = 0.062]. In the EGFR 2+/3+ subgroup, adding nimotuzumab also failed to show additional benefit than chemotherapy alone. Both groups were well tolerated. Less than 10% of patients in both arms developed grade 3/4 toxicity. Combination of nimotuzumab and S-1-cisplatin provided no additional benefit than chemotherapy alone in the first-line treatment of unresectable or metastatic gastric cancer. PMID:26061330

  4. Phase II multi-institutional prospective randomised trial comparing S-1+paclitaxel with S-1+cisplatin in patients with unresectable and/or recurrent advanced gastric cancer

    PubMed Central

    Mochiki, E; Ogata, K; Ohno, T; Toyomasu, Y; Haga, N; Fukai, Y; Aihara, R; Ando, H; Uchida, N; Asao, T; Kuwano, H

    2012-01-01

    Background: A combination of S-1 and cisplatin has been shown to be effective with acceptable safety for the first-line treatment of far-advanced gastric cancer in Japan. This is the first randomised phase II trial to compare S-1+paclitaxel with S-1+cisplatin in this setting. Methods: Patients with unresectable and/or recurrent advanced gastric cancer were randomly assigned to receive one of the two regimens: S-1 (40 mg m−2 twice daily) on days 1–14 plus paclitaxel (60 mg m−2) on days 1, 8, and 15 of a 4-week cycle (S-1+paclitaxel) or S-1 (40 mg m−2 twice daily) on days 1–21 plus cisplatin (60 mg m−2) on day 8 of a 5-week cycle (S-1+cisplatin). The primary end point was the response rate (RR). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. Results: A total of 83 patients were eligible for safety and efficacy analyses. In the S-1+paclitaxel and S-1+cisplatin groups, RRs (52.3% vs 48.7% P=0.74) and median PFS (9 vs 6 months; P=0.50) were similar. The median OS was similar in the S-1+paclitaxel and S-1+cisplatin groups (16 vs 17 months; P=0.84). The incidence of grade 3 or higher haematological toxicity was 19.0% with S-1+paclitaxel and 19.5% with S-1+cisplatin. The incidence of grade 3 or higher non-haematological toxicity was 14.2% with S-1+paclitaxel and 17.1% with S-1+cisplatin. Conclusion: S-1+paclitaxel was suggested to be a feasible and effective non-platinum-based regimen for chemotherapy in patients with advanced gastric cancer. Our results should be confirmed in multicenter, phase III-controlled clinical trials. PMID:22617130

  5. S1P lyase in thymic perivascular spaces promotes egress of mature thymocytes via up-regulation of S1P receptor 1.

    PubMed

    Maeda, Yasuhiro; Yagi, Hideki; Takemoto, Kana; Utsumi, Hiroyuki; Fukunari, Atsushi; Sugahara, Kunio; Masuko, Takashi; Chiba, Kenji

    2014-05-01

    Sphingosine 1-phosphate (S1P) and S1P receptor 1 (S1P1) play an important role in the egress of mature CD4 or CD8 single-positive (SP) thymocytes from the thymus. Fingolimod hydrochloride (FTY720), an S1P1 functional antagonist, induced significant accumulation of CD62L(high)CD69(low) mature SP thymocytes in the thymic medulla. Immunohistochemical staining using anti-S1P1 antibody revealed that S1P1 is predominantly expressed on thymocytes in the thymic medulla and is strongly down-regulated even at 3h after FTY720 administration. 2-Acetyl-4-tetrahydroxybutylimidazole (THI), an S1P lyase inhibitor, also induced accumulation of mature SP thymocytes in the thymic medulla with an enlargement of the perivascular spaces (PVS). At 6h after THI administration, S1P1-expressing thymocytes reduced partially as if to form clusters and hardly existed in the proximity of CD31-expressing blood vessels in the thymic medulla, suggesting S1P lyase expression in the cells constructing thymic medullary PVS. To determine the cells expressing S1P lyase in the thymus, we newly established a mAb (YK19-2) specific for mouse S1P lyase. Immunohistochemical staining with YK19-2 revealed that S1P lyase is predominantly expressed in non-lymphoid thymic stromal cells in the thymic medulla. In the thymic medullary PVS, S1P lyase was expressed in ER-TR7-positive cells (reticular fibroblasts and pericytes) and CD31-positive vascular endothelial cells. Our findings suggest that S1P lyase expressed in the thymic medullary PVS keeps the tissue S1P concentration low around the vessels and promotes thymic egress via up-regulation of S1P1.

  6. [Combination chemotherapy of S-1, docetaxel and CDDP produces a remarkable response in a patient with metastases of supraclavicular lymph nodes and gingival carcinoma of the mandible].

    PubMed

    Ishii, Shoichiro; Ueda, Takashi; Higuchi, Masataka; Mima, Takashi; Yakushiji, Noboru

    2010-09-01

    We report a 53-year-old female patient with an unresectable metastasis to the supraclavicular lymph node from a primary gingival carcinoma of the mandible. The patient had a history of tongue carcinoma and had undergone a radical neck dissection for the treatment of gingival carcinoma. She underwent combined chemotherapy consisting of S-1 (80 mg on days 1-14, followed by a 7-day rest), docetaxel (35mg/m2 by intravenous infusion on days 1 and 8), and CDDP (10mg/m2 by intravenous infusion on days 1 and 8) every 3 weeks. After three courses of the above chemotherapy regimen, a computerized tomography examination revealed a complete response. The patient did not experience any severe side effects during the course of chemotherapy. Combined S-1, docetaxel, and CDDP chemotherapy can thus be effective for unresectable recurrences of oral cancer in lymph nodes.

  7. Characterization of M2X formed during 5 MeV Fe2+ irradiation

    NASA Astrophysics Data System (ADS)

    Getto, E.; Sun, K.; Was, G. S.

    2017-03-01

    The growth of M2X phase in HT9 irradiated to high dpa was explored using self-ion irradiation. HT9 was pre-implanted with 10 appm He and irradiated with a raster-scanned Fe2+ beam with a damage rate of ∼1 × 10-3 dpa/s at 460 °C. The precipitation of M2X was observed and a combination of high resolution transmission electron microscopy (HRTEM), energy filtered transmission electron microscopy (EFTEM) and diffraction analysis was used to characterize the Cr-rich carbide observed at 250 dpa and above. Cr2C was determined to be semi-coherent with the matrix such that [ 100 ] Cr2 C / /[100]α and [ 001 ] Cr2 C / /[ 10 1 bar ] α .with a = 2.71 Å and c = 2.82 Å.

  8. Allosteric interaction of the neuromuscular blockers vecuronium and pancuronium with recombinant human muscarinic M2 receptors.

    PubMed

    Cembala, Thor M; Forde, Steven C O; Appadu, Balraj L; Lambert, David G

    2007-08-13

    Neuromuscular blocking drugs produce muscle weakness by interaction with nicotinic-acetylcholine receptors. Cardiovascular side effects have been reported. In this study the neuromuscular blocking drug vecuronium and the controls gallamine and pancuronium slowed the rate of atropine induced [(3)H]N-methylscopolamine dissociation from Chinese hamster ovary cells expressing recombinant human muscarinic M2 receptors K(off) values min(-1); vecuronium (125 nM), atropine 0.45+/-0.07+blocker 0.04+/-0.02; gallamine (21 nM), atropine 0.42+/-0.05+blocker 0.15+/-0.04; pancuronium(21 nM), atropine 0.36+/-0.03+blocker 0.03+/-0.01). These data indicate that vecuronium, gallamine and pancuronium interact with an allosteric site on the muscarinic M2 receptor (located on the heart) and this may explain some of their cardiac side effects.

  9. Proton conductance of influenza virus M2 protein in planar lipid bilayers.

    PubMed

    Vijayvergiya, Viksita; Wilson, Ryan; Chorak, Adam; Gao, Philip Fei; Cross, Timothy A; Busath, David D

    2004-09-01

    Purified M2 protein from the Udorn strain of influenza virus was reconstituted into planar lipid bilayers from liposomes. In 1 mM HCl, the single-channel conductance was measured as 6 pS with open probability of < or =0.03. The current voltage curve is linear over the achievable voltage range. The current amplitude is amantadine sensitive. In HCl solutions, the single-channel current was essentially invariant with changes in [Cl(-)], [Na(+)], and [tetraethylammonium] ([TEA(+)]), but dependent on [H(+)]. The reversal potential, determined with asymmetrical hydrogen chloride solution, is very close to the equilibrium potential of hydrogen. This appears to be the first report of single-channel proton currents with the full-length M2 protein.

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

    PubMed Central

    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

  11. Foton-M2 Russian/US Biology Experiments - Development, Implementation, and Operations

    NASA Technical Reports Server (NTRS)

    Ilyin, Eugene A.; Tairbekov, Murad G.; Vasques, Marilyn F.; Skidmore, Michael G.

    2006-01-01

    The Russian Foton-M2 unmanned research satellite launched from Baikonur, Kazakhstan on May 31, 2005. The satellite was recovered 16 days later in northern Kazakhstan near Kustanay. Prior to this mission, the long history of joint NASA/IMBP research using Russian unmanned spacecraft was in danger of withering due to inactivity. This cooperative history included 9 Bion Russian spaceflights in the period from 1975 to 1997 where NASA had participated first as a guest and finally as a contractual partner. In an effort to reinvigorate this long-standing collaboration, the Institute for Biomedical Problems (IMBP) invited NASA participation in Russian experiments that had been manifested to fly on the Foton-M2 mission.

  12. Foton-M2 Russian/US Biology Experiments - Development, Implementation, and Operations

    NASA Technical Reports Server (NTRS)

    Ilyin, Eugene A.; Tairbekov, Murad G.; Vasques, Marilyn F.; Skidmore, Michael G.

    2006-01-01

    The Russian Foton-M2 unmanned research satellite launched from Baikonur, Kazakhstan on May 31, 2005. The satellite was recovered 16 days later in northern Kazakhstan near Kustanay. Prior to this mission, the long history of joint NASA/IMBP research using Russian unmanned spacecraft was in danger of withering due to inactivity. This cooperative history included 9 Bion Russian spaceflights in the period from 1975 to 1997 where NASA had participated first as a guest and finally as a contractual partner. In an effort to reinvigorate this long-standing collaboration, the Institute for Biomedical Problems (IMBP) invited NASA participation in Russian experiments that had been manifested to fly on the Foton-M2 mission.

  13. Alternatively activated macrophages (M2 macrophages) in the skin of patient with localized scleroderma.

    PubMed

    Higashi-Kuwata, Nobuyo; Makino, Takamitsu; Inoue, Yuji; Takeya, Motohiro; Ihn, Hironobu

    2009-08-01

    Localized scleroderma is a connective tissue disorder that is limited to the skin and subcutaneous tissue. Macrophages have been reported to be particularly activated in patients with skin disease including systemic sclerosis and are potentially important sources for fibrosis-inducing cytokines, such as transforming growth factor beta. To clarify the features of immunohistochemical characterization of the immune cell infiltrates in localized scleroderma focusing on macrophages, skin biopsy specimens were analysed by immunohistochemistry. The number of cells stained with monoclonal antibodies, CD68, CD163 and CD204, was calculated. An evident macrophage infiltrate and increased number of alternatively activated macrophages (M2 macrophages) in their fibrotic areas were observed along with their severity of inflammation. This study revealed that alternatively activated macrophages (M2 macrophages) may be a potential source of fibrosis-inducing cytokines in localized scleroderma, and may play a crucial role in the pathogenesis of localized scleroderma.

  14. Impact of Detachment Methods on M2 Macrophage Phenotype and Function.

    PubMed

    Chen, Shaodong; So, Edward C; Strome, Scott E; Zhang, Xiaoyu

    2015-11-01

    The methods of cell detachment influence phenotype and function of human macrophages cultured in vitro. However, comparative studies defining the influence of cell detachment techniques on secondary characterization of M1 or M2 polarized macrophages are largely absent from the literature. In this study we evaluated the impact of trypsin, accutase, EDTA, PBS, and cell scraping on: A. cell recovery, B. phenotype and C. function of in vitro polarized macrophages. Our data demonstrate that while exposure to trypsin or accutase yields highly efficient recovery of viable cells, such chemical cleavage results in loss of select M2 cell surface markers with correlative changes in cell function. In contrast, phenotype and function are maintained following detachment by EDTA on ice. Our data suggest that seemingly "trivial" changes in methodologies for macrophage detachment induce both variable and profound changes on cell phenotype and function which can dramatically impact the results of polarization experiments. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. M2 protein from influenza A: from multiple structures to biophysical and functional insights.

    PubMed

    Cross, Timothy A; Dong, Hao; Sharma, Mukesh; Busath, David D; Zhou, Huan-Xiang

    2012-04-01

    The M2 protein from influenza A is a proton channel as a tetramer, with a single transmembrane helix from each monomer lining the pore. Val27 and Trp41 form gates at either end of the pore and His37 mediates the shuttling of protons across a central barrier between the N-terminal and C-terminal aqueous pore regions. Numerous structures of this transmembrane domain and of a longer construct that includes an amphipathic helix are now in the Protein Data Bank. Many structural differences are apparent from samples obtained in a variety of membrane mimetic environments. High-resolution structural results in lipid bilayers have provided novel insights into the functional mechanism of the unique HxxxW cluster in the M2 proton channel.

  16. The new VLT-DSM M2 unit: construction and electromechanical testing

    NASA Astrophysics Data System (ADS)

    Gallieni, Daniele; Biasi, Roberto

    2013-12-01

    We present the design, construction and validation of the new M2 unit of the VLT Deformable Secondary Mirror. In the framework of the Adaptive Optics Facility program, ADS and Microgate designed a new secondary unit which replaces the current Dornier one. The M2 is composed by the mechanical structure, a new hexapod positioner and the Deformable Secondary Mirror unit.The DSM is based on the well proven contactless, voice coil motor technology that has been already successfully implemented in the MMT, LBT and Magellan adaptive secondaries, and is considered a promising technical choice for the E-ELT M4 and the GMT ASM. The VLT adaptive unit has been fully integrated and, before starting the optical calibration, has completed the electromechanical characterization, focused on the dynamic performance. With respect to the previous units we introduced several improvements, both in hardware and control architecture that allowed achieving a significant enhancement of the system dynamics and reduction of power consumption.

  17. M2 to D2 and vice versa by 3-Lie and Lie bialgebra

    NASA Astrophysics Data System (ADS)

    Aali-Javanangrouh, M.; Rezaei-Aghdam, A.

    2016-11-01

    Using the concept of a 3-Lie bialgebra, which has recently been defined in arXiv:1604.04475, we construct a Bagger-Lambert-Gustavson (BLG) model for the M2-brane on a Manin triple of a special 3-Lie bialgebra. Then by using the correspondence and the relation between those 3-Lie bialgebra with Lie bialgebra, we reduce this model to an N=(4,4) WZW model (D2-brane), such that its algebraic structure is a Lie bialgebra with one 2-cocycle. In this manner by using the correspondence of the 3-Lie bialgebra and Lie bialgebra (for this special 3-Lie algebra) one can construct the M2-brane from a D2-brane and vice versa.

  18. Nonylphenol biodegradation characterizations and bacterial composition analysis of an effective consortium NP-M2.

    PubMed

    Bai, Naling; Abuduaini, Rexiding; Wang, Sheng; Zhang, Meinan; Zhu, Xufen; Zhao, Yuhua

    2017-01-01

    Nonylphenol (NP), ubiquitously detected as the degradation product of nonionic surfactants nonylphenol polyethoxylates, has been reported as an endocrine disrupter. However, most pure microorganisms can degrade only limited species of NP with low degradation efficiencies. To establish a microbial consortium that can effectively degrade different forms of NP, in this study, we isolated a facultative microbial consortium NP-M2 and characterized the biodegradation of NP by it. NP-M2 could degrade 75.61% and 89.75% of 1000 mg/L NP within 48 h and 8 days, respectively; an efficiency higher than that of any other consortium or pure microorganism reported so far. The addition of yeast extract promoted the biodegradation more significantly than that of glucose. Moreover, surface-active compounds secreted into the extracellular environment were hypothesized to promote high-efficiency metabolism of NP. The detoxification of NP by this consortium was determined. The degradation pathway was hypothesized to be initiated by oxidization of the benzene ring, followed by step-wise side-chain biodegradation. The bacterial composition of NP-M2 was determined using 16S rDNA library, and the consortium was found to mainly comprise members of the Sphingomonas, Pseudomonas, Alicycliphilus, and Acidovorax genera, with the former two accounting for 86.86% of the consortium. The high degradation efficiency of NP-M2 indicated that it could be a promising candidate for NP bioremediation in situ. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

    PubMed

    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.

  20. New Perspectives for the Production and Accumulation of (178m2)Hf Isomers

    DTIC Science & Technology

    2003-09-30

    contractor will investigate the production and accumulation of the nuclear isomer 178m2 Hafnium by spallation of Tungsten targets with high-energy...the Hafnium isomers are the best choice as they act as real batteries do: one can charge them (exciting the isomeric states through some nuclear...magnitude). All these features make the Hafnium isomers unique in the landscape of all the isomeric nuclei that can be produced through the nowadays

  1. M2 macrophages coexist with a Th1-driven profile in periapical cysts.

    PubMed

    Ribeiro, C M; de Carli, M L; Nonogaki, S; Nogueira, D A; Pereira, A A C; Sperandio, F F; Hanemann, J A C

    2017-08-30

    To evaluate the participation of both Th1 and Th2 responses in periapical cysts by assessing the presence of M2 macrophages, as well as acute IL-1 β, TNF-α and IL-6 cytokines. Twenty-four cases of periapical cysts were selected. Immuno-expressions of IL-1 β, IL-6, TNF-α and CD163 were analysed in the cystic capsules in both superficial and deeper regions. Data were analysed with paired Wilcoxon test and Spearman correlation coefficient (P ≤ 0.05). There was a higher expression of IL-1β, IL-6, TNF-α and M2 macrophages in the superficial region (P < 0.001) of cystic capsules. All acute cytokines had significant positive correlations amongst them regardless of the cystic capsule region. Regarding CD163, positive correlations occurred only with TNF-α (P = 0.007; r = 0.537) and IL-6 (P = 0.018; r = 0.478) in the superficial regions of the cystic capsule. M2 macrophages participated actively in the inflammatory response of periapical cysts and correlated with the expression of certain acute Th1-related cytokines. This illustrates the coexistence of an acute and chronic Th2-driven immune response in these lesions. Although M2 macrophages favour the healing process, their presence is not sufficient for periapical cyst regression, once an acute active response has occurred due to an infectious stimuli. © 2017 International Endodontic Journal. Published by John Wiley & Sons Ltd.

  2. A picrotoxin-specific conformational change in the glycine receptor M2-M3 loop.

    PubMed

    Hawthorne, Rebecca; Lynch, Joseph W

    2005-10-28

    The external loop linking the M2 and M3 transmembrane domains is crucial for coupling agonist binding to channel gating in the glycine receptor chloride channel (GlyR). A substituted cysteine accessibility scan previously showed that glycine activation increased the surface accessibility of 6 contiguous residues (Arg271-Lys276) toward the N-terminal end of the homomeric alpha1 GlyR M2-M3 loop. In the present study we used a similar approach to determine whether the allosteric antagonist, picrotoxin, could impose conformational changes to this domain that cannot be induced by varying agonist concentrations alone. Picrotoxin slowed the reaction rate of a sulfhydryl-containing compound (MTSET) with A272C, S273C, and L274C. Before interpreting this as a picrotoxin-specific conformational change, it was necessary to eliminate the possibility of steric competition between picrotoxin and MTSET. Accordingly, we showed that picrotoxin and the structurally unrelated blocker, bilobalide, were both trapped in the R271C GlyR in the closed state and that a point mutation to the pore-lining Thr6' residue abolished inhibition by both compounds. We also demonstrated that the picrotoxin dissociation rate was linearly related to the channel open probability. These observations constitute a strong case for picrotoxin binding in the pore. We thus conclude that the picrotoxin-specific effects on the M2-M3 loop are mediated allosterically. This suggests that the M2-M3 loop responds differently to the occupation of different binding sites.

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

    PubMed

    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.

  4. M2 Proton Channel: Toward a Model of a Primitive Proton Pump

    NASA Astrophysics Data System (ADS)

    Wei, Chenyu; Pohorille, Andrew

    2015-06-01

    Transmembrane proton transfer was essential to early cellular systems in order to transduce energy for metabolic functions. The reliable, efficient and controlled generation of proton gradients became possible only with the emergence of active proton pumps. On the basis of features shared by most modern proton pumps we identify the essential mechanistic steps in active proton transport. Further, we discuss the mechanism of action of a small, transmembrane M2 proton channel from influenza A virus as a model for proton transport in protocells. The M2 channel is a 94-residue long, α-helical tetramer that is activated at low pH and exhibits high selectivity and directionality. A shorter construct, built of transmembrane fragments that are only 24 amino acids in length, exhibits very similar proton transport properties. Molecular dynamics simulations on the microsecond time-scale carried out for the M2 channel provided atomic level details on the activation of the channel in response to protonation of the histidine residue, His37. The pathway of proton conduction is mediated by His37, which accepts and donates protons at different interconverting conformation states when pH is lower than 6.5. The Val27 and Trp41 gates and the salt bridge between Asp44 and Arg45 further enhance the directionality of proton transport. It is argued that the architecture and the mechanism of action similar to that found in the M2 channel might have been the perfect starting point for evolution towards the earliest proton pumps, indicating that active proton transport could have readily emerged from simple, passive proton channels.

  5. Spreading depression requires microglia and is decreased by their M2a polarization from environmental enrichment.

    PubMed

    Pusic, Kae M; Pusic, Aya D; Kemme, Jordan; Kraig, Richard P

    2014-07-01

    Microglia play an important role in fine-tuning neuronal activity. In part, this involves their production of tumor necrosis factor-alpha (TNFα), which increases neuronal excitability. Excessive synaptic activity is necessary to initiate spreading depression (SD). Increased microglial production of proinflammatory cytokines promotes initiation of SD, which, when recurrent, may play a role in conversion of episodic to high frequency and chronic migraine. Previous work shows that this potentiation of SD occurs through increased microglial production of TNFα and reactive oxygen species, both of which are associated with an M1-skewed microglial population. Hence, we explored the role of microglia and their M1 polarization in SD initiation. Selective ablation of microglia from rat hippocampal slice cultures confirmed that microglia are essential for initiation of SD. Application of minocycline to dampen M1 signaling led to increased SD threshold. In addition, we found that SD threshold was increased in rats exposed to environmental enrichment. These rats had increased neocortical levels of interleukin-11 (IL-11), which decreases TNFα signaling and polarized microglia to an M2a-dominant phenotype. M2a microglia reduce proinflammatory signaling and increase production of anti-inflammatory cytokines, and therefore may protect against SD. Nasal administration of IL-11 to mimic effects of environmental enrichment likewise increased M2a polarization and increased SD threshold, an effect also seen in vitro. Similarly, application of conditioned medium from M2a polarized primary microglia to slice cultures also increased SD threshold. Thus, microglia and their polarization state play an essential role in SD initiation, and perhaps by extension migraine with aura and migraine.

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

    PubMed Central

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

    2013-01-01

    Background and Purpose 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’. Experimental Approach 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. Key Results In CHO-hM2 cells, iperoxo significantly exceeds ACh in Gi/Gs signalling competence. In the orthosteric loss-of-function mutant M2-Y1043.33A, 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. Conclusion and Implications 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. Linked Article This article is commented on by Langmead and Christopoulos, pp. 353–356 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12142 PMID:23062057

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

    NASA Astrophysics Data System (ADS)

    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

  8. Seasonal variability of the M2 tide in the seas adjacent to Korea

    NASA Astrophysics Data System (ADS)

    Kang, Sok Kuh; Chung, Jong-yul; Lee, Sang-Ryong; Yum, Ki-Dat

    1995-08-01

    Seasonal variability of the M2 tidal harmonic constants is revealed through analyses of monthly tidal data at 12 representative tidal stations in the seas adjacent to the Korean peninsula. The variability remain systematic over the 9 years (1965-1973) of data analysis with a range comparable to that of the 18.6 year nodal modulation. Spatial inhomogeneity of the seasonal variability in the observed harmonic constants is found to exist. The largest seasonal variability in M2 appears in the stations located along the Korea Strait. This variability is not explained by the equilibrium theory of tides, and such a variability or irregularities in the harmonic constants are considered as either a noise as done by Cartwright and Amin (1986), Deutsch Hydrography Zeitschrift, 39, 235-253, or a manifestation of frictional interaction as done by Godin and Gutierrez (1986) Continental Shelf Research, 5, 379-402 for the Bay of Fundy. Considering the opposite relation between monthly mean sea level differences in Izuhara-Pusan section and tidal characteristics in the Korea Strait, it is hypothesized that the interaction between the predominant tidal currents and oceanic currents varying with the seasons might be the main cause of the observed temporal variability in the M2 tide. The nonlinear effect of the Kuroshio is investigated along the shelf break region through scale analyses, which show that the presence of a mean current increases the non-linear terms in the momentum balance by about one order of magnitude. The seasonally different damping effect of the Tsushima Current to the M2 tide is also discussed to explain the process of dominant seasonal variability along the Korea Strait based on the actual current data, but further thorough investigation, considering the advection effect of the mean current, is required to investigate the associated dynamics more completely.

  9. M2 Internal Tide Propagation Through a Geostrophic Front Near the Critical Latitude

    NASA Astrophysics Data System (ADS)

    Chavanne, C. P.; Massad, A.; Heywood, K. J.

    2012-12-01

    A year-long (February 2009 - February 2010) record of ocean currents from instruments (RDI ADCP and Nortek Aquadopp) moored across the continental shelf and slope in the south-east Weddell Sea (~18 W, ~72.5 S) is analysed to investigate the propagation of M2 internal tides through a geostrophic front, the Antarctic Slope Front, near the M2 critical latitude (74.5 S). The record is long enough to separate M2 tides from local inertial currents, as confirmed by the downward phase propagation of M2 currents, indicative of upward energy propagation consistent with topographically-generated internal tides. Vertically-localized peaks of kinetic energy, indicative of internal tide beams, are found just above the bottom at the shelf break, and between 100 and 200 m depths at four of the five moorings. Ray tracing in the absence of background currents predicts internal ray paths inconsistent with the observed kinetic energy peak locations. The effects of the Antarctic Slope Front on internal tide propagation are investigated in two steps. Firstly, the background shears are neglected in the dispersion relation (except for their effect on the local buoyancy frequency), but allowed to refract the internal tides. Predicted internal ray paths are substantially modified from those in an ocean at rest, but they are still inconsistent with observations. Secondly, the background shears are allowed to modify the dispersion relation, dramatically modifying the predicted ray paths and vertical wavenumbers. These results demonstrate that geostrophic shears strongly affect internal tides propagation near their critical latitude, with implications on localization and parametrisation of internal-tide induced diapycnal mixing.

  10. Regional outbreak of CTX-M-2 β-lactamase-producing Proteus mirabilis in Japan.

    PubMed

    Nakano, Ryuichi; Nakano, Akiyo; Abe, Michiko; Inoue, Matsuhisa; Okamoto, Ryoichi

    2012-12-01

    Proteus mirabilis is a common cause of urinary tract infection. Wild-type P. mirabilis strains are usually susceptible to penicillins and cephalosporins, but occurrences of P. mirabilis producing extended-spectrum β-lactamases (ESBLs) have been recently reported. Here, we surveyed the prevalence of cefotaxime resistance among P. mirabilis strains at seven different hospitals in Kanagawa Prefecture, Japan, and investigated their molecular epidemiology to explain the mechanism of their spread. The prevalence of cefotaxime resistance among P. mirabilis increased annually, from 10.1 % in 1998 to 23.1 % in 2003, and increased drastically in 2004, exceeding 40 %. We collected 105 consecutive and non-duplicate cefotaxime-resistant P. mirabilis isolates (MIC 16 to >256 µg ml(-1)) from these hospitals from June 2004 to May 2005 and characterized their profile. PCR and sequence analysis revealed that all resistant strains produced exclusively CTX-M-2 β-lactamase. PFGE analysis identified 47 banding patterns with 83 % or greater similarity. These results indicated that a regional outbreak of P. mirabilis producing CTX-M-2 β-lactamase has occurred in Japan and suggest that the epidemic spread occurred within and across hospitals and communities by extended clonal strains. Plasmid analysis revealed that 44.8 % of plasmids harboured by bla(CTX-M-2) isolates had common profiles, encoding ISEcp1, IS26 and Int1, and belonged to incompatibility group T. Spread of the resistant isolates in Japan resulted from dissemination of narrow-host-range plasmids of the IncT group encoding bla(CTX-M-2). These findings indicate the rapidly developing problem of treating the species to prevent dissemination of ESBL producers.

  11. Alberta Stroke Program Early CT Score Infarct Location Predicts Outcome Following M2 Occlusion.

    PubMed

    Khan, Muhib; Baird, Grayson L; Goddeau, Richard P; Silver, Brian; Henninger, Nils

    2017-01-01

    Although it is generally thought that patients with distal middle cerebral artery (M2) occlusion have a favorable outcome, it has previously been demonstrated that a substantial minority will have a poor outcome by 90 days. We sought to determine whether assessing the Alberta Stroke Program Early CT Score (ASPECTS) infarct location allows for identifying patients at risk for a poor 90-day outcome. We retrospectively analyzed patients with isolated acute M2 occlusion admitted to a single academic center between January 2010 and August 2012. Infarct regions were defined according to ASPECTS system on the initial head computed tomography. Discriminant function analysis was used to define specific ASPECTS regions that are predictive of the 90-day functional outcome as defined as a modified Rankin Scale score of 3-6. In addition, logistic regression was used to model the relationship between each individual ASPECT region with poor outcome; for evaluation and comparison, odds ratios, c-statistics, and Akaike information criterion values were estimated for each region. Ninety patients with isolated M2 were included in the final analysis. ASPECTS score ≤6 predicted poor outcome in this cohort (sensitivity = 0.591, specificity = 0.838, p < 0.001). Using multiple approaches, we found that infarction in ASPECTS regions M3 and M6 were strongly associated with poor functional status by 90 days. Infarction in ASPECTS regions M3 and M6 are key predictors of functional outcome following isolated distal M2 occlusion. These findings will be helpful in stratifying outcomes if validated in future studies.

  12. Interaction of Tacrine at M1 and M2 Cholinoceptors in Guinea Pig Brain

    DTIC Science & Technology

    1993-01-01

    Alzheimer’s disease used for the preparation of cerebral cortex and cerebel- [1]. While oral doses alleviated some symp- lure for M, and M2 binding...determined by the Hartree Alzheimer’s disease progressed. Therefore, modification of the Lowry protein assay [10]. THA’s efficacy is yet to be...implications in the a radioligand binding technique. The equilibrium dis- sociation constant (KD) and apparent maximum num-treatment of Alzheimer’s disease 131

  13. Epitope Mapping of Avian Influenza M2e Protein: Different Species Recognise Various Epitopes

    PubMed Central

    Hasan, Noor Haliza; Ignjatovic, Jagoda; Tarigan, Simson; Peaston, Anne; Hemmatzadeh, Farhid

    2016-01-01

    A common approach for developing diagnostic tests for influenza virus detection is the use of mouse or rabbit monoclonal and/or polyclonal antibodies against a target antigen of the virus. However, comparative mapping of the target antigen using antibodies from different animal sources has not been evaluated before. This is important because identification of antigenic determinants of the target antigen in different species plays a central role to ensure the efficiency of a diagnostic test, such as competitive ELISA or immunohistochemistry-based tests. Interest in the matrix 2 ectodomain (M2e) protein of avian influenza virus (AIV) as a candidate for a universal vaccine and also as a marker for detection of virus infection in vaccinated animals (DIVA) is the rationale for the selection of this protein for comparative mapping evaluation. This study aimed to map the epitopes of the M2e protein of avian influenza virus H5N1 using chicken, mouse and rabbit monoclonal or monospecific antibodies. Our findings revealed that rabbit antibodies (rAbs) recognized epitope 6EVETPTRN13 of the M2e, located at the N-terminal of the protein, while mouse (mAb) and chicken antibodies (cAbs) recognized epitope 10PTRNEWECK18, located at the centre region of the protein. The findings highlighted the difference between the M2e antigenic determinants recognized by different species that emphasized the importance of comparative mapping of antibody reactivity from different animals to the same antigen, especially in the case of multi-host infectious agents such as influenza. The findings are of importance for antigenic mapping, as well as diagnostic test and vaccine development. PMID:27362795

  14. M2 proton channel: toward a model of a primitive proton pump.

    PubMed

    Wei, Chenyu; Pohorille, Andrew

    2015-06-01

    Transmembrane proton transfer was essential to early cellular systems in