Science.gov

Sample records for 10-8 mol m-2

  1. Geoscience salaries up by 10.8%

    NASA Astrophysics Data System (ADS)

    Bell, Peter M.

    According to a recent salary survey of over 4000 scientists in all fields by Research and Development (March 1984) geoscientists ranked fourth place for 1984. Mathematics, aeronautical engineering, and metallurgy had higher median salaries, but the discipline of geoscience had a higher median salary than that of physics, chemical engineering, mechanical engineering, electrical engineering, ceramics, chemistry, industrial engineering, biology, and other fields of research and development. The 1984 median salary for geoscientists was $40,950, up from the median value by 10.8%. In 1983, geoscience was ranked in ninth place.The geoscientist profile for 1984 was not unusual. The median age was 47.5 years, and the median years of experience was 18. Geoscientists are the best educated. Eighty-two percent of the geoscientists polled had advanced degrees beyond the bachelor's degree. Fifty-six percent of the geoscientists had the Ph.D. degree.

  2. 24 CFR 10.8 - Notice of proposed rulemaking.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 1 2010-04-01 2010-04-01 false Notice of proposed rulemaking. 10.8 Section 10.8 Housing and Urban Development Office of the Secretary, Department of Housing and Urban Development RULEMAKING: POLICY AND PROCEDURES Procedures § 10.8 Notice of proposed rulemaking. Each notice...

  3. MolView users guide

    SciTech Connect

    Walenz, B.P.

    1996-06-01

    A system for viewing molecular data in a CAVE virtual reality environment is presented. The system, called MolView, consists of a frontend driver program that prepares the data and a backend CAVE program that displays the data. Both are written so that modifications and extensions are relatively easy to accomplish.

  4. 28 CFR 10.8 - Information to be kept current.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 28 Judicial Administration 1 2010-07-01 2010-07-01 false Information to be kept current. 10.8... kept current. A supplemental statement must be filed with the Attorney General within thirty days after... information and documents previously filed accurate and current with respect to the preceding six...

  5. 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

  6. 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.

  7. 44 CFR 10.8 - Determination of requirement for environmental review.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... effort and concentrate resources on significant environmental issues. (1) Criteria. The criteria used for... for environmental review. 10.8 Section 10.8 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY, DEPARTMENT OF HOMELAND SECURITY GENERAL ENVIRONMENTAL CONSIDERATIONS Agency...

  8. 19 CFR 10.8a - Imported articles exported and reimported.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 19 Customs Duties 1 2012-04-01 2012-04-01 false Imported articles exported and reimported. 10.8a...; DEPARTMENT OF THE TREASURY ARTICLES CONDITIONALLY FREE, SUBJECT TO A REDUCED RATE, ETC. General Provisions Articles Exported and Returned § 10.8a Imported articles exported and reimported. (a) In addition...

  9. 19 CFR 10.8a - Imported articles exported and reimported.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 19 Customs Duties 1 2011-04-01 2011-04-01 false Imported articles exported and reimported. 10.8a...; DEPARTMENT OF THE TREASURY ARTICLES CONDITIONALLY FREE, SUBJECT TO A REDUCED RATE, ETC. General Provisions Articles Exported and Returned § 10.8a Imported articles exported and reimported. (a) In addition...

  10. 19 CFR 10.8a - Imported articles exported and reimported.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 19 Customs Duties 1 2010-04-01 2010-04-01 false Imported articles exported and reimported. 10.8a...; DEPARTMENT OF THE TREASURY ARTICLES CONDITIONALLY FREE, SUBJECT TO A REDUCED RATE, ETC. General Provisions Articles Exported and Returned § 10.8a Imported articles exported and reimported. (a) In addition...

  11. 19 CFR 10.8a - Imported articles exported and reimported.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 19 Customs Duties 1 2014-04-01 2014-04-01 false Imported articles exported and reimported. 10.8a...; DEPARTMENT OF THE TREASURY ARTICLES CONDITIONALLY FREE, SUBJECT TO A REDUCED RATE, ETC. General Provisions Articles Exported and Returned § 10.8a Imported articles exported and reimported. (a) In addition...

  12. 19 CFR 10.8 - Articles exported for repairs or alterations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 19 Customs Duties 1 2010-04-01 2010-04-01 false Articles exported for repairs or alterations. 10.8... Articles Exported and Returned § 10.8 Articles exported for repairs or alterations. (a) Except as otherwise... been exported for repairs or alterations and which are claimed to be subject to duty only on the...

  13. Atmospheric air pollutants: CO in Nitrogen, 5 μmol/mol

    NASA Astrophysics Data System (ADS)

    Konopelko, L. A.; Pankratov, V. V.; Pankov, A. A.; Ivahnenko, B. V.; Efremova, O. V.; Bakovec, N. V.; Mironchik, A. M.; Aleksandrov, V. V.

    2017-01-01

    This article presents the report on the COOMET supplementary comparison "Atmospheric air pollutants: CO in Nitrogen, 5 μmol/mol". Carbon monoxide (CO) is present in atmosphere due to different natural and anthropogenic sources. CO is a toxic gas and in concentrations higher than (3-5) μmol/mol it is hazardous to human health. 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 CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. International key comparison CCQM-K94: 10 μmol/mol dimethyl sulfide in nitrogen

    NASA Astrophysics Data System (ADS)

    Lee, S.; Heo, G. S.; Kim, Y.; Oh, S.; Han, Q.; Wu, H.; Konopelko, L. A.; Kustikov, Y. A.; Kolobova, A. V.; Efremova, O. V.; Pankratov, V. V.; Pavlov, M. V.; Culleton, L. P.; Brown, A. S.; Brookes, C.; Li, J.; Ziel, P. R.; van der Veen, A. M. H.

    2016-01-01

    Dimethyl sulfide (DMS) is an important compound in monitoring climate change and is monitored by the World Meteorological Organization Global Atmospheric Watch Volatile Organic Compounds (WMO-GAW VOC) program at several monitoring sites. It is essential that measurement results are accurate and consistent among the assigned values for primary gas mixtures to meet the WMO requirement. The purpose of this comparison is to compare the measurement capability of DMS at approximately 10 μ­mol/mol and expectation to contribute the establishment of traceability to single measurement scale for DMS between NMIs. 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 CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

  1. 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

  2. Anti-influenza M2e antibody

    SciTech Connect

    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.

  3. Anti-influenza M2e antibody

    SciTech Connect

    Bradbury, Andrew M

    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.

  4. 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

  5. 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

  6. 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.

  7. 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

  8. 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.

  9. 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

  10. 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.

  11. MolProbity for the masses—of data

    PubMed Central

    Chen, Vincent B.; Wedell, Jonathan R.; Wenger, R. Kent; Ulrich, Eldon L.

    2015-01-01

    MolProbity is a powerful software program for validating structures of proteins and nucleic acids. Although MolProbity includes scripts for batch analysis of structures, because these scripts analyze structures one at a time, they are not well suited for the validation of a large dataset of structures. We have created a version of MolProbity (MolProbity-HTC) that circumvents these limitations and takes advantage of a high-throughput computing cluster by using the HTCondor software. MolProbity-HTC enables the longitudinal analysis of large sets of structures, such as those deposited in the PDB or generated through theoretical computation—tasks that would have been extremely time-consuming using previous versions of MolProbity. We have used MolProbity-HTC to validate the entire PDB, and have developed a new visual chart for the BioMagResBank (BMRB) website that enables users to easily ascertain the quality of each model in an NMR ensemble and to compare the quality of those models to the rest of the PDB. PMID:26195077

  12. Optimized MOL-PCR for Characterization of Microbial Pathogens.

    PubMed

    Wuyts, Véronique; Roosens, Nancy H C; Bertrand, Sophie; Marchal, Kathleen; De Keersmaecker, Sigrid C J

    2016-01-06

    Characterization of microbial pathogens is necessary for surveillance, outbreak detection, and tracing of outbreak sources. This unit describes a multiplex oligonucleotide ligation-PCR (MOL-PCR) optimized for characterization of microbial pathogens. With MOL-PCR, different types of markers, like unique sequences, single-nucleotide polymorphisms (SNPs) and indels, can be simultaneously analyzed in one assay. This assay consists of a multiplex ligation for detection of the markers, a singleplex PCR for signal amplification, and hybridization to MagPlex-TAG beads for readout on a Luminex platform after fluorescent staining. The current protocol describes the MOL-PCR, as well as methods for DNA isolation, probe design, and data interpretation and it is based on an optimized MOL-PCR assay for subtyping of Salmonella Typhimurium.

  13. MOL1 is required for cambium homeostasis in Arabidopsis.

    PubMed

    Gursanscky, Nial Rau; Jouannet, Virginie; Grünwald, Karin; Sanchez, Pablo; Laaber-Schwarz, Martina; Greb, Thomas

    2016-05-01

    Plants maintain pools of pluripotent stem cells which allow them to constantly produce new tissues and organs. Stem cell homeostasis in shoot and root tips depends on negative regulation by ligand-receptor pairs of the CLE peptide and leucine-rich repeat receptor-like kinase (LRR-RLK) families. However, regulation of the cambium, the stem cell niche required for lateral growth of shoots and roots, is poorly characterized. Here we show that the LRR-RLK MOL1 is necessary for cambium homeostasis in Arabidopsis thaliana. By employing promoter reporter lines, we reveal that MOL1 is active in a domain that is distinct from the domain of the positively acting CLE41/PXY signaling module. In particular, we show that MOL1 acts in an opposing manner to the CLE41/PXY module and that changing the domain or level of MOL1 expression both result in disturbed cambium organization. Underlining discrete roles of MOL1 and PXY, both LRR-RLKs are not able to replace each other when their expression domains are interchanged. Furthermore, MOL1 but not PXY is able to rescue CLV1 deficiency in the shoot apical meristem. By identifying genes mis-expressed in mol1 mutants, we demonstrate that MOL1 represses genes associated with stress-related ethylene and jasmonic acid hormone signaling pathways which have known roles in coordinating lateral growth of the Arabidopsis stem. Our findings provide evidence that common regulatory mechanisms in different plant stem cell niches are adapted to specific niche anatomies and emphasize the importance of a complex spatial organization of intercellular signaling cascades for a strictly bidirectional tissue production.

  14. Comparison of primary standard gas mixtures: gravimetric production of carbon monoxide in nitrogen (3 μmol/mol)

    NASA Astrophysics Data System (ADS)

    Konopelko, L. A.; Kustikov, Y. A.; Kolobova, A. V.; Pankratov, V. V.; Pankov, A. A.; Efremova, O. V.; Augusto, Cristiane R.; Fioravante, Andreia L.; Ribeiro, Claudia C.; Teixeira, Denise C. G. S.; Elias, Elizandra C. S.; Oudwater, Rutger J.; Fagundes, Fátima A.; Silva, Marceli C.

    2016-01-01

    COOMET.QM-S3 is a supplementary comparison of primary standard gas mixtures—'Carbon monoxide in Nitrogen (3 μmol/mol)'. This is a bilateral comparison between VNIIM and INMETRO and it was conducted in 2013. Carbon monoxide is a toxic gas and in concentrations higher than 3-5 μmol/mol it is hazardous to human health. Therefore, it is important for NMIs to have the capability of an accurate carbon monoxide measurements. This comparison has shown that primary standard gas mixtures of carbon monoxide in nitrogen on the level of 3 μmol/mol, prepared in VNIIM and Inmetro, do not agree—the pair-wise degree of equivalence D (0.77%) is higher than the appropriate expanded uncertainty U(D) (0.29%). 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 CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

  15. 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.

  16. eMOL Evaluating electron-water scattering data

    NASA Astrophysics Data System (ADS)

    Mason, Nigel

    2013-09-01

    The eMOL (electron molecule) project has been established to establish the process by which such data will be reviewed, validated and recommended data sets published. In particular eMOL seeks to suggest whether any particular data set be used as a primary or secondary source of data for the wider community. Primary would mean that is judged to the best representation of that particular interaction/cross section and therefore be used as a ``recommended'' value for users. The first target to be reviewed by eMOL was water with 8 members of the eMOL board meeting in Vienna in May 2013. The Board used the most recent review of electron-water scattering (Itikawa and Mason J. Phys. Chem. Ref. Data 34 1-22 (2005)) as its reference point. Over 80 papers (collected and disseminated by eMOL's bibliometrician Dr D Jaksch) that had been published subsequent to this review were reviewed and recommendations made as to whether such data should replace recommendations in the earlier review. The Meeting also identified areas (cross sections) for future research, data inconsistencies and reviewed the allocation of uncertainty estimates for complete datasets (assembled from a combination of both experimental and theoretical data). In this presentation I will therefore both present the findings of this review and discuss this study as an exemplar of the wider eMOL programme which will review some 15 electron-molecule datasets in 2013-15 including many of interest to the GEC (plasma) community.

  17. Results of postirradiation examination of the in-pile blockage experiments MOL-7C/4 and MOL-7C/5

    SciTech Connect

    Weimar, P.; Schleisiek, K. )

    1991-10-01

    The Mol-7C in-pile local blockage experiments are performed in the BR-2 reactor at Mol, Belgium as a joint project of Kernforchungszentrum Karlsruhe (KfK) and Studiecentrum voor Kernenergie/Centre d'Etude de l'Energie Nuclearire-Mol. The main objective is to investigate the consequences of local cooling disturbances in liquid-metal-cooled reactor (LMR) fuel subassemblies. In the tests Mol-7C/4 and MOL-7C/5, fuel pins from KNK II are used with a burnup of 5 and 1.7%, respectively. An active central porous blockage is used to simulate the cooling disturbance. During irradiation, the blockage causes significant local damage, including melting of cladding and fuel. Extensive postirradiation examinations (PIE) are performed to investigate the extent of damage. In this paper a description and interpretation of results of the destructive PIE performed at the Hot Cells Laboratory at KfK is given, along with some conclusions related to LMR safety.

  18. 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.

  19. 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.

  20. Crystal and mol-ecular structure of aflatrem.

    PubMed

    Lenta, Bruno N; Ngatchou, Jules; Kenfack, Patrice T; Neumann, Beate; Stammler, Hans-Georg; Sewald, Norbert

    2015-11-01

    The crystal structure of the title compound, C32H39NO4, confirms the absolute configuration of the seven chiral centres in the mol-ecule. The molecule has a 1,1-dimethylprop-2-enyl substituent on the indole nucleus and this nucleus shares one edge with the five-membered ring which is, in turn, connected to a sequence of three edge-shared fused rings. The skeleton is completed by the 7,7-trimethyl-6,8-dioxabi-cyclo-[3.2.1]oct-3-en-2-one group connected to the terminal cyclohexene ring. The two cyclohexane rings adopt chair and half-chair conformations, while in the dioxabi-cyclo-[3.2.1]oct-3-en-2-one unit, the six-membered ring has a half-chair conformation. The indole system of the mol-ecule exhibits a tilt of 2.02 (1)° between its two rings. In the crystal, O-H⋯O hydrogen bonds connect mol-ecules into chains along [010]. Weak N-H⋯π inter-actions connect these chains, forming sheets parallel to (10-1).

  1. 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.

  2. 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...

  3. 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...

  4. 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

  5. Secure Data Aggregation Protocol for M2M Communications

    DTIC Science & Technology

    2015-03-24

    smart grid communications, which precisely meets the requirement of periodically collecting users’ electricity consumption while preserving privacy...address: rxlu@ntu.edu.sg - Institution: School of Electrical and Electronics Engineering, Nanyang Technological University - Mailing Address: 50...surveillance, smart metering, environmental monitoring, industrial automation and military scenarios [1][2]. Despite various M2M applications, the basic M2M

  6. Final report: international comparison APMP.QM-S7 methane in nitrogen at 2000 μmol/mol

    NASA Astrophysics Data System (ADS)

    Kim, Byungmoon; Bae, Hyounkil; Lee, Sangil; Oh, Sanghyub; Lin, Tsai-Yin; Huang, Chiug-Kun; Sinweeruthai, Ratirat; Rattanasombat, Soponrat; Laongsri, Bunthoon; Wongjuk, Arnuttachai; Li, Hou; Hui, Liu; Beng Keat, Teo; Mogale, David; Johri, Prabha; Tarhan, Tanil; Engin, Erinc

    2015-01-01

    Methane is one of the major greenhouse gases that affect climate change. To mitigate anthropogenic CH4 emissions effectively, it is necessary to measure and monitor CH4 emissions from fossil fuel combustion. Therefore, it is important for NMIs to have the capability of an accurate CH4 emissions measurement. The first key comparison on methane in nitrogen or air is the key comparison of CCQM-K82 (ambient level methane in air). As a supplementary comparison, the purpose of this comparison is to cover a concentration level that is not covered by previous key comparisons: this report describes the results of a supplementary comparison for methane in nitrogen at 2000 μmol/mol. Results from all participants, except two, agree well within their associated uncertainties. 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 CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

  7. Test of Equivalence Principle at 10(-8) Level by a Dual-Species Double-Diffraction Raman Atom Interferometer.

    PubMed

    Zhou, Lin; Long, Shitong; Tang, Biao; Chen, Xi; Gao, Fen; Peng, Wencui; Duan, Weitao; Zhong, Jiaqi; Xiong, Zongyuan; Wang, Jin; Zhang, Yuanzhong; Zhan, Mingsheng

    2015-07-03

    We report an improved test of the weak equivalence principle by using a simultaneous 85Rb-87Rb dual-species atom interferometer. We propose and implement a four-wave double-diffraction Raman transition scheme for the interferometer, and demonstrate its ability in suppressing common-mode phase noise of Raman lasers after their frequencies and intensity ratios are optimized. The statistical uncertainty of the experimental data for Eötvös parameter η is 0.8×10(-8) at 3200 s. With various systematic errors corrected, the final value is η=(2.8±3.0)×10(-8). The major uncertainty is attributed to the Coriolis effect.

  8. Diode laser spectra of CCl2F2 near 10.8 muon M: Air-broadening effects

    NASA Technical Reports Server (NTRS)

    Jennings, D. E.

    1977-01-01

    Laboratory spectra of CCL2F2 in the 10.8 micron region was recorded, using a tuneable diode laser spectrometer. Effects of air-broadening at pressures up to 48 Torr show that spectral structure should be exhibited under high resolution at altitudes as low as 19 Km. The single line, pressure-broadening coefficient for CCL2F2 was estimated to be 8 MHz/Torr FWHM.

  9. TNF counterbalances the emergence of M2 tumor macrophages

    PubMed Central

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

    2015-01-01

    Cancer is a form of 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. PMID:26365184

  10. 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.

  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. 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.

  13. 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.

  14. 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

  15. Hypolipidemic and antihyperlipidemic effects of Lagenaria siceraria (Mol.) fruit extracts.

    PubMed

    Ghule, B V; Ghante, M H; Saoji, A N; Yeole, P G

    2006-11-01

    Bottle gourd [(Lagenaria siceraria (Mol.) Stand.] fruit is ascribed with many therapeutic effects. The present study was undertaken to explore the antihyperlipidemic effect of four different extracts viz. petroleum ether, chloroform, alcoholic and aqueous extracts from bottle gourd in Triton-induced hyperlipidemic rats and their hypolipidemic effects in normocholesteremic rats. The study is comprised preliminary phytochemical screening of the extracts. Oral administration of the extracts, at doses of 200 and 400 mg/kg body weight in rats, dose-dependently inhibited the total cholesterol, triglycerides, low-density lipoproteins level, and significantly increased the high density lipoproteins level. However, petroleum ether extract did not show the significant effects. Both the chloroform and alcoholic extract exhibited more significant effects in lowering total cholesterol, triglycerides and low density lipoproteins along with increase in HDL as compared to the others. Preliminary phytochemical screening revealed the presence of flavonoids, sterols, cucurbitacin saponins, polyphenolics, proteins, and carbohydrates. The results obtained suggest marked antihyperlipidemic and hypolipidemic activity of the extracts.

  16. 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

  17. 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.

  18. Resistance-Mutation (N31) Effects on Drug Orientation and Channel Hydration in Amantadine-Bound Influenza A M2.

    PubMed

    Gleed, Mitchell L; Ioannidis, Harris; Kolocouris, Antonios; Busath, David D

    2015-09-03

    The mechanism of amantadine binding to the S31 variant of the M2 protein of Influenza A is well understood, but the reasons behind N31 M2 amantadine insensitivity remain under investigation. Many molecular dynamics studies have evaluated the influence of amantadine position within the channel pore on its ability to inhibit proton conductance in M2, but little is known about the influence of amantadine rotational orientation. Replica-exchange umbrella sampling, steered, and classic molecular dynamics simulations were performed on amantadine in the solid-state NMR structure of S31 M2 and an N31 M2 homologue, both in the homotetramer configuration, to explore the effects of the position and tilt angle of amantadine on inhibition of the M2 channel. Steered simulations show that amantadine rotates with the amine toward the bulk water as it passes into the hydrophobic entryway lined by Val27 side chains. Results from all simulation types performed indicate that amantadine has a strong, specific orientation with the amine turned inward toward the central cavity in the S31 M2 pore but has variable orientation and a strong propensity to remain outward pointing in N31 M2. Free energy profiles from umbrella sampling, measured relative to bulk water, show amantadine binds more strongly to the S31 M2 pore by 8 kcal/mol in comparison to amantadine in the N31 pore, suggesting that it can escape more readily from the N31 channel through the Val27 secondary gate, whereas it is captured by the S31 channel in the same region. Lower water density and distribution near amantadine in S31 M2 reveal that the drug inhibits proton conductance in S31 M2 because of its inward-pointing configuration, whereas in N31 M2, amantadine forms hydrogen bonds with an N31 side chain and does not widely occlude water occupancy in any configuration. Both amantadine's weaker binding to and weaker water occlusion in N31 M2 might contribute to its inefficacy as an inhibitor of the mutant protein.

  19. 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

  20. Dynamique moléculaire et canaux ioniques

    NASA Astrophysics Data System (ADS)

    Crouzy, S.

    2005-11-01

    Diffusion de neutrons et Dynamique Moléculaire (DM) sont deux techniques intimement liées car elles portent sur les mêmes échelles de temps: la première apporte des informations structurales ou dynamiques sur le système physique ou biologique, la seconde permet de décoder ces informations à travers un modèle facilitant l'interprétation des résultats. Au delà de l'intérêt que la technique de DM peut avoir en relation directe avec les neutrons, il est intéressant de comprendre comment les modèles sont construits et comment les techniques de simulation peuvent aller beaucoup plus loin que de simples modélisations. Nous décrirons brièvement, dans la suite de cet exposé, la technique de DM et les méthodes plus sophistiquées de calculs d'énergie libre et de potentiels de force moyenne à partir des simulations de DM. Puis nous verrons avec deux exemples tirés de nos travaux théoriques sur les canaux ioniques comment ces calculs peuvent nous donner accès à des vitesses de réaction ou des constantes d'affinité ou de liaison. La première étude porte sur un analogue de la gramicidine A qui forme un canal conducteur d'ions interrompus par le basculement d'un cycle dioxolane [1]. La seconde concerne le canal potassique KcsA dont nous avons étudié le blocage du coté extracellulaire par l'ion Tetra Ethyl Ammonium [2].

  1. 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

  2. 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.

  3. 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

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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.

  9. 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

  10. 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

  11. 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

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  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. Deep Sub-micro mol{\\cdot }mol^{-1} Water-Vapor Measurement by Dual-Ball SAW Sensors for Temperature Compensation

    NASA Astrophysics Data System (ADS)

    Takeda, N.; Oizumi, T.; Tsuji, T.; Akao, S.; Takayanagi, K.; Nakaso, N.; Yamanaka, K.

    2015-12-01

    A collimated surface acoustic wave (SAW) circles around the equator of a sphere hundreds of times. Because of the long distance travel of the collimated SAW, a small change in the SAW propagation caused by the environment of the sphere can be accumulated as a measurable range in amplitude and/or in delay time. So, a spherical SAW device enables highly sensitive water-vapor measurements. In this paper, deep sub \\upmu mol{\\cdot }mol^{-1} water-vapor detection by 1 mm diameter quartz crystal ball SAW sensors is described. To measure such a low water-vapor concentration in real time, it is necessary to compensate the temperature dependence of the ball SAW sensor, which is about 20 ppm{\\cdot }°C^{-1} in delay time change. A dual-frequency burst analog detector was developed for the temperature compensation in real time. By using a harmonic SAW sensor, which was excited by 80 MHz and 240 MHz at the same time, it was confirmed that the delay time drift for a temperature range of 21.0°C ± 1.0°C became less than 0.05 ppm in delay time change. By using dual-ball SAW sensors (which included a 150 MHz sensor with a water-vapor sensitive layer and a 240 MHz sensor as a reference), water-vapor concentrations from 0.1 \\upmu mol{\\cdot }mol^{-1} to 5 \\upmu mol{\\cdot }mol^{-1} were successfully measured. It appears that the delay time change is proportional to the square root of the water-vapor concentration. The detection limit determined by the electrical noise of the system was estimated at 0.01 \\upmu mol{\\cdot }mol^{-1}.

  5. Optical properties of LiNbO3:Mg(5.21 mol %) and LiNbO3:Fe(0.009 mol %):Mg(5.04 mol %) crystals

    NASA Astrophysics Data System (ADS)

    Sidorov, N. V.; Palatnikov, M. N.; Kruk, A. A.; Yanichev, A. A.; Makarova, O. V.; Teplyakova, N. A.; Pikoul, O. Yu.

    2014-02-01

    Using methods of electronic spectroscopy, laser conoscopy, photoinduced (photoreactive) light scattering, and Raman light-scattering spectroscopy, we have studied the optical homogeneity, optical transmission, and photorefractive properties of single crystals LiNbO3:Mg(5.21 mol %) and LiNbO3:Fe(0.009 mol %):Mg(5.04 mol %) that were grown from congruent melts. We have ascertained that doping with "nonphotorefractive" Mg2+ cations causes suppression of the photorefractive effect in a lithium-niobate crystal. Upon double doping (Fe:Mg), if the concentration of Mg2+ cations exceeds the threshold concentration, the photorefractive effect is almost not observed and the presence of "photorefractive" Fe cations does not affect the photorefractive effect as strongly as in congruent crystals doped with Fe.

  6. Geometric Corroboration of the Earliest Lensed Galaxy at z ≃ 10.8 from Robust Free-form Modelling

    NASA Astrophysics Data System (ADS)

    Chan, Brian M. Y.; Broadhurst, Tom; Lim, Jeremy; Diego, Jose M.; Zitrin, Adi; Coe, Dan; Ford, Holland C.

    2017-01-01

    A multiply lensed galaxy, MACS0647-JD, with a probable photometric redshift of z≃ {10.7}-0.4+0.6 is claimed to constitute one of the very earliest known galaxies, formed well before reionization was completed. However, spectral evidence that MACS0647-JD lies at high redshift has proven infeasible and so here we seek an independent-lensing-based “geometric redshift” derived from the angles between the three lensed images of MACS0647-JD, using our free-form mass model (WSLAP+) for the lensing cluster MACSJ0647.7+7015 (at z = 0.591). Our lens model uses the nine sets of multiple images, including those of MACS0647-JD, identified by the CLASH survey toward this cluster. We convincingly exclude the low-redshift regime of z < 3, for which convoluted critical curves are generated by our method, as the solution bends to accommodate the wide angles of MACS0647-JD for this low redshift. Instead, a best fit to all sets of lensed galaxy positions and redshifts provides a geometric redshift of z≃ {10.8}-0.4+0.3 for MACS0647-JD, strongly supporting the higher photometric redshift solution. Importantly, we find a tight linear relation between the relative brightnesses of all nine sets of multiply lensed images and their relative magnifications as predicted by our model. This agreement provides a benchmark for the quality of the lens model, and establishes the robustness of our free-form lensing method for measuring model-independent geometric source distances and for deriving objective central cluster mass distributions. After correcting for its magnification the luminosity of MACS0647-JD remains relatively high at MUV = ‑19.4, which is within a factor of a few in flux of some surprisingly luminous z ≃ 10–11 candidates discovered recently in Hubble blank field surveys.

  7. 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.

  8. 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.

  9. M2 tidal effects in greater cook strait, New Zealand

    NASA Astrophysics Data System (ADS)

    Kibblewhite, Alick C.; Ash, David E.

    1980-05-01

    The application of a M2 nonlinear numerical tidal model to the shelf seas of central New Zealand (~38.500 km2 area) is described. It has provided a preliminary assessment of tidal and residual currents, bottom stress, energy dissipation, and the stratification index. The existence of a permanent, tidally driven mesoscale eddy (~75 km diameter) is predicted nort of D'Urville Island. Large spatial gradients in bottom stress qualitatively agree with many features of the surficial sediment distribution. A comparison of all available bulk stratification data with the h/u3 stratification index clearly demonstrates the dominance of tidal versus wind mixing over the control of summer stratification. A potential application of the model to fisheries science is suggested through a comparison of the stratification index contour map and some observations of squid fishing vessel locations.

  10. 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

  11. GABA(A) receptor M2-M3 loop secondary structure and changes in accessibility during channel gating.

    PubMed

    Bera, Amal K; Chatav, Maya; Akabas, Myles H

    2002-11-08

    The gamma-aminobutyric acid type A (GABA(A)) receptor M2-M3 loop structure and its role in gating were investigated using the substituted cysteine accessibility method. Residues from alpha(1)Arg-273 to alpha(1)Ile-289 were mutated to cysteine, one at a time. MTSET(+) or MTSES(-) reacted with all mutants from alpha(1)R273C to alpha(1)Y281C, except alpha(1)P277C, in the absence and presence of GABA. The MTSET(+) closed-state reaction rate was >1000 liters/mol-s at alpha(1)N274C, alpha(1)S275C, alpha(1)K278C, and alpha(1)Y281C and was <300 liters/mol-s at alpha(1)R273C, alpha(1)L276C, alpha(1)V279C, alpha(1)A280C, and alpha(1)A284C. These two groups of residues lie on opposite sides of an alpha-helix. The fast reacting group lies on a continuation of the M2 segment channel-lining helix face. This suggests that the M2 segment alpha-helix extends about two helical turns beyond alpha(1)N274 (20'), aligned with the extracellular ring of charge. At alpha(1)S275C, alpha(1)V279C, alpha(1)A280C, and alpha(1)A284C the reaction rate was faster in the presence of GABA. The reagents had no functional effect on the mutants from alpha(1)A282C to alpha(1)I289C, except alpha(1)A284C. Access may be sterically hindered possibly by close interaction with the extracellular domain. We suggest that the M2 segment alpha-helix extends beyond the predicted extracellular end of the M2 segment and that gating induces a conformational change in and/or around the N-terminal half of the M2-M3 loop. Implications for coupling ligand-evoked conformational changes in the extracellular domain to channel gating in the membrane-spanning domain are discussed.

  12. Leptin promotes migration and invasion of breast cancer cells by stimulating IL-8 production in M2 macrophages

    PubMed Central

    Wang, Lin; Wang, Hong; Pang, Xueli; Li, Kuangfa; Dang, Weiqi; Tang, Hao; Wei, Lan; Su, Min; Tang, Cuiping; Chen, Tingmei

    2016-01-01

    This study aims to investigate the mechanisms underlying leptin-mediated crosstalk between tumor-associated macrophages (M2 macrophages) and breast cancer cells. THP1 human leukemic monocytes were induced to differentiate into M2 macrophages by PMA (100 nM) and IL-4 (20 ng/mL). Quantitative RT-PCR and Western blot revealed that leptin (100 nM) significantly increased the expression of leptin receptor (ObR) in the M2 macrophages (P < 0.01) and stimulated interleukin (IL)-8 expression in the M2 macrophages, mouse macrophage cells RAW264.7, and primary mouse peritoneal macrophages in a dose- and time-dependent manner. Leptin-induced IL-8 production was sensitive to the ERK inhibitor PD980590 (10 μmol/L), p38 MAPK inhibitor SB203580 (20 μmol/L), and anti-ObR neutralizing antibody (4 μg/mL). Leptin (100 ng/mL) substantially increased the phosphorylation of p38 and ERK1/2. Thus, leptin may induce IL-8 production in M2 macrophages by interacting with ObR to activate the p38 and ERK signaling pathways. Scratch and transwell chamber assay showed that both recombinant IL-8 and leptin-induced M2 macrophage-derived IL-8 promoted the migration and invasion of human breast cancer cells MCF7 and MDA-MB-231 (All P < 0.01). In a nude mice xenograft model of breast cancer (n = 5 per group), injection of leptin (0.1 μg/g) dramatically increased tumor volume and mass, reduced survival, exacerbated pulmonary metastasis, and elevated IL-8 and Ki67 expression in the tumor tissue (All P < 0.05) compared with PBS injection. Depletion of mouse macrophage by Clophosome®-clodronate liposome and injection of anti-mouse IL-8 neutralizing antibodies in the xenograft tumor significantly attenuated those leptin-mediated stimulations (All P < 0.05). These findings indicate that leptin may promote tumor growth and metastasis by stimulating IL-8 production in tumor-associated macrophage. PMID:27588409

  13. GridMol: a grid application for molecular modeling and visualization

    NASA Astrophysics Data System (ADS)

    Sun, Yanhua; Shen, Bin; Lu, Zhonghua; Jin, Zhong; Chi, Xuebin

    2008-02-01

    In this paper we present GridMol, an extensible tool for building a high performance computational chemistry platform in the grid environment. GridMol provides computational chemists one-stop service for molecular modeling, scientific computing and molecular information visualization. GridMol is not only a visualization and modeling tool but also simplifies control of remote Grid software that can access high performance computing resources. GridMol has been successfully integrated into China National Grid, the most powerful Chinese Grid Computing platform. In Section "Grid computing" of this paper, a computing example is given to show the availability and efficiency of GridMol. GridMol is coded using Java and Java3D for portability and cross-platform compatibility (Windows, Linux, MacOS X and UNIX). GridMol can run not only as a stand-alone application, but also as an applet through web browsers. In this paper, we will present the techniques for molecular visualization, molecular modeling and grid computing. GridMol is available free of charge under the GNU Public License (GPL) from our website: http://www.sccas.cn/ syh/GridMol/index.html.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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

  19. HackaMol: An Object-Oriented Modern Perl Library for Molecular Hacking on Multiple Scales

    DOE PAGES

    Riccardi, Demian M.; Parks, Jerry M.; Johs, Alexander; ...

    2015-03-20

    HackaMol is an open source, object-oriented toolkit written in Modern Perl that organizes atoms within molecules and provides chemically intuitive attributes and methods. The library consists of two components: HackaMol, the core that contains classes for storing and manipulating molecular information, and HackaMol::X, the extensions that use the core. We tested the core; it is well-documented and easy to install across computational platforms. Our goal for the extensions is to provide a more flexible space for researchers to develop and share new methods. In this application note, we provide a description of the core classes and two extensions: HackaMol::X::Calculator, anmore » abstract calculator that uses code references to generalize interfaces with external programs, and HackaMol::X::Vina, a structured class that provides an interface with the AutoDock Vina docking program.« less

  20. HackaMol: An Object-Oriented Modern Perl Library for Molecular Hacking on Multiple Scales

    SciTech Connect

    Riccardi, Demian M.; Parks, Jerry M.; Johs, Alexander; Smith, Jeremy C.

    2015-03-20

    HackaMol is an open source, object-oriented toolkit written in Modern Perl that organizes atoms within molecules and provides chemically intuitive attributes and methods. The library consists of two components: HackaMol, the core that contains classes for storing and manipulating molecular information, and HackaMol::X, the extensions that use the core. We tested the core; it is well-documented and easy to install across computational platforms. Our goal for the extensions is to provide a more flexible space for researchers to develop and share new methods. In this application note, we provide a description of the core classes and two extensions: HackaMol::X::Calculator, an abstract calculator that uses code references to generalize interfaces with external programs, and HackaMol::X::Vina, a structured class that provides an interface with the AutoDock Vina docking program.

  1. An Introduction to Using the Method of Levels (MOL) Therapy to Work with People Experiencing Psychosis.

    PubMed

    Tai, Sara J

    2016-01-01

    This paper provides a basic introduction to using method of levels (MOL) therapy with people experiencing psychosis. As MOL is a direct application of perceptual control theory (PCT), a brief overview of the three main theoretical principles of this theory--control, conflict, and reorganization will be outlined in relation to understanding psychosis. In particular, how these principles form the basis of problem conceptualisation and determine what an MOL therapist is required to do during therapy will be illustrated. A practical description of MOL will be given, using case examples and short excerpts of therapeutic interactions. Some direct contrasts will also be made with cognitive behaviour therapy for psychosis (CBTp) and psychodynamic approaches (PA) in order to help illustrate the theory and practice of MOL.

  2. HackaMol: An Object-Oriented Modern Perl Library for Molecular Hacking on Multiple Scales.

    PubMed

    Riccardi, Demian; Parks, Jerry M; Johs, Alexander; Smith, Jeremy C

    2015-04-27

    HackaMol is an open source, object-oriented toolkit written in Modern Perl that organizes atoms within molecules and provides chemically intuitive attributes and methods. The library consists of two components: HackaMol, the core that contains classes for storing and manipulating molecular information, and HackaMol::X, the extensions that use the core. The core is well-tested, well-documented, and easy to install across computational platforms. The goal of the extensions is to provide a more flexible space for researchers to develop and share new methods. In this application note, we provide a description of the core classes and two extensions: HackaMol::X::Calculator, an abstract calculator that uses code references to generalize interfaces with external programs, and HackaMol::X::Vina, a structured class that provides an interface with the AutoDock Vina docking program.

  3. Theoretical exploration of the nanoscale host-guest interactions between [n]cycloparaphenylenes (n = 10, 8 and 9) and fullerene C₆₀: from single- to three-potential well.

    PubMed

    Yuan, Kun; Zhou, Cai-Hua; Zhu, Yuan-Cheng; Zhao, Xiang

    2015-07-28

    The nanoscale host-guest interactions between [n]cycloparaphenylene ([n]CPP; n = 10, 8 and 9) nano-ring and fullerene C60 were explored theoretically. It is found that relatively small variations in the sizes of the [n]CPP host lead to very significant changes in encapsulation property toward the fullerene C60 guest. Expectedly, one stable inclusion-configuration of [10]CPP⊃C60 and one floating-configuration of [8]CPP⊃C60 are located on the potential surfaces of the two complexes, respectively. Unexpectedly, besides a floating-configuration (F-[9]CPP⊃C60), another stable inclusion-configuration (I-[9]CPP⊃C60) is also located on the potential surface of [9]CPP⊃C60 host-guest complex. Interaction energies and natural steric analysis show that these complexes are stabilized by balancing concave-convex π-π attractive and steric repulsive host-guest interactions. In contrast, the steric repulsive energy (Es) between host and guest of I-[9]CPP⊃C60 is as high as 233.12 kJ mol(-1), which is much larger than those in other complexes. The movements of C60 guest through the cavities of [n]CPP host (n = 10, 8 and 9) are simulated by calculating the energy profile, and the results interestingly reveal that the encapsulation of C60 by [10]CPP is in the manner of a single-potential well, by [8]CPP in the manner of a double-potential well, and by [9]CPP in the special manner of a three-potential well. We predict that the movement of C60 guest through the cavity of [9]CPP host should be experimentally observable owing to the relatively low energy barrier (<50 kJ mol(-1), M06-2X/6-31G(d)). Charge population analysis shows that an obvious charge transfer between host and guest takes place during the formation of I-[9]CPP⊃C60, which is different from those during the formation of [8]CPP⊃C60, [10]CPP⊃C60 and F-[9]CPP⊃C60. Additionally, the host-guest interaction regions were detected and visualized in real space based on the electron density and reduced density

  4. 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.

  5. MolAxis: Efficient and Accurate Identification of Channels in Macromolecules

    PubMed Central

    Yaffe, Eitan; Fishelovitch, Dan; Wolfson, Haim J.; Halperin, Dan; Nussinov, Ruth

    2009-01-01

    Channels and cavities play important roles in macromolecular functions, serving as access/exit routes for substrates/products, cofactor and drug binding, catalytic sites, and ligand/protein. In addition, channels formed by transmembrane proteins serve as transporters and ion channels. MolAxis is a new sensitive and fast tool for the identification and classification of channels and cavities of various sizes and shapes in macromolecules. MolAxis constructs corridors, which are pathways that represent probable routes taken by small molecules passing through channels. The outer medial axis of the molecule is the collection of points that have more than one closest atom. It is composed of two-dimensional surface patches and can be seen as a skeleton of the complement of the molecule. We have implemented in MolAxis a novel algorithm that uses state-of-the-art computational geometry techniques to approximate and scan a useful subset of the outer medial axis, thereby reducing the dimension of the problem and consequently rendering the algorithm extremely efficient. MolAxis is designed to identify channels that connect buried cavities to the outside of macromolecules and to identify transmembrane channels in proteins. We apply MolAxis to enzyme cavities and transmembrane proteins. We further utilize MolAxis to monitor channel dimensions along Molecular Dynamics trajectories of a human Cytochrome P450. MolAxis constructs high quality corridors for snapshots at picosecond time-scale intervals substantiating the gating mechanism in the 2e substrate access channel. We compare our results with previous tools in terms of accuracy, performance and underlying theoretical guarantees of finding the desired pathways. MolAxis is available on line as a web-server and as a standalone easy-to-use program (http://bioinfo3d.cs.tau.ac.il/MolAxis/). PMID:18393395

  6. Fotoexcitación de Moléculas Pequeñas

    NASA Astrophysics Data System (ADS)

    González Díaz, P. F.

    El modelo estocástico no puede justificar la excitación multi-fotónica de moléculas pequeñas o muy simétricas. Basándonos en un escenario de interacción radiación-molécula cooperativo para la absorción de N-1 fotones IR por un sistema de N niveles, se especula que un posible mecanismo para la excitación no estocástica de moléculas pudiera ser la generación de procesos caóticos intra-moleculares.

  7. Hydrocarbon gas standards at the pmol/mol level to support ambient atmospheric measurements.

    PubMed

    Rhoderick, George C; Duewer, David L; Ning, Li; DeSirant, Kathryn

    2010-02-01

    Studies of climate change increasingly recognize the diverse influences exerted by hydrocarbons in the atmosphere, including roles in particulates and ozone formation. Measurements of key non-methane hydrocarbons (NMHCs) suggest atmospheric concentrations ranging from low pmol/mol to nmol/mol, depending on location and compound. To accurately establish concentration trends and to relate measurement records from many laboratories and researchers, it is essential to have good calibration standards. Several of the world's National Metrology Institutes (NMIs) are developing primary and secondary reference gas standards at the nmol/mol level. While the U.S. NMI, the National Institute of Standards and Technology (NIST), has developed pmol/mol standards for halocarbons and some volatile organics, the feasibility of preparing well-characterized, stable standards for NMHCs at the pmol/mol level is not yet established. NIST recently developed a suite of primary standards by gravimetric dilution that contains 18 NMHCs covering the concentration range of 60 pmol/mol to 230 pmol/mol. Taking into account the small but chemically significant contribution of NMHCs in the high-purity diluent nitrogen used in their preparation, the relative concentrations and short-term stability (2 to 3 months) of these NMHCs in the primary standards have been confirmed by chromatographic analysis. The gravimetric values assigned from the methods used to prepare the materials and the analytical concentrations determined from chromatographic analysis generally agree to within +/-2 pmol/mol. However, anomalous results for several of the compounds reflect the difficulties inherent in avoiding contamination and making accurate measurements at these very low levels.

  8. Combined optical parametric oscillator with continuous tuning of radiation wavelength in the spectral range 2.5–10.8 μm

    NASA Astrophysics Data System (ADS)

    Kolker, D. B.; Sherstov, I. V.; Kostyukova, N. Yu.; Boyko, A. A.; Zenov, K. G.; Pustovalova, R. V.

    2017-02-01

    A combined optical parametric oscillator (OPO) with continuous tuning of the radiation wavelength in the spectral range 2.5–10.8 μm, optically pumped with the radiation from a Q-switched Nd : YLF laser (1.053 μm), is developed and tested. The oscillation is provided by an OPO1 based on a MgO : PPLN ‘fan-out’ structure in the spectral region 2.5–4.5 μm and by an OPO2 based on HgGa2S4 nonlinear crystals in the spectral region 4.18–10.8 μm, respectively. The angles of phase matching are measured for the HgGa2S4 crystals in the spectral range 4.18–10.8 μm for the type II conversion (eo-e), which virtually coincide with the calculated ones. The experimental absorption spectra of a gas mixture in the range 2.5–10.8 μm obtained using a gas-filled sealed-off photoacoustic cell are presented.

  9. Revision of the gas-phase acidity scale below 300 kcal mol(-1).

    PubMed

    Leito, Ivo; Raamat, Elin; Kütt, Agnes; Saame, Jaan; Kipper, Karin; Koppel, Ilmar A; Koppel, Ivar; Zhang, Min; Mishima, Masaaki; Yagupolskii, Lev M; Garlyauskayte, Romute Yu; Filatov, Andrey A

    2009-07-23

    The gas-phase acidity (GA) scale from (CF(3)CO)(2)NH to (C(2)F(5)SO(2))(2)NH--about a 24 kcal mol(-1) range of gas-phase acidities--was reexamined using the Fourier transform ion cyclotron resonance equilibrium measurement approach. Some additions and modifications to the standard methodology of GA measurements were introduced (estimation of partial pressures from mass spectra of the compounds, instead of the pressure gauge readings and use of long reaction times) to achieve higher reliability. Gas-phase acidities of 18 compounds were determined for the first time. The results reveal a contraction of the previously published values in this part of the scale. In particular, the GA values of (CF(3)SO(2))(2)NH and (C(2)F(5)SO(2))(2)NH (important components of lithium ion battery electrolytes and ionic liquids) were revised toward stronger acidities from 291.8 kcal mol(-1) to 286.5 kcal mol(-1) and from 289.4 kcal mol(-1) to 283.7 kcal mol(-1) (i.e., by 5.3 and 5.7 kcal mol(-1)), respectively. Experimental and computational evidence is presented in support of the current results.

  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. 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.

  12. 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

  13. International comparison of a hydrocarbon gas standard at the picomol per mol level.

    PubMed

    Rhoderick, George C; Duewer, David L; Apel, Eric; Baldan, Annarita; Hall, Bradley; Harling, Alice; Helmig, Detlev; Heo, Gwi Suk; Hueber, Jacques; Kim, Mi Eon; Kim, Yong Doo; Miller, Ben; Montzka, Steve; Riemer, Daniel

    2014-03-04

    Studies of climate change increasingly recognize the diverse influences of hydrocarbons in the atmosphere, including roles in particulates and ozone formation. Measurements of key nonmethane hydrocarbons (NMHCs) suggest atmospheric mole fractions ranging from low picomoles per mol (ppt) to nanomoles per mol (ppb), depending on location and compound. To accurately establish mole fraction trends and to relate measurement records from many laboratories and researchers, it is essential to have accurate, stable, calibration standards. In February of 2008, the National Institute of Standards and Technology (NIST) developed and reported on picomoles per mol standards containing 18 nonmethane hydrocarbon compounds covering the mole fraction range of 60 picomoles per mol to 230 picomoles per mol. The stability of these gas mixtures was only characterized over a short time period (2 to 3 months). NIST recently prepared a suite of primary standard gas mixtures by gravimetric dilution to ascertain the stability of the 2008 picomoles per mol NMHC standards suite. The data from this recent chromatographic intercomparison of the 2008 to the 2011 suites confirm a much longer stability of almost 5 years for 15 of the 18 hydrocarbons; the double-bonded alkenes of propene, isobutene, and 1-pentene showed instability, in line with previous publications. The agreement between the gravimetric values from preparation and the analytical mole fractions determined from regression illustrate the internal consistency of the suite within ±2 pmol/mol. However, results for several of the compounds reflect stability problems for the three double-bonded hydrocarbons. An international intercomparison on one of the 2008 standards has also been completed. Participants included National Metrology Institutes, United States government laboratories, and academic laboratories. In general, results for this intercomparison agree to within about ±5% with the gravimetric mole fractions of the hydrocarbons.

  14. 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.

  15. 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.

  16. 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,

  17. Mediterranean savanna of Acacia caven (Mol) is still a sink of CO2 in spite of severe hydrological drought conditions

    NASA Astrophysics Data System (ADS)

    Bravo-Martínez, F.; Meza, F. J.

    2012-12-01

    An eddy covariance tower was set up to monitor net ecosystem exchange (NEE) on a mediterranean shrubland of Acacia caven (Mol) in October 2010. This ecosystem (commonly referred as "espinal") is one of the most abundant land covers of Chile's central valley (2.000.000 ha). The last two years (2010-2011) were characterized by the occurrence of a severe drought (rainfall deficit 56%) and a small increase in temperature evaluated using a climatic change index (Peterson, 2005). We also detected a strong reduction in vegetation index during this period (evaluated using MODIS imagery). The historical analysis of the enhanced vegetation index (EVI) and leaf area index (LAI) showed that water status of the acacia savanna were at a minimum during this period (record of 14 years of data). The annual balance of NEE of 2011 was -54gC m-2 y-1, which means that the espinal is a sink of atmospheric CO2 notwithstanding the many stressors on photosynthesis. Monthly analysis of NEE shows the strong dependence of ecosystem fluxes on phenological state. Maximum rates of assimilation are a consequence of grassland activity, whereas secondary picks during the year (late spring and early autumn) are attributed to the semideciduos leaf of A. caven. Climatic conditions during the study season, confirm the tremendous plasticity of Acacia caven and its role as a colonizer of degraded sclerophyll forest because it adaptation to water and thermal stress.

  18. Polygenic expression of teratozoospermia and normal fertility in B10.MOL-TEN1 mouse strain.

    PubMed

    Hirawatari, Keitaro; Hanzawa, Naoto; Kuwahara, Maki; Aoyama, Hiroaki; Miura, Ikuo; Wakana, Shigeharu; Gotoh, Hideo

    2015-05-01

    Subfertility and infertility are two major reproductive health problems in human and domestic animals. The contribution of the genotype to these conditions is poorly understood. To examine the genetic basis of male subfertility, we analyzed its relationship to sperm morphology in B10.MOL-TEN1 mice, which shows high-frequencies (about 50%) of morphologically abnormal sperm. Drastic histological changes were also found in the testis of the B10.MOL-TEN1. Segregation analysis showed that the abnormal sperm phenotype in B10.MOL-TEN1 was inherited and was predictably controlled by at least three loci. We also found that male fertility of this strain was normal. These findings indicate a complicated relationship between sperm morphology and male subfertility.

  19. Proton Release from the Histidine-Tetrad in the M2 Channel of the Influenza A Virus

    PubMed Central

    2015-01-01

    The activity of the M2 proton channel of the influenza A virus is controlled by pH. The tautomeric state and conformation of His37, a key residue in the M2 transmembrane four-helix bundle, controls the gating of the channel. Previously, we compared the energetics and dynamics of two alternative conformations of the doubly protonated state at neutral pH, namely, a 4-fold symmetric “histidine-box” and a 2-fold symmetric “dimer-of-dimers”, and proposed a multiconfiguration model for this charge state. Here, we elaborate this model by further studying configurations of the His37 tetrad in the triply protonated state and its subsequent deprotonation via quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations, starting with the aforementioned configurations, to gain information about proton release in a viral membrane environment. Interestingly, the two configurations converge under acidic pH conditions. Protons can be transferred from one charged His37 to a neighboring water cluster at the C-terminal side of the channel when the Trp41 gate is open transiently. With limited backbone expansion, the free energy barrier for proton release to the viral interior at low pH is ∼6.5 kcal/mol in both models, which is much lower than at either neutral pH or for an isolated His37 cluster without a membrane environment. Our calculations also suggest that the M2 protein would seem to exclude the entrance of anions into the central channel through a special mechanism, due to the latter’s potential inhibitory effect on proton conduction. PMID:25317959

  20. COOMET.QM-K93 (COOMET 615/RU/13): key comparison in the field of measuring of the ethanol amount fraction in nitrogen (120 μmol/mol)

    NASA Astrophysics Data System (ADS)

    Konopelko, L. A.; Efremova, O. V.; Fatina, O. V.; Orshanskaia, A. A.; Rozhnov, M. S.; Melnyk, D. M.; Petryshyn, P. V.

    2016-01-01

    The relevance of the COOMET.QM-K93 comparison is founded on paying particular attention to reliability of measurements which are performed during the medical examination of drivers of vehicles in order to assess the degree of alcoholic intoxication. Standard gas mixtures of ethanol in nitrogen in cylinders under pressure play a key role in providing metrological assurance of breath-alcohol analyzers. Participating laboratories: VNIIM and Ukrmetrteststandart. This comparison was carried out in 2014-2015. This supplementary comparison supports CMC claims for: ethanol in the range 50-500 μmol/mol in a matrix of either nitrogen or synthetic air. Results: The results are consistent with the reference values. 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 CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

  1. Mol-ecular and crystal structure of gossypol tetra-methyl ether with an unknown solvate.

    PubMed

    Honkeldieva, Muhabbat; Talipov, Samat; Mardanov, Rustam; Ibragimov, Bakhtiyar

    2015-02-01

    The title compound, C34H38O8 (systematic name: 5,5'-diisopropyl-2,2',3,3'-tetra-meth-oxy-7,7'-dimethyl-2H,2'H-8,8'-bi-[naphtho-[1,8-bc]furan]-4,4'-diol), has been obtained from a gossypol solution in a mixture of dimethyl sulfate and methanol. The mol-ecule is situated on a twofold rotation axis, so the asymmetric unit contains one half-mol-ecule. In the mol-ecule, the hy-droxy groups are involved in intra-molecular O-H⋯O hydrogen bonds, and the two naphthyl fragments are inclined each to other by 83.8 (1)°. In the crystal, weak C-H⋯O and C-H⋯π inter-actions consolidate the packing, which exhibits channels with an approximate diameter of 6 Å extending along the c-axis direction. These channels are filled with highly disordered solvent mol-ecules, so their estimated scattering contribution was subtracted from the observed diffraction data using the SQUEEZE option in PLATON [Spek, A. L. (2015). Acta Cryst. C71, 9-18].

  2. Élaboration de films de molécules organiques par ablation par laser UV

    NASA Astrophysics Data System (ADS)

    Hernandez-Perez, M. A.; Garapon, C.; Champeaux, C.; Coleman, A. W.

    2006-12-01

    Les potentialités des méthodes de dépôt par ablation laser (PLD) pour la préparation de films minces de matériaux organiques sont illustrées par un bref rappel bibliographique et par des résultats expérimentaux concernant des molécules d'intérêt biologique (acides aminés, calix-arènes, protéines). Les films sont préparés par PLD avec un laser KrF sans dégradation de la structure chimique des molécules dans une gamme de fluences de quelques dizaines à quelques centaines de mJ/cm2. Les propriétés structurales et optiques des films sont étudiées en fonction de la fluence du laser et mettent en évidence des arrangements moléculaires particuliers induits par cette méthode de dépôt. Le guidage optique a été obtenu pour des films de toutes ces molécules.

  3. Simplifying and enhancing the use of PyMOL with horizontal scripts.

    PubMed

    Mooers, Blaine H M

    2016-10-01

    Scripts are used in PyMOL to exert precise control over the appearance of the output and to ease remaking similar images at a later time. We developed horizontal scripts to ease script development. A horizontal script makes a complete scene in PyMOL like a traditional vertical script. The commands in a horizontal script are separated by semicolons. These scripts are edited interactively on the command line with no need for an external text editor. This simpler workflow accelerates script development. In using PyMOL, the illustration of a molecular scene requires an 18-element matrix of view port settings. The default format spans several lines and is laborious to manually reformat for one line. This default format prevents the fast assembly of horizontal scripts that can reproduce a molecular scene. We solved this problem by writing a function that displays the settings on one line in a compact format suitable for horizontal scripts. We also demonstrate the mapping of aliases to horizontal scripts. Many aliases can be defined in a single script file, which can be useful for applying costume molecular representations to any structure. We also redefined horizontal scripts as Python functions to enable the use of the help function to print documentation about an alias to the command history window. We discuss how these methods of using horizontal scripts both simplify and enhance the use of PyMOL in research and education.

  4. 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

  5. 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

  6. Final report on international comparison CCQM-K74: Nitrogen dioxide, 10 µmol/mol

    NASA Astrophysics Data System (ADS)

    Flores, Edgar; Idrees, Faraz; Moussay, Philippe; Viallon, Joële; Wielgosz, Robert; Fernández, Teresa; Ramírez, Sergio; Rojo, Andrés; Shinji, Uehara; Waldén, Jari; Sega, Michela; Sang-Hyub, Oh; Macé, Tatiana; Couret, Cedric; Qiao, Han; Smeulders, Damian; Guenther, Franklin R.; Thorn, William J., III; Tshilongo, James; Godwill Ntsasa, Napo; Štovcík, Viliam; Valková, Miroslava; Konopelko, Leonid; Gromova, Elena; Nieuwenkamp, Gerard; Wessel, Rob M.; Milton, Martin; Harling, Alice; Vargha, Gergely; Tuma, Dirk; Kohl, Anka; Schulz, Gert

    2012-01-01

    There is a high international priority attached to activities which reduce NOx in the atmosphere. The current level of permitted emissions is typically between 50 µmol/mol and 100 µmol/mol, but lower values are expected in the future. Currently, ambient air quality monitoring regulations also require the measurement of NOx mole fractions as low as 0.2 µmol/mol. The production of accurate standards at these levels of mole fractions requires either dilution of a stable higher concentration gas standard or production by a dynamic technique, for example one based on permeation tubes. The CCQM-K74 key comparison was designed to evaluate the level of comparability of National Metrology Institutes' measurement capabilities and standards for nitrogen dioxide (NO2) at a nominal mole fraction of 10 µmol/mol. The measurements of this key comparison took place from June 2009 to May 2010. Seventeen laboratories took part in this comparison coordinated by the BIPM and VSL. The key comparison reference value was based on BIPM measurement results, and the standard measurement uncertainty of the reference value was 0.042 µmol/mol. This key comparison demonstrated that the results of the majority of the participants agreed within limits of ±3% relative to the reference value. The results of only one laboratory lay significantly outside these limits. Likewise this comparison made clear that a full interpretation of the results of the comparison needed to take into account the presence of nitric acid (in the range 100 nmol/mol to 350 nmol/mol) in the cylinders circulated as part of the comparison, as well as the possible presence of nitric acid in the primary standards used by participating laboratories. Main text. To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCQM, according to the

  7. 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

  8. 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

  9. Optimized anisotropic magnetoelectric response of Fe61.6Co16.4Si10.8B11.2/PVDF/Fe61.6Co16.4Si10.8B11.2 laminates for AC/DC magnetic field sensing

    NASA Astrophysics Data System (ADS)

    Reis, S.; Silva, M. P.; Castro, N.; Correia, V.; Gutierrez, J.; Lasheras, A.; Lanceros-Mendez, S.; Martins, P.

    2016-05-01

    The anisotropic magnetoelectric (ME) effect on a Fe61.6Co16.4Si10.8B11.2/PVDF Fe61.6Co16.4Si10.8B11.2 laminate composite has been used for the development of a magnetic field sensor able to detect both the magnitude and direction of AC and DC magnetic fields. The accuracy (99% for both AC and DC sensors), linearity (92% for the DC sensor and 99% for the AC sensor) and reproducibility (99% for both sensors) indicate the suitability of the sensor for applications. Furthermore, the sensitivity of the Fe61.6Co16.4Si10.8B11.2/PVDF/Fe61.6Co16.4Si10.8B11.2 anisotropic magnetic sensor—15 and 1400 mV Oe-1 for the DC and AC fields, respectively—are the highest reported in the literature for polymer-based ME materials. Such features, combined with its flexibility, versatility, light weight, low cost and low-temperature fabrication, lead to the suitability of the developed sensor for use in magnetic sensor applications.

  10. 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

  11. The ExoMol database: Molecular line lists for exoplanet and other hot atmospheres

    NASA Astrophysics Data System (ADS)

    Tennyson, Jonathan; Yurchenko, Sergei N.; Al-Refaie, Ahmed F.; Barton, Emma J.; Chubb, Katy L.; Coles, Phillip A.; Diamantopoulou, S.; Gorman, Maire N.; Hill, Christian; Lam, Aden Z.; Lodi, Lorenzo; McKemmish, Laura K.; Na, Yueqi; Owens, Alec; Polyansky, Oleg L.; Rivlin, Tom; Sousa-Silva, Clara; Underwood, Daniel S.; Yachmenev, Andrey; Zak, Emil

    2016-09-01

    The ExoMol database (www.exomol.com) provides extensive line lists of molecular transitions which are valid over extended temperatures ranges. The status of the current release of the database is reviewed and a new data structure is specified. This structure augments the provision of energy levels (and hence transition frequencies) and Einstein $A$ coefficients with other key properties, including lifetimes of individual states, temperature-dependent cooling functions, Land\\'e $g$-factors, partition functions, cross sections, $k$-coefficients and transition dipoles with phase relations. Particular attention is paid to the treatment of pressure broadening parameters. The new data structure includes a definition file which provides the necessary information for utilities accessing ExoMol through its application programming interface (API). Prospects for the inclusion of new species into the database are discussed.

  12. Towards J/mol Accuracy for the Cohesive Energy of Solid Argon.

    PubMed

    Schwerdtfeger, Peter; Tonner, Ralf; Moyano, Gloria E; Pahl, Elke

    2016-09-26

    The cohesive energies of argon in its cubic and hexagonal closed packed structures are computed with an unprecedented accuracy of about 5 J mol(-1) (corresponding to 0.05 % of the total cohesive energy). The same relative accuracy with respect to experimental data is also found for the face-centered cubic lattice constant deviating by ca. 0.003 Å. This level of accuracy was enabled by using high-level theoretical, wave-function-based methods within a many-body decomposition of the interaction energy. Static contributions of two-, three-, and four-body fragments of the crystal are all individually converged to sub-J mol(-1) accuracy and complemented by harmonic and anharmonic vibrational corrections. Computational chemistry is thus achieving or even surpassing experimental accuracy for the solid-state rare gases.

  13. 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.

  14. 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.

  15. 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

  16. SigMol: repertoire of quorum sensing signaling molecules in prokaryotes.

    PubMed

    Rajput, Akanksha; Kaur, Karambir; Kumar, Manoj

    2016-01-04

    Quorum sensing is a widespread phenomenon in prokaryotes that helps them to communicate among themselves and with eukaryotes. It is driven through quorum sensing signaling molecules (QSSMs) in a density dependent manner that assists in numerous biological functions like biofilm formation, virulence factors secretion, swarming motility, bioluminescence, etc. Despite immense implications, dedicated resources of QSSMs are lacking. Therefore, we have developed SigMol (http://bioinfo.imtech.res.in/manojk/sigmol), a specialized repository of these molecules in prokaryotes. SigMol harbors information on QSSMs pertaining to different quorum sensing signaling systems namely acylated homoserine lactones (AHLs), diketopiperazines (DKPs), 4-hydroxy-2-alkylquinolines (HAQs), diffusible signal factors (DSFs), autoinducer-2 (AI-2) and others. Database contains 1382: entries of 182: unique signaling molecules from 215: organisms. It encompasses biological as well as chemical aspects of signaling molecules. Biological information includes genes, preliminary bioassays, identification assays and applications, while chemical detail comprises of IUPAC name, SMILES and structure. We have provided user-friendly browsing and searching facilities for easy data retrieval and comparison. We have gleaned information of diverse QSSMs reported in literature at a single platform 'SigMol'. This comprehensive resource will assist the scientific community in understanding intraspecies, interspecies or interkingdom networking and further help to unfold different facets of quorum sensing and related therapeutics.

  17. Azahar: a PyMOL plugin for construction, visualization and analysis of glycan molecules

    NASA Astrophysics Data System (ADS)

    Arroyuelo, Agustina; Vila, Jorge A.; Martin, Osvaldo A.

    2016-08-01

    Glycans are key molecules in many physiological and pathological processes. As with other molecules, like proteins, visualization of the 3D structures of glycans adds valuable information for understanding their biological function. Hence, here we introduce Azahar, a computing environment for the creation, visualization and analysis of glycan molecules. Azahar is implemented in Python and works as a plugin for the well known PyMOL package (Schrodinger in The PyMOL molecular graphics system, version 1.3r1, 2010). Besides the already available visualization and analysis options provided by PyMOL, Azahar includes 3 cartoon-like representations and tools for 3D structure caracterization such as a comformational search using a Monte Carlo with minimization routine and also tools to analyse single glycans or trajectories/ensembles including the calculation of radius of gyration, Ramachandran plots and hydrogen bonds. Azahar is freely available to download from http://www.pymolwiki.org/index.php/Azahar and the source code is available at https://github.com/agustinaarroyuelo/Azahar.

  18. 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.

  19. Characterization of the gene and protein of the common alpha 1-antitrypsin normal M2 allele.

    PubMed Central

    Nukiwa, T; Brantly, M L; Ogushi, F; Fells, G A; Crystal, R G

    1988-01-01

    The normal M2 variant of alpha 1-antitrypsin (alpha 1AT) was cloned from a genomic DNA library of an individual homozygous for this allele. Sequencing of all coding exons of the M2 gene revealed it was identical to the common M1(Val213) gene except for two bases (M1(Val213) CGT Arg101, M2 CAT His101; M1(Val213) GAA Glu376 M2 GAC Asp376). Analysis of the sequence of the M1(Val213) and M2 genes around residue 101 revealed the M1 Arg101----M2 His101 caused a loss of the cutting site for the restriction endonuclease RsaI. Using this enzyme, as well as 19-mer oligonucleotides probes centered at residues 101 and 376, evaluation of genomic DNA from 22 M1 alleles and 14 M2 alleles revealed that residue 101 was Arg in all M1 alleles and His in all M2 alleles, while residue 376 was Glu in all M1 alleles and Asp in all M2 alleles. Despite the differences in sequence at two amino acids, the M1(Val213) and M2 proteins function similarly as assessed by quantification of the association rate constant of each for their natural substrate neutrophil elastase. In the context that there are two mutations separating the M1(Val213) and M2 alleles, it is likely that there is another alpha 1AT variant that was an intermediate in the evolution of these genes. Images Figure 2 Figure 4 Figure 1 Figure 3 PMID:2901226

  20. 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…

  1. 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.

  2. 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.

  3. 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.

  4. 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…

  5. 12 CFR Appendix M2 to Part 226 - Actual Repayment Disclosures

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 3 2010-01-01 2010-01-01 false Actual Repayment Disclosures M2 Appendix M2 to Part 226 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE... nearest whole year if the estimate contains a fractional year less than 0.5, and rounded up to the...

  6. 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

  7. 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.

  8. 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

  9. 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.

  10. Design of a 10.8 kWh, 28V Ni-MH Battery Using Commercial Ni-MH Cells

    NASA Technical Reports Server (NTRS)

    Hellen, Robert M.; Darcy, Eric C.

    2000-01-01

    This paper describes the design of a 10.8 kWh, 28V, Ni-MH battery using commercial off-the shelf (COTS) 4/3A Ni-MH cells for the X-38 vehicle, an experimental version of the Crew Return Vehicle (CRY). This will be an autonomous vehicle that will enable International Space Station crews to return to earth in the event of a medical, or other, emergency. The X-38 will be powered by 3 batteries: a 32 V primary battery, which will power the vehicle avionics for up to 7 hours for a loiter and de-orbit phase of the descent; a 28 V Ni-MH battery which will take over for the primary battery after de-orbit until landing, and a 270V Ni-Cd battery, which will be used to power electromechanical actuators and the winches controlling a parachute for landing.

  11. Wet chemical synthesis and photocatalytic activity of potassium niobate K{sub 6}Nb{sub 10.8}O{sub 30} powders

    SciTech Connect

    Zhang Gaoke Hu Yanjun; Ding Xinmiao; Zhou Jin; Xie Junwei

    2008-09-15

    The nanometer potassium niobate powders with tungsten bronze (TB)-type structure were synthesized by a wet chemical method and characterized by X-ray diffraction (XRD) and field emission scanning electron microscope (FESEM). X-ray photoelectron spectroscopy (XPS) analysis confirmed the niobium with mixed valence states exists in the crystal structure of the photocatalyst, which may be advantage for increasing the photocatalytic activity. The band gap of K{sub 6}Nb{sub 10.8}O{sub 30} powders was estimated to be about 2.92 eV and shows a markedly blue-shift as compared to that of the sample obtained by the solid-state reaction. The photocatalytic activity of the samples was evaluated by degradation of acid red G under UV irradiation and the photocatalytic reaction follows first-order kinetics. The photocatalytic activity of the as-prepared sample is much higher than that of sample synthesized by solid-state reaction, and slightly higher than that of P25-TiO{sub 2}. - Graphical abstract: The K{sub 6}Nb{sub 10.8}O{sub 30} powders with TB-type structure were synthesized by a wet chemical method at lower temperature. The particle size of the as-prepared powders is much smaller than that of the sample by obtained solid-state method and its photocatalytic activity is much higher than that of the latter and slightly higher than that of P25-TiO{sub 2}.

  12. ExoMol: Molecular Line List for Exoplanets and Other Atmospheres

    NASA Astrophysics Data System (ADS)

    Tennyson, Jonathan; Yurchenko, Sergei N.; Polyansky, Oleg

    2016-06-01

    The discovery of extrasolar planets is one of the major scientific advances of the last two decades. Thousands of planets have now been detected and astronomers are beginning to characterize their composition and physical characteristics. To do this requires a huge quantity of spectroscopic data most of which are not available from laboratory studies. The ExoMol project [1] is generating a comprehensive solution to this problem by providing spectroscopic data on all the molecular transitions of importance in the atmospheres of exoplanets. These data are widely applicable to other problems such studies on cool stars, brown dwarfs and circumstellar environments as well as industrial and technological problems on earth. ExoMol employs a mixture of first principles and empirically tuned quantum mechanical methods to compute comprehensive and very large rotation-vibration and rovibronic line lists. Results span a variety of closed (NaH, SiO, PN, NaCl, KCl, CS) and open (BeH, MgH, CaH, AlO, VO) shell diatomics to triatomics (HCN/HNC, SO_2, H_2S, H_3^+), tetratomics (H_2CO, PH_3, SO_3, H_2O_2), plus methane [2] and nitric acid [3]. This has led directly to the detection of new species in the atmospheres of exoplanets [4]. A new comprehensive data release has just been completed [5]. Progress on and future prospects of the project will be summarised. J. Tennyson, S. N. Yurchenko, Mon. Not. R. astr. Soc., 425, 21, 2012. S. N. Yurchenko, J. Tennyson, J. Bailey, M. D. J. Hollis, G Tinetti, Proc. Nat. Acad. Sci., 111, 9379, 2014. A. I. Pavlyuchko, S. N. Yurchenko, J. Tennyson, Mon. Not. R. astr. Soc., 452, 1702, 2015. A. Tsiaras et al, Astrophys. J., in press. J. Tennyson et al, J. Mol. Spectrosc., in press.

  13. MolProbity: all-atom structure validation for macromolecular crystallography.

    PubMed

    Chen, Vincent B; Arendall, W Bryan; Headd, Jeffrey J; Keedy, Daniel A; Immormino, Robert M; Kapral, Gary J; Murray, Laura W; Richardson, Jane S; Richardson, David C

    2010-01-01

    MolProbity is a structure-validation web service that provides broad-spectrum solidly based evaluation of model quality at both the global and local levels for both proteins and nucleic acids. It relies heavily on the power and sensitivity provided by optimized hydrogen placement and all-atom contact analysis, complemented by updated versions of covalent-geometry and torsion-angle criteria. Some of the local corrections can be performed automatically in MolProbity and all of the diagnostics are presented in chart and graphical forms that help guide manual rebuilding. X-ray crystallography provides a wealth of biologically important molecular data in the form of atomic three-dimensional structures of proteins, nucleic acids and increasingly large complexes in multiple forms and states. Advances in automation, in everything from crystallization to data collection to phasing to model building to refinement, have made solving a structure using crystallography easier than ever. However, despite these improvements, local errors that can affect biological interpretation are widespread at low resolution and even high-resolution structures nearly all contain at least a few local errors such as Ramachandran outliers, flipped branched protein side chains and incorrect sugar puckers. It is critical both for the crystallographer and for the end user that there are easy and reliable methods to diagnose and correct these sorts of errors in structures. MolProbity is the authors' contribution to helping solve this problem and this article reviews its general capabilities, reports on recent enhancements and usage, and presents evidence that the resulting improvements are now beneficially affecting the global database.

  14. Classification moléculaire du cancer du sein au Maroc

    PubMed Central

    Fouad, Abbass; Yousra, Akasbi; Kaoutar, Znati; Omar, El Mesbahi; Afaf, Amarti; Sanae, Bennis

    2012-01-01

    Introduction La classification moléculaire des cancers du sein basée sur l'expression génique puis sur le profil protéique a permis de distinguer cinq groupes moléculaires: luminal A, luminal B, Her2/neu, basal-like et non-classées. L'objectif de cette étude réalisée au CHU Hassan II de Fès est de classer 335 cancers du sein infiltrant en groupes moléculaires, puis de les corréler avec les caractéristiques clinicopathologiques. Méthodes Etude rétrospective étalée sur 45 mois, comportant 335 patientes colligées au CHU pour le diagnostic et le suivi. Les tumeurs sont analysées histologiquement et classées après une étude immunohistochimique en groupes: luminal A, luminal B, Her2+, basal-like et non-classées. Résultats 54.3% des tumeurs sont du groupe luminal A, 16% luminal B, 11.3% Her2+, 11.3% basal-like et 7% non-classées. Le groupe luminal A renferme le plus faible taux de grade III, d'emboles vasculaires ainsi que de métastases; alors que le groupe des non-classées et basal-like représentent un taux élevé de grade III, une faible proportion d'emboles vasculaires et d'envahissement ganglionnaire. Ces facteurs sont significativement élevés dans les groupes luminal B et Her2+ avec un taux de survie globale de 78% et 76% respectivement. Dans le groupe luminal A, la survie globale des patientes est élevée (87%) alors qu'elle n'est que de 49% dans le groupe des triples négatifs (basal-like et non-classés). Conclusion Le groupe luminal B est différent du luminal A et il est de pronostic péjoratif vis à vis du groupe Her2+. Les caractéristiques clinicopathologiques concordent avec le profil moléculaire donc devraient être pris en considération comme facteurs pronostiques. PMID:23396646

  15. Dick Mol. 'Sir Mammoth' leads charge to uncover Ice Age fossils.

    PubMed

    Stone, R

    2000-12-15

    Dick Mol may be an amateur, but he's had more success than most professionals in his chosen field of paleontology. As scientific coordinator of a major expedition that's gathering the remains of woolly mammoths and other Pleistocene fauna from Siberia's Taimyr Peninsula, this 45-year-old customs officer at Amsterdam airport has been featured in a documentary on the Discovery Channel and in a sequel to appear next March. The work has brought him international recognition for his studies on quaternary paleontology, the study of the Pleistocene and today's Holocene Epochs.

  16. Beneficial effects of Lagenaria siceraria (Mol.) Standley fruit epicarp in animal models.

    PubMed

    Deshpande, J R; Choudhari, A A; Mishra, M R; Meghre, V S; Wadodkar, S G; Dorle, A K

    2008-04-01

    Lagenaria siceraria (Mol.) Standley fruit (bottle gourd), a commonly used vegetable in India is described as cardiotonic and as a general tonic in Ayurveda. Keeping in view the presence of free radical scavenging activity in L. siceraria and involvement of free radicals in the development of various disorders, present studies were designed to evaluate the ethanolic extract of L. siceraria fruit against the disorders where free radicals play a major role in pathogenesis. The extract was found effective as hepatoprotective, antioxidant, antihyperglycemic, immunomodulatory, antihyperlipidemic and cardiotonic agent. The results showed that the radical scavenging capacity of L. siceraria fruit may be responsible for various biological activities studied.

  17. Moléculas orgánicas obtenidas en simulaciones experimentales del medio interestelar.

    NASA Astrophysics Data System (ADS)

    Muñoz-Caro, Guillermo Manuel

    Las nubes moleculares son regiones de formación de estrellas, con temperaturas cinéticas entre 10-50 K y densidades de 103-106 átomos cm-3. Su materia está formada por gas y polvo interestelar. Estas partículas de polvo están cubiertas por una fina capa de hielo, de unos 0.01 μm, que contiene H2O y a menudo CO, CO2, CH3OH y NH3. El hielo es presumiblemente irradiado por fotones ultravioleta y rayos cósmicos en las zonas poco profundas de las nubes moleculares y las regiones circunestelares. En un sistema de vacío, P ˜ 10-7 mbar, simulamos la deposición de hielo a partir de 10 K y la irradiación ultravioleta por medio de una lámpara de descarga de hidrógeno activada con microondas. La evolución del hielo se observa por medio de un espectrómetro infrarrojo. De este modo es posible determinar la composición del hielo observado en el medio interestelar y predecir la presencia de moléculas aún no detectadas en el espacio, que han sido producto del procesamiento del hielo en nuestros experimentos. También es posible calentar el sistema hasta temperatura ambiente para sublimar el hielo depositado. Cuando el hielo ha sido previamente irradiado, se observa un residuo compuesto por moléculas orgánicas complejas, algunas prebióticas, como varios ácidos carboxílicos, aminas, amidas, ésteres y en menor proporción moléculas heterocíclicas y aminoácidos. Algunas de estas moléculas podrían detectarse en estado gaseoso por medio de observaciones milimétricas y de radio. También podrían estar presentes en el polvo cometario, cuyo análisis químico está planeado por las misiones Stardust y Rosetta. Mientras tanto, nuestro grupo está llevando a cabo el análisis de partículas de polvo interplanetario (IDPs), algunas de las cuales pueden ser de origen cometario. Al igual que ocurre con los productos obtenidos por irradiación del hielo en nuestros experimentos, algunas IDPs son ricas en material orgánico que contiene oxígeno.

  18. Microbes at their best: first Mol Micro Meeting Würzburg.

    PubMed

    Böhm, Alex; Papenfort, Kai; Lopez, Daniel; Vogel, Jörg

    2011-11-01

    Founded on ground-breaking discoveries such as the operon model by Jacob and Monod more than 50 years ago, molecular microbiology is now one of the most vibrant disciplines of the life sciences. The first Mol Micro Meeting Würzburg ('M3W') hosted more than 160 scientists from 14 countries to exchange their latest ideas in this field of research. Divided into the four main sessions Gene Regulation, Pathogenesis, Microbial Cell Biology and Signalling, the conference provided insight into current advances and future goals and challenges.

  19. 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

  20. 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

  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. 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.

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. PyMOL mControl: Manipulating molecular visualization with mobile devices.

    PubMed

    Lam, Wendy W T; Siu, Shirley W I

    2017-01-02

    Viewing and manipulating three-dimensional (3D) structures in molecular graphics software are essential tasks for researchers and students to understand the functions of molecules. Currently, the way to manipulate a 3D molecular object is mainly based on mouse-and-keyboard control that is usually difficult and tedious to learn. While gesture-based and touch-based interactions are increasingly popular in interactive software systems, their suitability in handling molecular graphics has not yet been sufficiently explored. Here, we designed the gesture-based and touch-based interaction methods to manipulate virtual objects in PyMOL utilizing the motion and touch sensors in a mobile device. Three fundamental viewing controls-zooming, translation and rotation-and frequently used functions were implemented. Results from a pilot user study reveal that task performances on viewing controls using a mobile device are slightly reduced as compared to mouse-and-keyboard method. However, it is considered to be more suitable for oral presentations and equally suitable for education scenarios such as school classes. Overall, PyMOL mControl provides an alternative way to manipulate objects in molecular graphic software with new user experiences. The software is freely available at http://cbbio.cis.umac.mo/mcontrol.html. © 2016 by The International Union of Biochemistry and Molecular Biology, 45(1):76-83, 2017.

  8. NEAR-INFRARED AND MILLIMETER-WAVELENGTH OBSERVATIONS OF Mol 160: A MASSIVE YOUNG PROTOSTELLAR CORE

    SciTech Connect

    Wolf-Chase, Grace; Smutko, Michael; Sherman, Reid; Harper, Doyal A.; Medford, Michael

    2012-02-01

    We have discovered two compact sources of shocked H{sub 2} 2.12 {mu}m emission coincident with Mol 160 (IRAS 23385+6053), a massive star-forming core thought to be a precursor to an ultracompact H II region. The 2.12 {mu}m sources lie within 2'' (0.05 pc) of a millimeter-wavelength continuum peak where the column density is {>=}10{sup 24} cm{sup -2}. We estimate that the ratio of molecular hydrogen luminosity to bolometric luminosity is >0.2%, indicating a high ratio of mechanical to radiant luminosity. CS J = 2{yields}1 and HCO{sup +} J = 1{yields}0 observations with the Combined Array for Research in Millimeter-wave Astronomy (CARMA) indicate that the protostellar molecular core has a peculiar velocity of {approx}2 km s{sup -1} with respect to its parent molecular cloud. We also observed 95 GHz CH{sub 3}OH J = 8{yields}7 Class I maser emission from several locations within the core. Comparison with previous observations of 44 GHz CH{sub 3}OH maser emission shows that the maser sources have a high mean ratio of 95 GHz to 44 GHz intensity. Our observations strengthen the case that Mol 160 (IRAS 23385+6053) is a rapidly accreting massive protostellar system in a very early phase of its evolution.

  9. MolProbity: all-atom contacts and structure validation for proteins and nucleic acids

    PubMed Central

    Davis, Ian W.; Leaver-Fay, Andrew; Chen, Vincent B.; Block, Jeremy N.; Kapral, Gary J.; Wang, Xueyi; Murray, Laura W.; Arendall, W. Bryan; Snoeyink, Jack; Richardson, Jane S.; Richardson, David C.

    2007-01-01

    MolProbity is a general-purpose web server offering quality validation for 3D structures of proteins, nucleic acids and complexes. It provides detailed all-atom contact analysis of any steric problems within the molecules as well as updated dihedral-angle diagnostics, and it can calculate and display the H-bond and van der Waals contacts in the interfaces between components. An integral step in the process is the addition and full optimization of all hydrogen atoms, both polar and nonpolar. New analysis functions have been added for RNA, for interfaces, and for NMR ensembles. Additionally, both the web site and major component programs have been rewritten to improve speed, convenience, clarity and integration with other resources. MolProbity results are reported in multiple forms: as overall numeric scores, as lists or charts of local problems, as downloadable PDB and graphics files, and most notably as informative, manipulable 3D kinemage graphics shown online in the KiNG viewer. This service is available free to all users at http://molprobity.biochem.duke.edu. PMID:17452350

  10. MolProbity: all-atom contacts and structure validation for proteins and nucleic acids.

    PubMed

    Davis, Ian W; Leaver-Fay, Andrew; Chen, Vincent B; Block, Jeremy N; Kapral, Gary J; Wang, Xueyi; Murray, Laura W; Arendall, W Bryan; Snoeyink, Jack; Richardson, Jane S; Richardson, David C

    2007-07-01

    MolProbity is a general-purpose web server offering quality validation for 3D structures of proteins, nucleic acids and complexes. It provides detailed all-atom contact analysis of any steric problems within the molecules as well as updated dihedral-angle diagnostics, and it can calculate and display the H-bond and van der Waals contacts in the interfaces between components. An integral step in the process is the addition and full optimization of all hydrogen atoms, both polar and nonpolar. New analysis functions have been added for RNA, for interfaces, and for NMR ensembles. Additionally, both the web site and major component programs have been rewritten to improve speed, convenience, clarity and integration with other resources. MolProbity results are reported in multiple forms: as overall numeric scores, as lists or charts of local problems, as downloadable PDB and graphics files, and most notably as informative, manipulable 3D kinemage graphics shown online in the KiNG viewer. This service is available free to all users at http://molprobity.biochem.duke.edu.

  11. MolProbity’s Ultimate Rotamer-Library Distributions for Model Validation

    PubMed Central

    Hintze, Bradley J.; Lewis, Steven M.; Richardson, Jane S.; Richardson, David C.

    2016-01-01

    Here we describe the updated MolProbity rotamer-library distributions derived from an order-of-magnitude larger and more stringently quality-filtered dataset of about 8000 (vs. 500) protein chains, and we explain the resulting changes and improvements to model validation as seen by users. To include only sidechains with satisfactory justification for their given conformation, we added residue-specific filters for electron-density value and model-to-density fit. The combined new protocol retains a million residues of data, while cleaning up false-positive noise in the multi-χ datapoint distributions. It enables unambiguous characterization of conformational clusters nearly 1000-fold less frequent than the most common ones. We describe examples of local interactions that favor these rare conformations, including the role of authentic covalent bond-angle deviations in enabling presumably strained sidechain conformations. Further, along with favored and outlier, an allowed category (0.3% to 2.0% occurrence in reference data) has been added, analogous to Ramachandran validation categories. The new rotamer distributions are used for current rotamer validation in Mol-Probity and PHENIX, and for rotamer choice in PHENIX model-building and refinement. The multi-dimensional χ distributions and Top8000 reference dataset are freely available on GitHub. These rotamers are termed “ultimate” because data sampling and quality are now fully adequate for this task, and also because we believe the future of conformational validation should integrate sidechain with backbone criteria. PMID:27018641

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  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. 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

  19. 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.

  20. 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.

  1. 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

  2. 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

  3. Enhanced M1/M2 macrophage ratio promotes orthodontic root resorption.

    PubMed

    He, D; Kou, X; Luo, Q; Yang, R; Liu, D; Wang, X; Song, Y; Cao, H; Zeng, M; Gan, Y; Zhou, Y

    2015-01-01

    Mechanical force-induced orthodontic root resorption is a major clinical challenge in orthodontic treatment. Macrophages play an important role in orthodontic root resorption, but the underlying mechanism remains unclear. In this study, we examined the mechanism by which the ratio of M1 to M2 macrophage polarization affects root resorption during orthodontic tooth movement. Root resorption occurred when nickel-titanium coil springs were applied on the upper first molars of rats for 3 to 14 d. Positively stained odontoclasts or osteoclasts with tartrate-resistant acid phosphatase were found in resorption areas. Meanwhile, M1-like macrophages positive for CD68 and inducible nitric oxide synthase (iNOS) persistently accumulated on the compression side of periodontal tissues. In addition, the expressions of the M1 activator interferon-γ and the M1-associated pro-inflammatory cytokine tumor necrosis factor (TNF)-α were upregulated on the compression side of periodontal tissues. When the coil springs were removed at the 14th day after orthodontic force application, root resorption was partially rescued. The number of CD68(+)CD163(+) M2-like macrophages gradually increased on the compression side of periodontal tissues. The levels of M2 activator interleukin (IL)-4 and the M2-associated anti-inflammatory cytokine IL-10 also increased. Systemic injection of the TNF-α inhibitor etanercept or IL-4 attenuated the severity of root resorption and decreased the ratio of M1 to M2 macrophages. These data imply that the balance between M1 and M2 macrophages affects orthodontic root resorption. Root resorption was aggravated by an enhanced M1/M2 ratio but was partially rescued by a reduced M1/M2 ratio.

  4. CO2 laser photoacoustic measurements of ethanol absorption coefficients within infrared region of 9.2-10.8 μm

    NASA Astrophysics Data System (ADS)

    Ivascu, I. R.; Matei, C. E.; Patachia, M.; Bratu, A. M.; Dumitras, D. C.

    2016-06-01

    Absorption coefficients of the ethanol vapors at atmospheric pressure and room temperature were measured by photoacoustic technique using a cw, line-tunable, frequency-stabilized CO2 laser as radiation source. The spectrum of the employed CO2 laser includes 54 lines with wavelengths in the infrared region of 9.2-10.8 μm and power levels up to 4.7 W. Measurements revealed a predominant absorption for ethanol within 9.4 μm band of the CO2 laser spectrum, where the highest values of the absorption coefficients were recorded: 3.68 cm- 1 atm- 1 at 9R(20) line and 3.65 cm- 1 atm- 1 at 9R(22) line. The estimated detection range covers six orders of magnitude, from a minimum of 30 ppbV to a maximum of 4% concentration of ethanol in nitrogen, which proves the suitability of the photoacoustic technique for accurate measurements of the ethanol concentration in various applications.

  5. CO2 laser photoacoustic measurements of ethanol absorption coefficients within infrared region of 9.2-10.8 μm.

    PubMed

    Ivascu, I R; Matei, C E; Patachia, M; Bratu, A M; Dumitras, D C

    2016-06-15

    Absorption coefficients of the ethanol vapors at atmospheric pressure and room temperature were measured by photoacoustic technique using a cw, line-tunable, frequency-stabilized CO2 laser as radiation source. The spectrum of the employed CO2 laser includes 54 lines with wavelengths in the infrared region of 9.2-10.8μm and power levels up to 4.7W. Measurements revealed a predominant absorption for ethanol within 9.4μm band of the CO2 laser spectrum, where the highest values of the absorption coefficients were recorded: 3.68cm(-1)atm(-1) at 9R(20) line and 3.65cm(-1)atm(-1) at 9R(22) line. The estimated detection range covers six orders of magnitude, from a minimum of 30ppbV to a maximum of 4% concentration of ethanol in nitrogen, which proves the suitability of the photoacoustic technique for accurate measurements of the ethanol concentration in various applications.

  6. Perovskite CH3NH3PbI3(Cl) Single Crystals: Rapid Solution Growth, Unparalleled Crystalline Quality, and Low Trap Density toward 10(8) cm(-3).

    PubMed

    Lian, Zhipeng; Yan, Qingfeng; Gao, Taotao; Ding, Jie; Lv, Qianrui; Ning, Chuangang; Li, Qiang; Sun, Jia-Lin

    2016-08-03

    Single crystal reflects the intrinsic physical properties of a material, and single crystals with high-crystalline quality are highly desired for the acquisition of high-performance devices. We found that large single crystals of perovskite CH3NH3PbI3(Cl) could be grown rapidly from chlorine-containing solutions. Within 5 days, CH3NH3PbI3(Cl) single crystal as large as 20 mm × 18 mm × 6 mm was harvested. As a most important index to evaluate the crystalline quality, the full width at half-maximum (fwhm) in the high-resolution X-ray rocking curve (HR-XRC) of as-grown CH3NH3PbI3(Cl) single crystal was measured as 20 arcsec, which is far superior to so far reported CH3NH3PbI3 single crystals (∼1338 arcsec). The unparalleled crystalline quality delivered a low trap-state density of down to 7.6 × 10(8) cm(-3), high carrier mobility of 167 ± 35 cm(2) V(-1) s(-1), and long transient photovoltaic carrier lifetime of 449 ± 76 μs. The improvement in the crystalline quality, together with the rapid growth rate and excellent carrier transport property, provides state-of-the-art single crystalline hybrid perovskite materials for high-performance optoelectronic devices.

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. Mechanism of influenza A M2 transmembrane domain assembly in lipid membranes

    PubMed Central

    Georgieva, Elka R.; Borbat, Peter P.; Norman, Haley D.; Freed, Jack H.

    2015-01-01

    M2 from influenza A virus functions as an oligomeric proton channel essential for the viral cycle, hence it is a high-priority pharmacological target whose structure and functions require better understanding. We studied the mechanism of M2 transmembrane domain (M2TMD) assembly in lipid membranes by the powerful biophysical technique of double electron-electron resonance (DEER) spectroscopy. By varying the M2TMD-to-lipid molar ratio over a wide range from 1:18,800 to 1:160, we found that M2TMD exists as monomers, dimers, and tetramers whose relative populations shift to tetramers with the increase of peptide-to-lipid (P/L) molar ratio. Our results strongly support the tandem mechanism of M2 assembly that is monomers-to-dimer then dimers-to-tetramer, since tight dimers are abundant at small P/L’s, and thereafter they assemble as dimers of dimers in weaker tetramers. The stepwise mechanism found for a single-pass membrane protein oligomeric assembly should contribute to the knowledge of the association steps in membrane protein folding. PMID:26190831

  12. Molécule unique, nanotube de carbone et exaltation Raman

    NASA Astrophysics Data System (ADS)

    Débarre, A.; Jaffiol, R.; Julien, C.; Nutarelli, D.; Tchénio, P.

    2004-11-01

    La spectroscopie Raman fournit une analyse détaillée de la structure chimique d'un objet, à température ambiante. La section efficace de diffusion Raman d'un objet petit est souvent faible et son signal ne pourra être détecté sans utiliser un processus d'exaltation efficace de la diffusion. Cet article décrit quelques avancées dans le domaine de l'exaltation de surface de la diffusion Raman. Il est illustré par des résultats expérimentaux que nous avons obtenus sur des molécules uniques. Parfois, le signal de certains objets petits peut être détecté sans effet d'exaltation supplémentaire, comme le montre l'exemple de nanotubes remplis, dits peapods.

  13. W4 theory for computational thermochemistry : in pursuit of confident sub-kJ/mol predictions.

    SciTech Connect

    Karton, A.; Rabinovich, E.; Martin, J. M. L.; Ruscic, B.; Chemistry; Weizmann Institute of Science

    2006-01-01

    In an attempt to improve on our earlier W3 theory [A. D. Boese et al., J. Chem. Phys. 120, 4129 (2004)] we consider such refinements as more accurate estimates for the contribution of connected quadruple excitations ({cflx T}{sub 4}), inclusion of connected quintuple excitations ({cflx T}{sub 5}), diagonal Born-Oppenheimer corrections (DBOC), and improved basis set extrapolation procedures. Revised experimental data for validation purposes were obtained from the latest version of the Active Thermochemical Tables thermochemical network. The recent CCSDT(Q) method offers a cost-effective way of estimating {cflx T}{sub 4} but is insufficient by itself if the molecule exhibits some nondynamical correlation. The latter considerably slows down basis set convergence for {cflx T}{sub 4}, and anomalous basis set convergence in highly polar systems makes two-point extrapolation procedures unusable. However, we found that the CCSDTQ-CCSDT(Q) difference converges quite rapidly with the basis set, and that the formula 1.10[CCSDT(Q)/cc-pVTZ+CCSDTQ/cc-pVDZ-CCSDT(Q)/cc-pVDZ] offers a very reliable as well as fairly cost-effective estimate of the basis set limit {cflx T}{sub 4} contribution. The {cflx T}{sub 5} contribution converges very rapidly with the basis set, and even a simple double-zeta basis set appears to be adequate. The largest {cflx T}{sub 5} contribution found in the present work is on the order of 0.5 kcal/mol (for ozone). DBOCs are significant at the 0.1 kcal/mol level in hydride systems. Post-CCSD(T) contributions to the core-valence correlation energy are only significant at that level in systems with severe nondynamical correlation effects. Based on the accumulated experience, a new computational thermochemistry protocol for first- and second-row main-group systems, to be known as W4 theory, is proposed. Its computational cost is not insurmountably higher than that of the earlier W3 theory, while performance is markedly superior. Our W4 atomization energies for

  14. GTKDynamo: a PyMOL plug-in for QC/MM hybrid potential simulations

    PubMed Central

    Bachega, José Fernando R.; Timmers, Luís Fernando S.M.; Assirati, Lucas; Bachega, Leonardo R.; Field, Martin J.; Wymore, Troy

    2014-01-01

    Hybrid quantum chemical (QC)/molecular mechanical (MM) potentials are very powerful tools for molecular simulation. They are especially useful for studying processes in condensed phase systems, such as chemical reactions, that involve a relatively localized change in electronic structure and where the surrounding environment contributes to these changes but can be represented with more computationally efficient functional forms. Despite their utility, however, these potentials are not always straightforward to apply since the extent of significant electronic structure changes occurring in the condensed phase process may not be intuitively obvious. To facilitate their use we have developed an open-source graphical plug-in, GTKDynamo, that links the PyMOL visualization program and the pDynamo QC/MM simulation library. This article describes the implementation of GTKDynamo and its capabilities and illustrates its application to QC/MM simulations. PMID:24137667

  15. Automated Aufbau of antibody structures from given sequences using Macromoltek's SmrtMolAntibody.

    PubMed

    Berrondo, Monica; Kaufmann, Susana; Berrondo, Manuel

    2014-08-01

    This study was a part of the second antibody modeling assessment. The assessment is a blind study of the performance of multiple software programs used for antibody homology modeling. In the study, research groups were given sequences for 11 antibodies and asked to predict their corresponding structures. The results were measured using root-mean-square deviation (rmsd) between the submitted models and X-ray crystal structures. In 10 of 11 cases, the results using SmrtMolAntibody show good agreement between the submitted models and X-ray crystal structures. In the first stage, the average rmsd was 1.4 Å. Average rmsd values for the framework was 1.2 Å and for the H3 loop was 3.0 Å. In stage two, there was a slight improvement with an rmsd for the H3 loop of 2.9 Å.

  16. Moléculas orgánicas no-rígidas

    NASA Astrophysics Data System (ADS)

    Senent Díez, M. L.

    Se destaca la importancia del estudio espectroscópico ab initio de una serie de moléculas no-rígidas detectadas en el medio interestelar (acetona, dimetil-eter, etanol, metanol, metilamina, ldots), así como los últimos avances del desarrollo de la metodología para el tratamiento teórico de estas especies. Se describe, a modo de ejemplo, el análisis del espectro roto-torsional de la molécula de glicoaldehido que ha sido recientemente detectada en el centro Galáctico Sagitario B2 (N) [1]. Esta especie presenta dos movimientos de gran amplitud que interaccionan, descansan en el Infrarrojo Lejano y le confiere propiedades no-rígidas. La molécula puede existir en posiciones cis y trans y presenta cinco confórmeros estables, tres de simetría Cs (I, II y IV) y un doble mínimo trans de simetría C1 (III) . La conformación favorita, I, presenta simetría Cs y se estabiliza por la formación de un puente de hidrógeno entre los grupos OH y C=O. Los mínimos secundarios II, III, y IV se han determinado a 1278.2 cm-1 (trans, Cs), 1298.8 cm-1 (trans, C1) y 1865.2 cm-1 (cis, Cs) con cálculos MP4/cc-pVQZ que incluyen sustituciones triples. Para determinar que vibraciones interaccionan con las torsiones, se ha realizado un análisis armónico en los mínimos. Las frecuencias fundamentales armónicas correspondientes al mínimo I se han calculado en 213.4 cm-1 (torsión C-C) y 425.7 cm-1 (torsión OH). Es de esperar que tan sólo dos vibraciones, la flexión del grupo C-C-O y el aleteo del hidrógeno del grupo aldehídico puedan desplazar el espectro torsional de la molécula aislada. Para determinar el espectro torsional, se ha determinado la superficie de potencial en dos dimensiones mediante el cálculo ab initio de las geometrías y energías de 74 conformaciones seleccionadas. Estas últimas se han ajustado a un doble serie de Fourier. A partir de la PES y de los parámetros cinéticos del Hamiltoniano vibracional se han obtenido frecuencias e intensidades

  17. The atomistic structure of yttria stabilised zirconia at 6.7 mol%: an ab initio study.

    PubMed

    Parkes, Michael A; Tompsett, David A; d'Avezac, Mayeul; Offer, Gregory J; Brandon, Nigel P; Harrison, Nicholas M

    2016-11-16

    Yttria stabilized zirconia (YSZ) is an important oxide ion conductor used in solid oxide fuel cells, oxygen sensing devices, and for oxygen separation. Doping pure zirconia (ZrO2) with yttria (Y2O3) stabilizes the cubic structure against phonon induced distortions and this facilitates high oxide ion conductivity. The local atomic structure of the dopant is, however, not fully understood. X-ray and neutron diffraction experiments have established that, for dopant concentrations below 40 mol% Y2O3, no long range order is established. A variety of local structures have been suggested on the basis of theoretical and computational models of dopant energetics. These studies have been restricted by the difficulty of establishing force field models with predictive accuracy or exploring the large space of dopant configurations with first principles theory. In the current study a comprehensive search for all symmetry independent configurations (2857 candidates) is performed for 6.7 mol% YSZ modelled in a 2 × 2 × 2 periodic supercell using gradient corrected density functional theory. The lowest energy dopant structures are found to have oxygen vacancy pairs preferentially aligned along the 〈210〉 crystallographic direction in contrast to previous results which have suggested that orientation along the 〈111〉 orientation is favourable. Analysis of the defect structures suggests that the Y(3+)-Ovac interatomic separation is an important parameter for determining the relative configurational energies. Current force field models are found to be poor predictors of the lowest energy structures. It is suggested that the energies from a simple point charge model evaluated at unrelaxed geometries is actually a better descriptor of the energy ordering of dopant structures. Using these observations a pragmatic procedure for identifying low energy structures in more complicated material models is suggested. Calculation of the oxygen vacancy migration activation energies within

  18. 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.

  19. 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.

  20. 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.

  1. [[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.

  2. 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.

  3. 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

  4. 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

  5. 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

  6. 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.

  7. 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

  8. 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.

  9. 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

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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.

  16. Final report of key comparison APMP.QM-K53—comparison of gravimetric preparative capability with 100 μmol/mol of oxygen in nitrogen (bilateral comparison between NIM and KRISS)

    NASA Astrophysics Data System (ADS)

    Lee, Jeongsoon; Lee, JinBok; Moon, Dongmin; Han, Qiao; Zhou, Zeyi

    2015-01-01

    This bilateral comparison, which is traceable to CCQM-K53, was carried out to support NIM's capability for the preparation of stable gas species in nitrogen. The target amount of substance was 100 μmol/mol of oxygen in nitrogen, which was prepared gravimetrically by the participant. The comparison showed that the NIM and KRISS gravimetric values were consistent with each other to within the expanded uncertainty of 0.200 μmol/mol. Therefore the comparison is well linked to the CCQM-K53 and offers a gravimetric preparation capability of oxygen in nitrogen at a level of 100 μmol/mol to the participant. 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 CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

  17. 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

  18. 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.

  19. 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.

  20. 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.

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. [Use of mesquite cotyledon (Prosopis chilensis (Mol) Shuntz) in the manufacturing of cereal bars].

    PubMed

    Estévez, A M; Escobar, B; Ugarte, V

    2000-06-01

    Cereal bars with peanut and walnut has shown to be snack foods of good organoleptic characteristics and high caloric value, due to their content of protein, lipids and carbohydrates. Cotyledons of mezquite seeds have a high protein content which biological quality improves with thermal processing like toasting, microwave or moist heat under pressure. The purposes of this research were to study the use of mezquite cotyledon (Prosopis chilensis (Mol) Stuntz) in cereal bars with two different levels of peanut or walnut; and to determine the effect of two thermal treatment applied on the cotyledon upon the bar characteristics. Twelve different kind of bars were developed through the combination of two levels of peanut or walnut (15% and 18%); the use of mezquite cotyledon (0% and 6%); and the application of two thermal processing to the cotyledon (microwave and toasting). Cereal bars were analysed for chemical, physical and sensory characteristics: moisture, water activity, proximate chemical composition, sensory quality and acceptability. Moisture content of bars with peanut ranged between 10.4% and 10.9%; and for those with walnut, between 10.5% and 12.3%. Protein content was higher in the bars with mezquite cotiledon, being higher those with peanut. Thermal processing did not have any effect on the chemical composition. Bars with mezquite cotyledon treated by microwave showed a higher acceptability.

  14. The large scale in-situ PRACLAY heater and seal tests in URL HADES, Mol, Belgium

    SciTech Connect

    Xiangling Li; Guangjing Chen; Verstricht, Jan; Van Marcke, Philippe; Troullinos, Ioannis

    2013-07-01

    In Belgium, the URL HADES was constructed in the Boom Clay formation at the Mol site to investigate the feasibility of geological disposal in a clay formation. Since 1995, the URL R and D programme has focused on large scale demonstration tests like the PRACLAY Heater and Seal tests. The main objective of the Heater Test is to demonstrate that the thermal load generated by the heat-emitting waste will not jeopardise the safety functions of the host rock. The primary objective of the Seal Test is to provide suitable hydraulic boundary conditions for the Heater Test. The Seal Test also provides an opportunity to investigate the in-situ behaviour of a bentonite-based EBS. The PRACLAY gallery was constructed in 2007 and the hydraulic seal was installed in 2010. The bentonite is hydrated both naturally and artificially. The swelling, total pressure and pore pressure of the bentonite are continuously measured and analysed by numerical simulations to get a better understanding of this hydration processes. The timing of switching on the heater depends on the progress of the bentonite hydration, as a sufficient seal swelling is needed to fulfill its role. A set of conditions to be met for the heater switch-on and its schedule will be given. (authors)

  15. Using the PyMOL application to reinforce visual understanding of protein structure.

    PubMed

    Rigsby, Rachel E; Parker, Alison B

    2016-09-10

    Visualization of chemical concepts can be challenging for many students. This is arguably a critical skill for beginning students of biochemistry to develop, since new information is often presented visually in the form of textbook figures. It is recommended that visual literacy be explicitly taught in the classroom rather than assuming that students will develop this skill on their own.  The activity described here is designed to assist students in their development of understanding of basic representations of protein three-dimensional structure as well as various types of ligands (small molecules, ions) through the use of the iPad application PyMOL.  It has been used as a laboratory exercise but can also be used in a typical 50-minute class period with a portion of the activity assigned as homework. © 2016 by The International Union of Biochemistry and Molecular Biology, 44(5):433-437, 2016.

  16. molSimplify: A toolkit for automating discovery in inorganic chemistry.

    PubMed

    Ioannidis, Efthymios I; Gani, Terry Z H; Kulik, Heather J

    2016-08-15

    We present an automated, open source toolkit for the first-principles screening and discovery of new inorganic molecules and intermolecular complexes. Challenges remain in the automatic generation of candidate inorganic molecule structures due to the high variability in coordination and bonding, which we overcome through a divide-and-conquer tactic that flexibly combines force-field preoptimization of organic fragments with alignment to first-principles-trained metal-ligand distances. Exploration of chemical space is enabled through random generation of ligands and intermolecular complexes from large chemical databases. We validate the generated structures with the root mean squared (RMS) gradients evaluated from density functional theory (DFT), which are around 0.02 Ha/au across a large 150 molecule test set. Comparison of molSimplify results to full optimization with the universal force field reveals that RMS DFT gradients are improved by 40%. Seamless generation of input files, preparation and execution of electronic structure calculations, and post-processing for each generated structure aids interpretation of underlying chemical and energetic trends. © 2016 Wiley Periodicals, Inc.

  17. 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

  18. 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

  19. 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

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

    NASA Technical Reports Server (NTRS)

    1963-01-01

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

  1. 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

  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. 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

  6. 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

  7. 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

  8. 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

  9. 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.

  10. 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

  11. 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.

  12. 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

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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

  1. 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

  2. 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

  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. 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

  5. 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

  6. 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.

  7. ExoMol molecular line lists - XIII. The spectrum of CaO

    NASA Astrophysics Data System (ADS)

    Yurchenko, Sergei N.; Blissett, Audra; Asari, Usama; Vasilios, Marcus; Hill, Christian; Tennyson, Jonathan

    2016-03-01

    An accurate line list for calcium oxide is presented covering transitions between all bound ro-vibronic levels from the five lowest electronic states X 1Σ+, A' 1Π, A 1Σ+, a 3Π, and b 3Σ+. The ro-vibronic energies and corresponding wavefunctions were obtained by solving the fully coupled Schrödinger equation. Ab initio potential energy, spin-orbit, and electronic angular momentum curves were refined by fitting to the experimental frequencies and experimentally derived energies available in the literature. Using our refined model we could (1) reassign the vibronic states for a large portion of the experimentally derived energies (van Groenendael A., Tudorie M., Focsa C., Pinchemel B., Bernath P. F., 2005, J. Mol. Spectrosc., 234, 255), (2) extended this list of energies to J = 61-118 and (3) suggest a new description of the resonances from the A 1Σ+-X 1Σ+ system. We used high level ab initio electric dipole moments reported previously (Khalil H., Brites V., Le Quere F., Leonard C., 2011, Chem. Phys., 386, 50) to compute the Einstein A coefficients. Our work is the first fully coupled description of this system. Our line list is the most complete catalogue of spectroscopic transitions available for 40Ca16O and is applicable for temperatures up to at least 5000 K. CaO has yet to be observed astronomically but its transitions are characterized by being particularly strong which should facilitate its detection. The CaO line list is made available in an electronic form as supplementary data to this article and at www.exomol.com.

  8. Dietary fibre concentrate from Chilean algarrobo (Prosopis chilensis (Mol.) Stuntz) pods: purification and characterization.

    PubMed

    Estévez, Ana María; Figuerola, Fernando; Bernuy, Enrique; Sáenz, Carmen

    2014-12-01

    Prosopis species are generally fast-growing, drought-resistant, nitrogen-fixing trees or shrubs. Fruits of Prosopis spp are indehiscent pods, where pericarp is formed by the epicarp, light brown in colour, and fibrous nature; the mesocarp known as pulp, which is rich in sugars; and the endocarp. The aim of this work was to obtain a fibre concentrate from the pods of Prosopis chilensis Mol. (Stuntz) and to determine the chemical, physical, and technological properties of the pod flour (PF) and of a fibre concentrate or pod purified flour (PPF). Acetone, ethanol, and water at different conditions of time and temperature were used in the purification process. PF showed 53.7 g/100 g of total sugar content, 4.2 g/100 g of reducing sugar content, 41.8 g/100 g of total dietary fibre, 35.8 g/100 g of insoluble fibre, and 6.0 g/100 g of soluble fibre content. The PPF has a total sugar content of 3.8 g/100 g, reducing sugar content of 2.2 g/100 g, total dietary fibre content of 80.8 g/100 g, insoluble fibre content of 75.1 g/100 g, and soluble fibre content of 5.7 g/100 g. The scanning electron microscopy analysis showed the existence of voids in the structure of PPF flour, which reveals the efficiency of the purification process with a high decrease in the total sugar content.

  9. KVFinder: steered identification of protein cavities as a PyMOL plugin

    PubMed Central

    2014-01-01

    Background The characterization of protein binding sites is a major challenge in computational biology. Proteins interact with a wide variety of molecules and understanding of such complex interactions is essential to gain deeper knowledge of protein function. Shape complementarity is known to be important in determining protein-ligand interactions. Furthermore, these protein structural features have been shown to be useful in assisting medicinal chemists during lead discovery and optimization. Results We developed KVFinder, a highly versatile and easy-to-use tool for cavity prospection and spatial characterization. KVFinder is a geometry-based method that has an innovative customization of the search space. This feature provides the possibility of cavity segmentation, which alongside with the large set of customizable parameters, allows detailed cavity analyses. Although the main focus of KVFinder is the steered prospection of cavities, we tested it against a benchmark dataset of 198 known drug targets in order to validate our software and compare it with some of the largely accepted methods. Using the one click mode, we performed better than most of the other methods, staying behind only of hybrid prospection methods. When using just one of KVFinder’s customizable features, we were able to outperform all other compared methods. KVFinder is also user friendly, as it is available as a PyMOL plugin, or command-line version. Conclusion KVFinder presents novel usability features, granting full customizable and highly detailed cavity prospection on proteins, alongside with a friendly graphical interface. KVFinder is freely available on http://lnbio.cnpem.br/bioinformatics/main/software/. PMID:24938294

  10. 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

  11. 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

  12. Gene-trap mutagenesis using Mol/MSM-1 embryonic stem cells from MSM/Ms mice.

    PubMed

    Nakahara, Mai; Tateyama, Hiroki; Araki, Masatake; Nakagata, Naomi; Yamamura, Ken-ichi; Araki, Kimi

    2013-06-01

    The MSM/Ms strain is derived from the Japanese wild mouse Mus musculus molossinus and displays characteristics not observed in common laboratory strains. Functional genomic analyses using genetically engineered MSM/Ms mice will reveal novel phenotypes and gene functions/interactions. We previously reported the establishment of a germline-competent embryonic stem (ES) cell line, Mol/MSM-1, from the MSM/Ms strain. To analyze its usefulness for insertional mutagenesis, we performed gene-trapping using these cells. In the present study, we compared the gene-trap events between Mol/MSM-1 and a conventional ES cell line, KTPU8, derived from the F1 progeny of a C57BL/6 × CBA cross. We introduced a promoter-trap vector carrying the promoterless β-galactosidase/neomycin-resistance fusion gene into Mol/MSM-1 and KTPU8 cells, isolated clones, and identified the trapped genes by rapid amplification of cDNA 5'-ends (5'-RACE), inverse PCR, or plasmid rescue. Unexpectedly, the success rate of 5'-RACE in Mol/MSM trap clones was 47 %, lower than the 87 % observed in KTPU8 clones. Genomic analysis of the 5'-RACE-failed clones revealed that most had trapped ribosomal RNA gene regions. The percentage of ribosomal RNA region trap clones was 41 % in Mol/MSM-1 cells, but less than 10 % in KTPU8 cells. However, within the Mol/MSM-1 5'-RACE-successful clones, the trapping frequency of annotated genes, the chromosomal distribution of vector insertions, the frequency of integration into an intron around the start codon-containing exon, and the functional spectrum of trapped genes were comparable to those in KTPU8 cells. By selecting 5'-RACE-successful clones, it is possible to perform gene-trapping efficiently using Mol/MSM-1 ES cells and promoter-trap vectors.

  13. 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,

  14. International comparison CCQM-K82: methane in air at ambient level (1800 to 2200) nmol/mol

    NASA Astrophysics Data System (ADS)

    Flores, Edgar; Viallon, Joële; Choteau, Tiphaine; Moussay, Philippe; Wielgosz, Robert I.; Kang, Namgoo; Kim, Byung Moon; Zalewska, Ewelina; H van der Veen, Adriaan (A. M.; Konopelko, Leonid; Wu, Hai; Han, Qiao; Rhoderick, George; Guenther, Franklin R.; Watanabe, Takuro; Shimosaka, Takuya; Kato, Kenji; Hall, Brad; Brewer, Paul

    2015-01-01

    The CCQM-K82 comparison was designed to evaluate the degrees of equivalence of NMI capabilities for methane in air primary reference mixtures in the range (1800 to 2200) nmol/mol. The balance gas for the standards was either scrubbed dry real air or synthetic air. CH4 in air standards have been produced by a number of laboratories for many years, with more recent developments focused on standards at atmospheric measurement concentrations and aimed at obtaining agreement between independently produced standards. A comparison of the differences in primary gas standards for methane in air was previously performed in 2003 (CCQM-P41 Greenhouse gases. 1 and 2) with a standard deviation of results around the reference value of 30 nmol/mol and 10 nmol/mol for a more limited set of standards. This can be contrasted with the level of agreement required from field laboratories routinely measuring atmospheric methane levels, set by Data Quality Objectives (DQO) established by the World Meteorological Organization (WMO) to reflect the scientifically desirable level of compatibility for CH4 measurements at the global scale, currently set at 2 nmol/mol (1 sigma). The measurements of this key comparison took place from May 2012 to June 2012. Eight laboratories took part in this comparison coordinated by the BIPM and NIST. Key comparison reference values were calculated based on Cavity Ring Down Spectroscopy Measurements performed at the BIPM, combined with participant's gravimetric values to identify a consistent set of standards. Regression analysis allowed predicted values for each standard to be calculated which acted as the KCRVs. In this comparison reported standard uncertainties by participants ranged from 0.50 nmol/mol to 2.4 nmol/mol and the uncertainties of individual KCRVs ranged from 0.68 nmol/mol to 0.71 nmol/mol. The standard deviation of the ensemble of standards about the KCRV value was 1.70 nmol/mol. This represents a greater than tenfold improvement in the level

  15. Analyse de la dynamique temporelle d'une molécule unique en matrice sol-gel

    NASA Astrophysics Data System (ADS)

    Débarre, A.; Tchénio, P.; Azoulay, J.; Jaf Iol, R.; Nutarelli, D.

    2002-06-01

    L'un des enjeux des études de molécules uniques est de développer des sondes très locales d'un environnement donné. De telles informations ne sont pas accessibles dans les expériences classiques où de nombreuses molécules sont détectées simultanément. Celles-ci ne permettent de déterminer que la valeur moyenne de la distribution d'un paramètre. Parmi les paramètres temporels, la durée de vie des états excités atteints par la molécule occupe une place particulière. Ce paramètre, qui est lié aux propriétés quantiques de la molécule peut varier considérablement si des transferts d'énergie s'établissent entre la molécule et son environnement immédiat. Un autre exemple est la mesure du nombre total de photons émis par la molécule avant qu'elle n'émette plus ( photoblanchiment ). L'arrêt définitif de l'émission est très directement lié aux interactions lumineuses ou collisionnelles que la molécule subit dans les états excités où elle est portée. Cet article décrit d'une part le dispositif expérimental qui a été développé pour déterminer plusieurs paramètres temporels sur la même molécule, et d'autre part les premiers résultats acquis dans des matériaux sol-gels dopés par des molécules dérivées du pérylène[1].

  16. Thermodynamics of antagonist binding to rat muscarinic M2 receptors: antimuscarinics of the pridinol, sila-pridinol, diphenidol and sila-diphenidol type.

    PubMed Central

    Waelbroeck, M.; Camus, J.; Tastenoy, M.; Lambrecht, G.; Mutschler, E.; Kropfgans, M.; Sperlich, J.; Wiesenberger, F.; Tacke, R.; Christophe, J.

    1993-01-01

    1. We studied the effect of temperature on the binding to rat heart M2 muscarinic receptors of antagonists related to the carbon/silicon pairs pridinol/sila-pridinol and diphenidol/sila-diphenidol (including three germanium compounds) and six structurally related pairs of enantiomers [(R)- and (S)-procyclidine, (R)- and (S)-trihexyphenidyl, (R)- and (S)-tricyclamol, (R)- and (S)-trihexyphenidyl methiodide, (R)- and (S)-hexahydro-diphenidol and (R)- and (S)-hexbutinol]. Binding affinities were determined in competition experiments using [3H]-N-methyl-scopolamine chloride as radioligand. The reference drugs were scopolamine and N-methyl-scopolamine bromide. 2. The affinity of the antagonists either increased or decreased with temperature. van't Hoff plots were linear in the 278-310 degrees K temperature range. Binding of all antagonists was entropy driven. Enthalpy changes varied from large negative values (down to -29 kJ mol-1) to large positive values (up to +30 kJ mol-1). 3. (R)-configurated drugs had a 10 to 100 fold greater affinity for M2 receptors than the corresponding (S)-enantiomers. Enthalpy and entropy changes of the respective enantiomers were different but no consistent pattern was observed. 4. When silanols (R3SiOH) were compared to carbinols (R3COH), the affinity increase caused by C/Si exchange varied between 3 and 10 fold for achiral drugs but was negligible in the case of chiral drugs. Silanols induced more favourable enthalpy and less favourable entropy changes than the corresponding carbinols when binding. Organogermanium compounds (R4Ge) when compared to their silicon counterparts (R4Si) showed no significant difference in affinity as well as in enthalpy and entropy changes. 5. Exchange of a cyclohexyl by a phenyl moiety was associated with an increase or a decrease in drug affinity (depending on the absolute configuration in the case of chiral drugs) and generally also with a more favourable enthalpy change and a less favourable entropy change

  17. Phase transformation and wear studies of plasma sprayed yttria stabilized zirconia coatings containing various mol% of yttria

    SciTech Connect

    Aruna, S.T. Balaji, N.; Rajam, K.S.

    2011-07-15

    Plasma sprayable grade zirconia powders doped with various mol% of yttria (0, 2, 3, 4, 6, 8 and 12 mol%) were synthesized by a chemical co-precipitation route. The coprecipitation conditions were adjusted such that the powders possessed good flowability in the as calcined condition and thus avoiding the agglomeration step like spray drying. Identical plasma spray parameters were used for plasma spraying all the powders on stainless steel plates. The powders and plasma sprayed coatings were characterized by X-ray diffractometry, Scanning Electron Microscopy and Raman spectroscopy. Zirconia powders are susceptible to phase transformations when subjected to very high temperatures during plasma spraying and XRD is insensitive to the presence of some non crystalline phases and hence Raman spectroscopy was used as an important tool. The microstructure of the plasma sprayed coatings showed a bimodal distribution containing fully melted and unmelted zones. The microhardness and wear resistance of the plasma sprayed coatings were determined. Among the plasma sprayed coatings, 3 mol% yttria stabilized zirconia coating containing pure tetragonal zirconia showed the highest wear resistance. - Research Highlights: {yields} Preparation plasma sprayable YSZ powders without any agglomeration process and plasma spraying {yields} Phase transformation studies of plasma sprayed YSZ coatings by XRD and Raman spectroscopy {yields} Microstructure of the plasma sprayed coatings exhibited bimodal distribution {yields} Plasma sprayed 3 mol% YSZ coating exhibited the highest wear resistance {yields} Higher wear resistance is due to the higher fracture toughness of tetragonal 3 mol% YSZ phase.

  18. 75 FR 74740 - Measure M2 Natural Community Conservation Plan/Habitat Conservation Plan/Master Streambed...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-01

    ... Fish and Wildlife Service Measure M2 Natural Community Conservation Plan/Habitat Conservation Plan... Environmental Impact Report (EIR)/EIS for the Measure M2 (M2) Natural Community Conservation Plan/Habitat Conservation Plan/Master Streambed Alteration Agreement (NCCP/HCP/ MSAA). We are furnishing this notice...

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The second matrix (M2) gene of avian metapneumovirus subgroup C (aMPV-C) virus contains two overlapping open reading frames (ORFs), encoding two putative proteins, M2-1 and M2-2. Both proteins are believed to be involved in the RNA transcription or replication process. To further characterize the fu...

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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

    2017-04-01

    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 proinflammatory and immunosuppressive mediator and promotes tumor progression. In this study, we examined the relationship between the lactic acid concentration and expression of lactate dehydrogenase-A (LDHA) and glucose transporter-1 (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 a M2 macrophage marker, arginase I (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, colony stimulating factor 1 receptor (CSF1R) and CD163, normalized using a pan-macrophage marker, CD68. Tumors with lower levels of CD68 showed a higher concentration of lactic acid, while 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. This article is protected by copyright. All rights reserved.

  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. 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

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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.

  16. 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 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.

  17. 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

  18. Structure of the atypical bacteriocin pectocin M2 implies a novel mechanism of protein uptake

    PubMed Central

    Grinter, Rhys; Josts, Inokentijs; Zeth, Kornelius; Roszak, Aleksander W; McCaughey, Laura C; Cogdell, Richard J; Milner, Joel J; Kelly, Sharon M; Byron, Olwyn; Walker, Daniel

    2014-01-01

    The colicin-like bacteriocins are potent protein antibiotics that have evolved to efficiently cross the outer membrane of Gram-negative bacteria by parasitizing nutrient uptake systems. We have structurally characterized the colicin M-like bacteriocin, pectocin M2, which is active against strains of Pectobacterium spp. This unusual bacteriocin lacks the intrinsically unstructured translocation domain that usually mediates translocation of these bacteriocins across the outer membrane, containing only a single globular ferredoxin domain connected to its cytotoxic domain by a flexible α-helix, which allows it to adopt two distinct conformations in solution. The ferredoxin domain of pectocin M2 is homologous to plant ferredoxins and allows pectocin M2 to parasitize a system utilized by Pectobacterium to obtain iron during infection of plants. Furthermore, we identify a novel ferredoxin-containing bacteriocin pectocin P, which possesses a cytotoxic domain homologous to lysozyme, illustrating that the ferredoxin domain acts as a generic delivery module for cytotoxic domains in Pectobacterium. PMID:24865810

  19. M1 and M2 Macrophages: The Chicken and the Egg of Immunity

    PubMed Central

    Mills, Charles D.; Ley, Klaus

    2015-01-01

    The purpose of this perspective is to describe a critical advance in understanding how immune responses work. Macrophages are required for all animal life: ‘Inhibit’ type macrophages in all animals (called M1) can rapidly kill pathogens, and are thus the primary host defense, and ‘Heal’ type macrophages (M2) routinely repair and maintain tissue integrity. Macrophages perform these activities in all animals without T cells, and also in T cell-deficient vertebrates. Although adaptive immunity can amplify macrophage polarization, the long-held notion that macrophages need to be ‘activated’ or ‘alternatively activated’ by T cells is incorrect; indeed, immunology has had it backward. M1/M2-type macrophages necessarily direct T cells toward Th1- or Th2-like activities, respectively. That such macrophage-innate activities are the central directing element in immune responses is a dramatic change in understanding how immune systems operate. Most important, this revelation is opening up whole new approaches to immunotherapy. For example, many modern diseases, such as cancer and atherosclerosis, may not display ‘foreign’ antigens. However, there are clear imbalances in M1/M2-type responses. Correcting such innate imbalances can result in better health. Macrophages are the chicken and the egg of immunity. PMID:25138714

  20. M1 and M2 macrophages: the chicken and the egg of immunity.

    PubMed

    Mills, Charles D; Ley, Klaus

    2014-01-01

    The purpose of this perspective is to describe a critical advance in understanding how immune responses work. Macrophages are required for all animal life: 'Inhibit' type macrophages in all animals (called M1) can rapidly kill pathogens, and are thus the primary host defense, and 'Heal' type macrophages (M2) routinely repair and maintain tissue integrity. Macrophages perform these activities in all animals without T cells, and also in T cell-deficient vertebrates. Although adaptive immunity can amplify macrophage polarization, the long-held notion that macrophages need to be 'activated' or 'alternatively activated' by T cells is incorrect; indeed, immunology has had it backward. M1/M2-type macrophages necessarily direct T cells toward Th1- or Th2-like activities, respectively. That such macrophage-innate activities are the central directing element in immune responses is a dramatic change in understanding how immune systems operate. Most important, this revelation is opening up whole new approaches to immunotherapy. For example, many modern diseases, such as cancer and atherosclerosis, may not display 'foreign' antigens. However, there are clear imbalances in M1/M2-type responses. Correcting such innate imbalances can result in better health. Macrophages are the chicken and the egg of immunity.

  1. M2-F3 and project personnel after the 100th flight

    NASA Technical Reports Server (NTRS)

    1972-01-01

    The 100th flight of the heavy-weight lifting bodies was completed on October 5, 1972, with pilot Bill Dana soaring to an altitude of 66,300 feet and a Mach number of 1.370 (about 904 miles per hour) in the M2-F3. This was call for a celebration as the crew responsible for maintaining and operating the vehicle, the engineers who requested the flight, the pilots who flew the M2, and the Director of the NASA Flight Research Center gather in front of the M2-F3 lifting body for a photograph. Kneeling left to right are Bill Dana, (unknown person),* Jay King, and Herb Anderson. In the cockpit is Bill Szuwalski. Standing left to right are: Dale Reed, Robert Kempel, Milt Thompson, Bill Clifton, an Air Force fire fighter, Jerry Brandt, Johnny Armstrong, an Air Force fire fighter, Gary Layton, Jack Kolf, Ming Tang, (unknown person),* Byron Gibbs, Joe Huxman, (unknown person)*, Bill Mersereau, Bill Arnold, John Manke, Dr. Bill Winters, (unknown person)*, Bill LePage, Glenn Ford, Lee Scherer, Director of Center, (two unknown people),* Stan Butchart, and Berwin Kock. *=Identification incomplete at this time.)

  2. Dynamic RACH Partition for Massive Access of Differentiated M2M Services

    PubMed Central

    Du, Qinghe; Li, Wanyu; Liu, Lingjia; Ren, Pinyi; Wang, Yichen; Sun, Li

    2016-01-01

    In machine-to-machine (M2M) networks, a key challenge is to overcome the overload problem caused by random access requests from massive machine-type communication (MTC) devices. When differentiated services coexist, such as delay-sensitive and delay-tolerant services, the problem becomes more complicated and challenging. This is because delay-sensitive services often use more aggressive policies, and thus, delay-tolerant services get much fewer chances to access the network. To conquer the problem, we propose an efficient mechanism for massive access control over differentiated M2M services, including delay-sensitive and delay-tolerant services. Specifically, based on the traffic loads of the two types of services, the proposed scheme dynamically partitions and allocates the random access channel (RACH) resource to each type of services. The RACH partition strategy is thoroughly optimized to increase the access performances of M2M networks. Analyses and simulation demonstrate the effectiveness of our design. The proposed scheme can outperform the baseline access class barring (ACB) scheme, which ignores service types in access control, in terms of access success probability and the average access delay. PMID:27043568

  3. Characterization of the hrpZ gene from Pseudomonas syringae pv. maculicolaM2

    PubMed Central

    Álvarez-Mejía, César; Rodríguez-Ríos, Dalia; Hernández-Guzmán, Gustavo; López-Ramírez, Varinia; Valenzuela-Soto, Humberto; Marsch, Rodolfo

    2015-01-01

    Pseudomonas syringae pv. maculicola is a natural pathogen of members of the Brassicaceae plant family. Using a transposon-based mutagenesis strategy in Pseudomonas syringaepv. maculicola M2 (PsmM2), we conducted a genetic screen to identify mutants that were capable of growing in M9 medium supplemented with a crude extract from the leaves of Arabidopsis thaliana. A mutant containing a transposon insertion in the hrpZ gene (PsmMut8) was unable to infect adult plants from Arabidopsis thaliana or Brassica oleracea, suggesting a loss of pathogenicity. The promotorless cat reporter present in the gene trap was expressed if PsmMut8 was grown in minimal medium (M9) supplemented with the leaf extract but not if grown in normal rich medium (KB). We conducted phylogenetic analysis using hrpAZB genes, showing the classical 5-clade distribution, and nucleotide diversity analysis, showing the putative position for selective pressure in this operon. Our results indicate that the hrpAZB operon from Pseudomonas syringaepv. maculicola M2 is necessary for its pathogenicity and that its diversity would be under host-mediated diversifying selection. PMID:26413080

  4. Characterization of the hrpZ gene from Pseudomonas syringae pv. maculicola M2.

    PubMed

    Álvarez-Mejía, César; Rodríguez-Ríos, Dalia; Hernández-Guzmán, Gustavo; López-Ramírez, Varinia; Valenzuela-Soto, Humberto; Marsch, Rodolfo

    2015-01-01

    Pseudomonas syringae pv. maculicola is a natural pathogen of members of the Brassicaceae plant family. Using a transposon-based mutagenesis strategy in Pseudomonas syringaepv. maculicola M2 (PsmM2), we conducted a genetic screen to identify mutants that were capable of growing in M9 medium supplemented with a crude extract from the leaves of Arabidopsis thaliana. A mutant containing a transposon insertion in the hrpZ gene (PsmMut8) was unable to infect adult plants from Arabidopsis thaliana or Brassica oleracea, suggesting a loss of pathogenicity. The promotorless cat reporter present in the gene trap was expressed if PsmMut8 was grown in minimal medium (M9) supplemented with the leaf extract but not if grown in normal rich medium (KB). We conducted phylogenetic analysis using hrpAZB genes, showing the classical 5-clade distribution, and nucleotide diversity analysis, showing the putative position for selective pressure in this operon. Our results indicate that the hrpAZB operon from Pseudomonas syringaepv. maculicola M2 is necessary for its pathogenicity and that its diversity would be under host-mediated diversifying selection.

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

    PubMed Central

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

    2016-01-01

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

  6. The outer envelopes of globular clusters - I. NGC 7089 (M2)

    NASA Astrophysics Data System (ADS)

    Kuzma, P. B.; Da Costa, G. S.; Mackey, A. D.; Roderick, T. A.

    2016-10-01

    We present the results of a wide-field imaging survey of the periphery of the Milky Way globular cluster NGC 7089 (M2). Data were obtained with MegaCam on the Magellan Clay Telescope and the Dark Energy Camera on the Blanco Telescope. We find that M2 is embedded in a diffuse stellar envelope extending to a radial distance of at least ˜60 arcmin (˜210 pc) - five times the nominal tidal radius of the cluster. The envelope appears nearly circular in shape, has a radial density decline well described by a power law of index γ = -2.2 ± 0.2, and contains approximately 1.6 per cent of the luminosity of the entire system. While the origin of the envelope cannot be robustly identified using the presently available data, the fact that M2 also hosts stellar populations exhibiting a broad dispersion in the abundances of both iron and a variety of neutron capture elements suggests that this object might plausibly constitute the stripped nucleus of a dwarf galaxy that was long ago accreted and destroyed by the Milky Way.

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

    PubMed Central

    Cheng, Bo; Wei, Zesan

    2014-01-01

    In recent years, the increased interest in energy conservation and environmental protection, combined with the development of modern communication and computer technology, has resulted in the replacement of distributed heating by central heating in urban areas. This paper proposes a Representational State Transfer (REST) Machine-to-Machine (M2M) gateway for wireless remote monitoring for a district central heating network. In particular, we focus on the resource-oriented RESTful M2M gateway architecture, and present an uniform devices abstraction approach based on Open Service Gateway Initiative (OSGi) technology, and implement the resource mapping mechanism between resource address mapping mechanism between RESTful resources and the physical sensor devices, and present the buffer queue combined with polling method to implement the data scheduling and Quality of Service (QoS) guarantee, and also give the RESTful M2M gateway open service Application Programming Interface (API) set. The performance has been measured and analyzed. Finally, the conclusions and future work are presented. PMID:25436650

  8. Dynamic RACH Partition for Massive Access of Differentiated M2M Services.

    PubMed

    Du, Qinghe; Li, Wanyu; Liu, Lingjia; Ren, Pinyi; Wang, Yichen; Sun, Li

    2016-03-30

    In machine-to-machine (M2M) networks, a key challenge is to overcome the overload problem caused by random access requests from massive machine-type communication (MTC) devices. When differentiated services coexist, such as delay-sensitive and delay-tolerant services, the problem becomes more complicated and challenging. This is because delay-sensitive services often use more aggressive policies, and thus, delay-tolerant services get much fewer chances to access the network. To conquer the problem, we propose an efficient mechanism for massive access control over differentiated M2M services, including delay-sensitive and delay-tolerant services. Specifically, based on the traffic loads of the two types of services, the proposed scheme dynamically partitions and allocates the random access channel (RACH) resource to each type of services. The RACH partition strategy is thoroughly optimized to increase the access performances of M2M networks. Analyses and simulation demonstrate the effectiveness of our design. The proposed scheme can outperform the baseline access class barring (ACB) scheme, which ignores service types in access control, in terms of access success probability and the average access delay.

  9. The catalytic role of the M2 metal ion in PP2Cα.

    PubMed

    Pan, Chang; Tang, Jun-yi; Xu, Yun-fei; Xiao, Peng; Liu, Hong-da; Wang, Hao-an; Wang, Wen-bo; Meng, Fan-guo; Yu, Xiao; Sun, Jin-peng

    2015-02-24

    PP2C family phosphatases (the type 2C family of protein phosphatases; or metal-dependent phosphatase, PPM) constitute an important class of signaling enzymes that regulate many fundamental life activities. All PP2C family members have a conserved binuclear metal ion active center that is essential for their catalysis. However, the catalytic role of each metal ion during catalysis remains elusive. In this study, we discovered that mutations in the structurally buried D38 residue of PP2Cα (PPM1A) redefined the water-mediated hydrogen network in the active site and selectively disrupted M2 metal ion binding. Using the D38A and D38K mutations of PP2Cα as specific tools in combination with enzymology analysis, our results demonstrated that the M2 metal ion determines the rate-limiting step of substrate hydrolysis, participates in dianion substrate binding and stabilizes the leaving group after P-O bond cleavage. The newly characterized catalytic role of the M2 metal ion in this family not only provides insight into how the binuclear metal centers of the PP2C phosphatases are organized for efficient catalysis but also helps increase our understanding of the function and substrate specificity of PP2C family members.

  10. Human mesenchymal stromal cell-secreted lactate induces M2-macrophage differentiation by metabolic reprogramming

    PubMed Central

    Civini, Sara; Pacelli, Consiglia; Dieng, Mame Massar; Lemieux, William; Jin, Ping; Bazin, Renée; Patey, Natacha; Marincola, Francesco M.; Moldovan, Florina; Zaouter, Charlotte; Trudeau, Louis-Eric; Benabdhalla, Basma; Louis, Isabelle; Beauséjour, Christian; Stroncek, David; Le Deist, Françoise; Haddad, Elie

    2016-01-01

    Human mesenchymal stromal cells (MSC) have been shown to dampen immune response and promote tissue repair, but the underlying mechanisms are still under investigation. Herein, we demonstrate that umbilical cord-derived MSC (UC-MSC) alter the phenotype and function of monocyte-derived dendritic cells (DC) through lactate-mediated metabolic reprogramming. UC-MSC can secrete large quantities of lactate and, when present during monocyte-to-DC differentiation, induce instead the acquisition of M2-macrophage features in terms of morphology, surface markers, migratory properties and antigen presentation capacity. Microarray expression profiling indicates that UC-MSC modify the expression of metabolic-related genes and induce a M2-macrophage expression signature. Importantly, monocyte-derived DC obtained in presence of UC-MSC, polarize naïve allogeneic CD4+ T-cells into Th2 cells. Treatment of UC-MSC with an inhibitor of lactate dehydrogenase strongly decreases lactate concentration in culture supernatant and abrogates the effect on monocyte-to-DC differentiation. Metabolic analysis further revealed that UC-MSC decrease oxidative phosphorylation in differentiating monocytes while strongly increasing the spare respiratory capacity proportional to the amount of secreted lactate. Because both MSC and monocytes are recruited in vivo at the site of tissue damage and inflammation, we propose the local increase of lactate concentration induced by UC-MSC and the consequent enrichment in M2-macrophage generation as a mechanism to achieve immunomodulation. PMID:27070086

  11. Channel opening by anesthetics and GABA induces similar changes in the GABAA receptor M2 segment.

    PubMed

    Rosen, Ayelet; Bali, Moez; Horenstein, Jeffrey; Akabas, Myles H

    2007-05-01

    For many general anesthetics, their molecular basis of action involves interactions with GABA(A) receptors. Anesthetics produce concentration-dependent effects on GABA(A) receptors. Low concentrations potentiate submaximal GABA-induced currents. Higher concentrations directly activate the receptors. Functional effects of anesthetics have been characterized, but little is known about the conformational changes they induce. We probed anesthetic-induced conformational changes in the M2 membrane-spanning, channel-lining segment using disulfide trapping between engineered cysteines. Previously, we showed that oxidation by copper phenanthroline in the presence of GABA of the M2 6' cysteine mutants, alpha(1)T261Cbeta(1)T256C and alpha(1)beta(1)T256C resulted in formation of an intersubunit disulfide bond between the adjacent beta-subunits that significantly increased the channels' spontaneous open probability. Oxidation in GABA's absence had no effect. We examined the effect on alpha(1)T261Cbeta(1)T256C and on alpha(1)beta(1)T256C of oxidation by copper phenanthroline in the presence of potentiating and directly activating concentrations of the general anesthetics propofol, pentobarbital, and isoflurane. Oxidation in the presence of potentiating concentration of anesthetics had little effect. Oxidation in the presence of directly activating anesthetic concentrations significantly increased the channels' spontaneous open probability. We infer that activation by anesthetics and GABA induces a similar conformational change at the M2 segment 6' position that is related to channel opening.

  12. Conformational variability of the glycine receptor M2 domain in response to activation by different agonists.

    PubMed

    Pless, Stephan A; Dibas, Mohammed I; Lester, Henry A; Lynch, Joseph W

    2007-12-07

    Models describing the structural changes mediating Cys loop receptor activation generally give little attention to the possibility that different agonists may promote activation via distinct M2 pore-lining domain structural rearrangements. We investigated this question by comparing the effects of different ligands on the conformation of the external portion of the homomeric alpha1 glycine receptor M2 domain. Conformational flexibility was assessed by tethering a rhodamine fluorophore to cysteines introduced at the 19' or 22' positions and monitoring fluorescence and current changes during channel activation. During glycine activation, fluorescence of the label attached to R19'C increased by approximately 20%, and the emission peak shifted to lower wavelengths, consistent with a more hydrophobic fluorophore environment. In contrast, ivermectin activated the receptors without producing a fluorescence change. Although taurine and beta-alanine were weak partial agonists at the alpha1R19'C glycine receptor, they induced large fluorescence changes. Propofol, which drastically enhanced these currents, did not induce a glycine-like blue shift in the spectral emission peak. The inhibitors strychnine and picrotoxin elicited fluorescence and current changes as expected for a competitive antagonist and an open channel blocker, respectively. Glycine and taurine (or beta-alanine) also produced an increase and a decrease, respectively, in the fluorescence of a label attached to the nearby L22'C residue. Thus, results from two separate labeled residues support the conclusion that the glycine receptor M2 domain responds with distinct conformational changes to activation by different agonists.

  13. Fasciola hepatica tegumental antigens indirectly induce an M2 macrophage-like phenotype in vivo.

    PubMed

    Adams, P N; Aldridge, A; Vukman, K V; Donnelly, S; O'Neill, S M

    2014-10-01

    The M2 subset of macrophages has a critical role to play in host tissue repair, tissue fibrosis and modulation of adaptive immunity during helminth infection. Infection with the helminth, Fasciola hepatica, is associated with M2 macrophages in its mammalian host, and this response is mimicked by its excretory-secretory products (FhES). The tegumental coat of F. hepatica (FhTeg) is another major source of immune-modulatory molecules; we have previously shown that FhTeg can modulate the activity of both dendritic cells and mast cells inhibiting their ability to prime a Th1 immune response. Here, we report that FhTeg does not induce Th2 immune responses but can induce M2-like phenotype in vivo that modulates cytokine production from CD4(+) cells in response to anti-CD3 stimulation. FhTeg induces a RELMα expressing macrophage population in vitro, while in vivo, the expression of Arg1 and Ym-1/2 but not RELMα in FhTeg-stimulated macrophages was STAT6 dependent. To support this finding, FhTeg induces RELMα expression in vivo prior to the induction of IL-13. FhTeg can induce IL-13-producing peritoneal macrophages following intraperitoneal injection This study highlights the important role of FhTeg as an immune-modulatory source during F. hepatica infection and sheds further light on helminth-macrophage interactions.

  14. The catalytic role of the M2 metal ion in PP2Cα

    NASA Astrophysics Data System (ADS)

    Pan, Chang; Tang, Jun-Yi; Xu, Yun-Fei; Xiao, Peng; Liu, Hong-Da; Wang, Hao-An; Wang, Wen-Bo; Meng, Fan-Guo; Yu, Xiao; Sun, Jin-Peng

    2015-02-01

    PP2C family phosphatases (the type 2C family of protein phosphatases; or metal-dependent phosphatase, PPM) constitute an important class of signaling enzymes that regulate many fundamental life activities. All PP2C family members have a conserved binuclear metal ion active center that is essential for their catalysis. However, the catalytic role of each metal ion during catalysis remains elusive. In this study, we discovered that mutations in the structurally buried D38 residue of PP2Cα (PPM1A) redefined the water-mediated hydrogen network in the active site and selectively disrupted M2 metal ion binding. Using the D38A and D38K mutations of PP2Cα as specific tools in combination with enzymology analysis, our results demonstrated that the M2 metal ion determines the rate-limiting step of substrate hydrolysis, participates in dianion substrate binding and stabilizes the leaving group after P-O bond cleavage. The newly characterized catalytic role of the M2 metal ion in this family not only provides insight into how the binuclear metal centers of the PP2C phosphatases are organized for efficient catalysis but also helps increase our understanding of the function and substrate specificity of PP2C family members.

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

    PubMed Central

    Du, Yongzhao

    2016-01-01

    For asymmetric laser beams, the values of beam quality factor 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 non-uniqueness, a new beam quality characterization method named as M2-curve is developed. The M2-curve not only contains the beam quality factor Mx2 and My2 in the x-direction and y-direction, respectively; but also introduces a curve of Mxα2 versus rotation angle α of coordinate axis. Moreover, we also present a real-time measurement method to demonstrate beam propagation factor M2-curve with a modified self-referencing Mach-Zehnder interferometer based-wavefront sensor (henceforth SRI-WFS). The feasibility of the proposed method is demonstrated with the theoretical analysis and experiment in multimode beams. The experimental results showed that the proposed measurement method is simple, fast, and a single-shot measurement procedure without movable parts. PMID:27916845

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

    PubMed

    Cheng, Bo; Wei, Zesan

    2014-11-27

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

  17. M2 baroclinic tide variability modulated by the ocean circulation south of Japan

    NASA Astrophysics Data System (ADS)

    Varlamov, Sergey M.; Guo, Xinyu; Miyama, Toru; Ichikawa, Kaoru; Waseda, Takuji; Miyazawa, Yasumasa

    2015-05-01

    We analyze a concurrent simulation result of the ocean circulation and tidal currents using a data-assimilative ocean general circulation model covering the Western North Pacific with horizontal resolution of 1/36° to investigate possible interactions between them. Four sites of active M2 internal tide variability in open ocean (hot spots), such as Tokara Strait, Izu Ridge, Luzon Strait, and Ogasawara Ridge, are detected from both the satellite observation and the simulation. Energy cycle analysis of the simulated M2 baroclinic tide indicates two types of the hot spots: dissipation (Tokara Strait and Izu Ridge) and radiation (Luzon Strait and Ogasawara Ridge) dominant sites. Energy conversion from barotropic to baroclinic M2 tides at the hot spots is modulated considerably by the lower-frequency changes in the density field. Modulation at the two spots (Tokara Strait and Izu Ridge) is affected by the Kuroshio path variation together with the seasonal variation of the shallow thermocline. At the other two sites, influence from changes in the relatively deep stratification through the Kuroshio intrusion into South China Sea (Luzon Strat) and mesoscale eddy activity (Ogasawara Ridge) is dominant in the modulation.

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

    PubMed Central

    Ockenga, Wymke; Kühne, Sina; Bocksberger, Simone; Banning, Antje; Tikkanen, Ritva

    2013-01-01

    Acetylcholine is an important neurotransmitter whose effects are mediated by two classes of receptors. The nicotinic acetylcholine receptors are ion channels, whereas the muscarinic receptors belong to the large family of G protein coupled seven transmembrane helix receptors. Beyond its function in neuronal systems, it has become evident that acetylcholine also plays an important role in non-neuronal cells such as epithelial and immune cells. Furthermore, many cell types in the periphery are capable of synthesizing acetylcholine and express at least some of the receptors. In this review, we summarize the non-neuronal functions of the muscarinic acetylcholine receptors, especially those of the M2 muscarinic receptor in epithelial cells. We will review the mechanisms of signaling by the M2 receptor but also the cellular trafficking and ARF6 mediated endocytosis of this receptor, which play an important role in the regulation of signaling events. In addition, we provide an overview of the M2 receptor in human pathological conditions such as autoimmune diseases and cancer. PMID:24705159

  19. Parthenolide Relieves Pain and Promotes M2 Microglia/Macrophage Polarization in Rat Model of Neuropathy.

    PubMed

    Popiolek-Barczyk, Katarzyna; Kolosowska, Natalia; Piotrowska, Anna; Makuch, Wioletta; Rojewska, Ewelina; Jurga, Agnieszka M; Pilat, Dominika; Mika, Joanna

    2015-01-01

    Neuropathic pain treatment remains a challenge because pathomechanism is not fully understood. It is believed that glial activation and increased spinal nociceptive factors are crucial for neuropathy. We investigated the effect of parthenolide (PTL) on the chronic constriction injury to the sciatic nerve (CCI)-induced neuropathy in rat. We analyzed spinal changes in glial markers and M1 and M2 polarization factors, as well as intracellular signaling pathways. PTL (5 µg; i.t.) was preemptively and then daily administered for 7 days after CCI. PTL attenuated the allodynia and hyperalgesia and increased the protein level of IBA1 (a microglial/macrophage marker) but did not change GFAP (an astrocyte marker) on day 7 after CCI. PTL reduced the protein level of M1 (IL-1β, IL-18, and iNOS) and enhanced M2 (IL-10, TIMP1) factors. In addition, it downregulated the phosphorylated form of NF-κB, p38MAPK, and ERK1/2 protein level and upregulated STAT3. In primary microglial cell culture we have shown that IL-1β, IL-18, iNOS, IL-6, IL-10, and TIMP1 are of microglial origin. Summing up, PTL directly or indirectly attenuates neuropathy symptoms and promotes M2 microglia/macrophages polarization. We suggest that neuropathic pain therapies should be shifted from blanketed microglia/macrophage suppression toward maintenance of the balance between neuroprotective and neurotoxic microglia/macrophage phenotypes.

  20. Parthenolide Relieves Pain and Promotes M2 Microglia/Macrophage Polarization in Rat Model of Neuropathy

    PubMed Central

    Popiolek-Barczyk, Katarzyna; Kolosowska, Natalia; Makuch, Wioletta; Rojewska, Ewelina; Jurga, Agnieszka M.; Pilat, Dominika

    2015-01-01

    Neuropathic pain treatment remains a challenge because pathomechanism is not fully understood. It is believed that glial activation and increased spinal nociceptive factors are crucial for neuropathy. We investigated the effect of parthenolide (PTL) on the chronic constriction injury to the sciatic nerve (CCI)-induced neuropathy in rat. We analyzed spinal changes in glial markers and M1 and M2 polarization factors, as well as intracellular signaling pathways. PTL (5 µg; i.t.) was preemptively and then daily administered for 7 days after CCI. PTL attenuated the allodynia and hyperalgesia and increased the protein level of IBA1 (a microglial/macrophage marker) but did not change GFAP (an astrocyte marker) on day 7 after CCI. PTL reduced the protein level of M1 (IL-1β, IL-18, and iNOS) and enhanced M2 (IL-10, TIMP1) factors. In addition, it downregulated the phosphorylated form of NF-κB, p38MAPK, and ERK1/2 protein level and upregulated STAT3. In primary microglial cell culture we have shown that IL-1β, IL-18, iNOS, IL-6, IL-10, and TIMP1 are of microglial origin. Summing up, PTL directly or indirectly attenuates neuropathy symptoms and promotes M2 microglia/macrophages polarization. We suggest that neuropathic pain therapies should be shifted from blanketed microglia/macrophage suppression toward maintenance of the balance between neuroprotective and neurotoxic microglia/macrophage phenotypes. PMID:26090236

  1. Synthesis and Immunogenicity Assessment of Elastin-Like Polypeptide-M2e Construct as an Influenza Antigen

    PubMed Central

    Ingrole, Rohan S.; Tao, Wenqian; Tripathy, Jatindra N.; Gill, Harvinder S.

    2014-01-01

    The 23 amino acid-long extracellular domain of the influenza virus transmembrane protein M2 (M2e) has remained highly conserved since the 1918 pandemic, and is thus considered a good candidate for development of a universal influenza A vaccine. However, M2e is poorly immunogenic. In this study we assessed the potential of increasing immunogenicity of M2e by constructing a nanoscale-designed protein polymer containing the M2e sequence and an elastin-like polypeptide (ELP) nanodomain consisting of alanine and tyrosine guest residues (ELP(A2YA2)24). The ELP nanodomain was included to increase antigen size, and to exploit the inherent thermal inverse phase transition behavior of ELPs to purify the protein polymer. The ELP(A2YA2)24 + M2e nanodomained molecule was recombinantly synthesized. Characterization of its inverse phase transition behavior demonstrated that attachment of M2e to ELP(A2YA2)24 increased its transition temperature compared to ELP(A2YA2)24. Using a dot blot test we determined that M2e conjugated to ELP is recognizable by M2e–specific antibodies, suggesting that the conjugation process does not adversely affect the immunogenic property of M2e. Further, upon vaccinating mice with ELP(A2YA2)24 + M2e it was found that indeed the nanodomained protein enhanced M2e–specific antibodies in mouse serum compared to free M2e peptide and ELP(A2YA2)24. The immune serum could also recognize M2 expressed on influenza virions. Overall, this data suggests the potential of using molecules containing M2e–ELP nano-domains to develop a universal influenza vaccine. PMID:25825595

  2. SULFUR- AND SILICON-BEARING MOLECULES IN PLANETARY NEBULAE: THE CASE OF M2-48

    SciTech Connect

    Edwards, J. L.; Ziurys, L. M.

    2014-10-20

    Molecular-line observations of the bipolar planetary nebula (PN) M2-48 have been conducted using the Sub-Millimeter Telescope and the 12 m antenna of the Arizona Radio Observatory at 1, 2, and 3 mm. M2-48 is estimated to be ∼4800 yr old, midway through the PN evolutionary track. SiO and SO{sub 2} were detected in this source—the first identification of either molecule in a PN. CN, HCN, HNC, CS, SO, HCO{sup +}, N{sub 2}H{sup +}, and several {sup 13}C isotopologues such as {sup 13}CN, H{sup 13}CN, and H{sup 13}CO{sup +} were also observed toward this object. A radiative transfer analysis of multiple SiO transitions indicates a gas kinetic temperature of T {sub K} ∼ 55 K and a density of n(H{sub 2}) ∼ 9 × 10{sup 5} cm{sup –3} in M2-48, in agreement with previous CS and CO modeling. After CO, CN, and SO were found to be the most prevalent molecules in this nebula, with fractional abundances, relative to H{sub 2}, of f ∼ 3.8 × 10{sup –7} and 2.4 × 10{sup –7}, respectively. SO{sub 2} and HCN are also abundant, with f ∼ 1.2 × 10{sup –7}, indicating an [SO]/[SO{sub 2}] ratio of ∼2. Relatively high ion abundances were measured in M2-48 as well, with f ∼ 10{sup –7} for both HCO{sup +} and N{sub 2}H{sup +}. An [HCN]/[HNC] ratio of ∼2 was determined, as typically observed in other PNe, independent of age. The high abundances of SO and SO{sub 2}, along with the presence of SiO with f ∼ 2.9 × 10{sup –8}, suggest O/C > 1 in this source; furthermore, the prevalence of CN and N{sub 2}H{sup +} indicates nitrogen enrichment. The {sup 12}C/{sup 13}C ratio of ∼3 in the nebula was also established. These factors indicate hot-bottom burning occurred in the progenitor star of M2-48, suggesting an initial mass > 4 M {sub ☉}.

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

    PubMed Central

    Soldano, Stefano; Pizzorni, Carmen; Paolino, Sabrina; Trombetta, Amelia Chiara; Montagna, Paola; Brizzolara, Renata; Ruaro, Barbara; Sulli, Alberto; Cutolo, Maurizio

    2016-01-01

    Background Alternatively activated (M2) macrophages are phenotypically characterized by the expression of specific markers, mainly macrophage scavenger receptors (CD204 and CD163) and mannose receptor-1 (CD206), and participate in the fibrotic process by over-producing pro-fibrotic molecules, such as transforming growth factor-beta1 (TGFbeta1) and metalloproteinase (MMP)-9. Endothelin-1 (ET-1) is implicated in the fibrotic process, exerting its pro-fibrotic effects through the interaction with its receptors (ETA and ETB). The study investigated the possible role of ET-1 in inducing the transition from cultured human macrophages into M2 cells. Methods Cultured human monocytes (THP-1 cell line) were activated into macrophages (M0 macrophages) with phorbol myristate acetate and subsequently maintained in growth medium (M0-controls) or treated with either ET-1 (100nM) or interleukin-4 (IL-4, 10ng/mL, M2 inducer) for 72 hours. Similarly, primary cultures of human peripheral blood monocyte (PBM)-derived macrophages obtained from healthy subjects, were maintained in growth medium (untreated cells) or treated with ET-1 or IL-4 for 6 days. Both M0 and PBM-derived macrophages were pre-treated with ET receptor antagonist (ETA/BRA, bosentan 10-5M) for 1 hour before ET-1 stimulation. Protein and gene expression of CD204, CD206, CD163, TGFbeta1 were analysed by immunocytochemistry, Western blotting and quantitative real time polymerase chain reaction (qRT-PCR). Gene expression of interleukin(IL)-10 and macrophage derived chemokine (CCL-22) was evaluated by qRT-PCR. MMP-9 production was investigated by gel zymography. Results ET-1 significantly increased the expression of M2 phenotype markers CD204, CD206, CD163, IL-10 and CCL-22, and the production of MMP-9 in both cultures of M0 and PBM-derived macrophages compared to M0-controls and untreated cells. In cultured PBM-derived macrophages, ET-1 increased TGFbeta1 protein and gene expression compared to untreated cells. The ET-1

  4. Thermal testing results of an electroformed nickel secondary (M2) mirror

    NASA Astrophysics Data System (ADS)

    Smith, David R.; Gale, David M.; Cabrera Cuevas, Lizeth; Lucero Álvarez, Maribel; Castro Santos, David; Olmos Tapia, Arak

    2016-07-01

    To support higher-frequency operation, the Large Millimeter Telescope/Gran Telescopio Milimetrico (or LMT/GTM) is replacing its existing monolithic aluminum secondary mirror (M2). The new mirror is a segmented design based on the same electroformed nickel reflector panel technology that is already in use for the primary reflector segments. While the new M2 is lighter and has better surface accuracy than the original mirror, the electroformed panels are more sensitive to high temperatures. During the design phase, concerns were raised over the level of temperature increase that could occur at M2 during daytime observations. Although the panel surface is designed to scatter visible light, the LMT primary mirror is large enough to cause substantial solar heating, even at significant angular separation from the Sun. To address these concerns, the project conducted a series of field tests, within the constraint of having minimum impact on night time observations. The supplier sent two coupon samples of a reflector panel prepared identically to their proposed M2 surface. Temperature sensors were mounted on the samples and they were temporarily secured to the existing M2 mirror at different distances from the center. The goal was to obtain direct monitoring of the surface temperature under site thermal conditions and the concentration effects from the primary reflector. With the sensors installed, the telescope was then commanded to track the Sun with an elevation offset. Initially, elevation offsets from as far as 40 degrees to as close as 6 degrees were tested. The 6 degree separation test quickly passed the target maximum temperature and the telescope was returned to a safer separation. Based on these initial results, a second set of tests was performed using elevation separations from 30 degrees to 8 degrees. To account for the variability of site conditions, the temperature data were analyzed using multiple metrics. These metrics included maximum temperature, final

  5. First Global Climate Model Simulations of the M2 Pliocene Glacial

    NASA Astrophysics Data System (ADS)

    Dolan, A.; Haywood, A.; Hunter, S. J.; Tindall, J.; Valdes, P. J.

    2013-12-01

    The Pliocene Epoch (5.2 to 2.6 Ma) and specifically the PRISM interval (3.0 to 3.3 Ma) have frequently been targeted to investigate warm intervals in Earth history (e.g. Haywood et al., 2013). However, climate variability within the Pliocene is often overlooked. Although not as dramatic as the glacial and interglacial cycles that typified the Pleistocene, the Pliocene also exhibited climate variability and periods which were apparently cooler than modern (Lisiecki and Raymo, 2005). Of particular interest is the major cooling event that occurred around 3.3 Ma during Marine Isotope Stage (MIS) M2. This 'Pliocene glacial' punctuates an otherwise relatively warm background climate and has been referred to as a failed attempt of the climate to reach a full glacial state (De Schepper et al., 2009; Haug and Tiedemann, 1998). The onset of full Northern Hemisphere (NH) glaciation finally occurred at the end of the Pliocene (~ 2.75 Ma). Although numerous temperature reconstructions from around the world's oceans tend to capture the MIS M2 cooling event, the exact nature of M2 remains enigmatic. Sea level records vary but suggest a maximum sea level drop of ~65 m compared to modern, which in itself is significant enough to necessitate the growth of a NH ice sheet (Dwyer and Chandler, 2009). Previous ice sheet modelling suggests that ~8 m sea level equivalent (SLE) ice could be stored on Antarctica (Pollard and DeConto, 2009) and this larger ice sheet (compared to modern) is potentially supported by the increase in ice-rafted debris (IRD) found offshore of East Antarctica during this time (Passchier, 2011). IRD in the North Atlantic would suggest the presence of an ice sheet on Greenland (e.g. Kleiven et al., 2002), but the locations of other ice caps in the NH are not determined due to the destructive nature of subsequent Pleistocene ice sheet advances. Moreover, recent evidence questions whether the climate in the NH was favourable at all for the initiation of ice sheets

  6. Dale Reed with model in front of M2-F1

    NASA Technical Reports Server (NTRS)

    1967-01-01

    Dale Reed with a model of the M2-F1 in front of the actual lifting body. Reed used the model to show the potential of the lifting bodies. He first flew it into tall grass to test stability and trim, then hand-launched it from buildings for longer flights. Finally, he towed the lifting-body model aloft using a powered model airplane known as the 'Mothership.' A timer released the model and it glided to a landing. Dale's wife Donna used a 9 mm. camera to film the flights of the model. Its stability as it glided--despite its lack of wings--convinced Milt Thompson and some Flight Research Center engineers including the center director, Paul Bikle, that a piloted lifting body was possible. The lifting body concept evolved in the mid-1950s as researchers considered alternatives to ballistic reentries of piloted space capsules. The designs for hypersonic, wingless vehicles were on the boards at NASA Ames and NASA Langley facilities, while the US Air Force was gearing up for its Dyna-Soar program, which defined the need for a spacecraft that would land like an airplane. Despite favorable research on lifting bodies, there was little support for a flight program. Dryden engineer R. Dale Reed was intrigued with the lifting body concept, and reasoned that some sort of flight demonstration was needed before wingless aircraft could be taken seriously. In February 1962, he built a model lifting body based upon the Ames M2 design, and air-launched it from a radio controlled 'mothership.' Home movies of these flights, plus the support of research pilot Milt Thompson, helped pursuade the facilities director, Paul Bikle, to give the go-ahead for the construction of a full-scale version, to be used as a wind-tunnel model and possibly flown as a glider. Comparing lifting bodies to space capsules, an unofficial motto of the project was, 'Don't be Rescued from Outer Space--Fly Back in Style.' The construction of the M2-F1 was a joint effort by Dryden and a local glider manufacturer, the

  7. Carboxyl- and amino-functionalized polystyrene nanoparticles differentially affect the polarization profile of M1 and M2 macrophage subsets.

    PubMed

    Fuchs, Ann-Kathrin; Syrovets, Tatiana; Haas, Karina A; Loos, Cornelia; Musyanovych, Anna; Mailänder, Volker; Landfester, Katharina; Simmet, Thomas

    2016-04-01

    Macrophages are key regulators of innate and adaptive immune responses. Exposure to microenvironmental stimuli determines their polarization into proinflammatory M1 and anti-inflammatory M2 macrophages. M1 exhibit high expression of proinflammatory TNF-α and IL-1β, and M2 promote tissue repair, but likewise support tumor growth and cause immune suppression by expressing IL-10. Thus, the M1/M2 balance critically determines tissue homeostasis. By using carboxyl- (PS-COOH) and amino-functionalized (PS-NH2) polystyrene nanoparticles, the effects of surface decoration on the polarization of human macrophages were investigated. The nanoparticles did not compromise macrophage viability nor did they affect the expression of the M1 markers CD86, NOS2, TNF-α, and IL-1β. By contrast, in M2, both nanoparticles impaired expression of scavenger receptor CD163 and CD200R, and the release of IL-10. PS-NH2 also inhibited phagocytosis of Escherichia coli by both, M1 and M2. PS-COOH did not impair phagocytosis by M2, but increased protein mass in M1 and M2, TGF-β1 release by M1, and ATP levels in M2. Thus, nanoparticles skew the M2 macrophage polarization without affecting M1 markers. Given the critical role of the M1 and M2 polarization for the immunological balance in patients with cancer or chronic inflammation, functionalized nanoparticles might serve as tools for reprogramming the M1/M2 polarization.

  8. Orientation photoinduite de nouvelles molécules pour l'optique non linéaire

    NASA Astrophysics Data System (ADS)

    Ngan, N. T. K.; Dumont, M.

    2002-06-01

    Dans les films de polymères utilisés pour les composants de télécommunication, l'orientation photoinduite de molécules de colorants permet de réaliser une biréfringence ou une non centrosymétrie (X^{(2)}). Le mécanisme d'orientation comporte un pompage optique sélectif (“hole buming angulaire”), suivi, soit d'une photodégradation, soit d'un retour à l'état initial, accompagné d'une rotation (“redistribution angulaire”). Seul ce second cas conduit à une orientation importante, par accumulation des molécules dans la direction la moins pompée. C'est le cas des molécules photoisomérisables de façon réversible, tels les azobenzènes. Nous présentons ici une nouvelle molécule azoïque octupolaire qui est un excellent candidat pour l'orientation tout-optique.

  9. Protective effect of Lagenaria siceraria (Mol) against membrane-bound enzyme alterations in isoproterenol-induced cardiac damage in rats.

    PubMed

    Vijayakumar, M; Selvi, V; Krishnakumari, S

    2012-01-01

    This study was aimed at evaluating the preventive role of the ethanolic extract of Lagenaria siceraria (Mol) fruit on membrane-bound enzymes, such as sodium potassium-dependent adenosine triphosphatase (Na(+)/K(+) ATPase), calcium-dependent adenosine triphosphatase (Ca(2+) ATPase) and magnesium-dependent adenosine triphosphatase (Mg(2+) ATPase) on isoproterenol (ISO)-induced myocardial infarction (MI) in rats. Male albino Wistar rats were pretreated with the ethanolic extract of L. siceraria (Mol) fruit (125, 250 and 500 mg kg(-1) body weight) for a period of 30 days. After the treatment period, ISO (85mg kg(-1) body weight) was subcutaneously injected into rats at 24-h intervals for 2 days. ISO-induced rats showed a significant (p < 0.05) decrease in the activity of Na(+)/K(+) ATPase and an increase in the activities of Ca(2+) and Mg(2+) ATPases in the heart tissues. Pre-treatment with the ethanolic extract of L. siceraria (Mol) fruit for a period of 30 days exhibited a significant (p < 0.05) effect in ISO-induced rats. Thus, our study shows that the ethanolic extract of L. siceraria (Mol) fruit has membrane-stabilising role in ISO-induced MI in rats.

  10. Towards efficient mobile M2M communications: survey and open challenges.

    PubMed

    Pereira, Carlos; Aguiar, Ana

    2014-10-20

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

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

    PubMed Central

    Pereira, Carlos; Aguiar, Ana

    2014-01-01

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

  12. Role for Microglia in Sex Differences after ischemic stroke: Importance of M2

    PubMed Central

    Bodhankar, Sheetal; Lapato, Andrew; Chen, Yingxin; Vandenbark, Arthur A.; Saugstad, Julie A.; Offner, Halina

    2015-01-01

    Inflammation plays a critical role in the pathogenesis of ischemic stroke. This process depends, in part, upon proinflammatory factors released by activated resident central nervous system (CNS) microglia (MG). Previous studies demonstrated that transfer of IL-10+ B-cells reduced infarct volumes in male C57BL/6J recipient mice when given 24 h prior to or therapeutically at 4 h or 24 h after experimental stroke induced by 60 min middle cerebral artery occlusion (MCAO). The present study assesses possible sex differences in immunoregulation by IL-10+ B-cells on primary male vs. female MG cultured from naïve and ischemic stroke-induced mice. Thus, MG cultures were treated with recombinant (r)IL-10, rIL-4 or IL-10+ B-cells after lipopolysaccharide (LPS) activation and evaluated by flow cytometry for production of proinflammatory and anti-inflammatory factors. We found that IL-10+ B-cells significantly reduced MG production of TNF-α, IL-1β and CCL3 post-MCAO and increased their expression of the anti-inflammatory M2 marker, CD206, by cell-cell interactions. Moreover, MG from female vs. male mice had higher expression of IL-4 and IL-10 receptors and increased production of IL-4, especially after treatment with IL-10+ B-cells. These findings indicate that IL-10-producing B-cells play a crucial role in regulating MG activation, proinflammatory cytokine release and M2 phenotype induction, post-MCAO, with heightened sensitivity of female MG to IL-4 and IL-10. This study, coupled with our previous demonstration of increased numbers of transferred IL-10+ B-cells in the ischemic hemisphere, provide a mechanistic basis for local regulation by secreted IL-10 and IL-4 as well as direct B-cell/MG interactions that promote M2+-MG. PMID:26246072

  13. Optical trapping with superfocused high-M2 laser diode beam

    NASA Astrophysics Data System (ADS)

    Sokolovskii, G. S.; Dudelev, V. V.; Melissinaki, V.; Losev, S. N.; Soboleva, K. K.; Deryagin, A. G.; Kuchinskii, V. I.; Farsari, M.; Sibbett, W.; Rafailov, E. U.

    2015-03-01

    Many applications of high-power laser diodes demand tight focusing. This is often not possible due to the multimode nature of semiconductor laser radiation possessing beam propagation parameter M2 values in double-digits. We propose a method of `interference' superfocusing of high-M2 diode laser beams with a technique developed for the generation of Bessel beams based on the employment of an axicon fabricated on the tip of a 100 μm diameter optical fiber with high-precision direct laser writing. Using axicons with apex angle 1400 and rounded tip area as small as ~10 μm diameter, we demonstrate 2-4 μm diameter focused laser `needle' beams with approximately 20 μm propagation length generated from multimode diode laser with beam propagation parameter M2=18 and emission wavelength of 960 nm. This is a few-fold reduction compared to the minimal focal spot size of ~11 μm that could be achieved if focused by an `ideal' lens of unity numerical aperture. The same technique using a 1600 axicon allowed us to demonstrate few-μm-wide laser `needle' beams with nearly 100 μm propagation length with which to demonstrate optical trapping of 5-6 μm rat blood red cells in a water-heparin solution. Our results indicate the good potential of superfocused diode laser beams for applications relating to optical trapping and manipulation of microscopic objects including living biological objects with aspirations towards subsequent novel lab-on-chip configurations.

  14. [The nuclear matrix proteins (mol. mass 38 and 50 kDa) are transported by chromosomes in mitosis].

    PubMed

    Murasheva, M I; Chentsov, Iu S

    2010-01-01

    It was shown by immunofluorescence method that serum M68 and serum K43 from patients with autoimmune disease stain interphase nuclei and periphery of mitotic chromosomes of pig kidney cells. Western blotting reveals the polypeptide with mol. mass of 50 kDa in serum M68, and the polypeptide with mol. mass of 38 kDa in serum K43. In the nuclear protein matrix, the antibodies to protein with mol. mass of 38 kDa stained only nucleolar periphery, while the antibodies to the protein with mol. mass of 50 kDa stained both the nucleolar periphery and all the interphase nucleus. It shows that among all components of nuclear protein matrix (lamina, internuclear network, residual nucleoli) only nucleolar periphery contains the 38 kDa protein, while the 50 kDa protein is a part of residual nucleolar periphery and takes part in nuclear protein network formation. In the interphase cells, both proteins were in situ localized in the nuclei, but one of them with mol. mass of 50 kDa was in the form of small clearly outlined granules, while the other (38 kDa) was in the form of small bright granules against the background of diffusely stained nuclei. Both proteins were also revealed as continuous ring around nucleolar periphery. During all mitotic stages, the 50 kDa protein was seen on the chromosomal periphery as a cover, and the 38 kDa protein formed separate fragments and granules around them. After nuclear and chromosome decondensation induced by hypotonic treatment, both antibodies stain interphase nuclei in diffuse manner, but in mitotic cells they stained the surface of the swollen chromosomes. The polypeptide with mol. mass of 50 kDa maintained strong connection with chromosome periphery both in norm and under condition of decondensation induced by hypotonic treatment and at subsequent recondensation in isotonic medium. In contrast, the protein with mol. mass of 38 kDa partially lost the contact with a chromosome during recondensation appearing also in the form of granules in

  15. Distinct interneuron types express m2 muscarinic receptor immunoreactivity on their dendrites or axon terminals in the hippocampus.

    PubMed

    Hájos, N; Papp, E C; Acsády, L; Levey, A I; Freund, T F

    1998-01-01

    In previous studies m2 muscarinic acetylcholine receptor-immunoreactive interneurons and various types of m2-positive axon terminals have been described in the hippocampal formation. The aim of the present study was to identify the types of interneurons expressing m2 receptor and to examine whether the somadendritic and axonal m2 immunostaining labels the same or distinct cell populations. In the CA1 subfield, neurons immunoreactive for m2 have horizontal dendrites, they are located at the stratum oriens/alveus border and have an axon that project to the dendritic region of pyramidal cells. In the CA3 subfield and the hilus, m2-positive neurons are multipolar and are scattered in all layers except stratum lacunosum-moleculare. In stratum pyramidale of the CA1 and CA3 regions, striking axon terminal staining for m2 was observed, surrounding the somata and axon initial segments of pyramidal cells in a basket-like manner. The co-localization of m2 with neurochemical markers and GABA was studied using the "mirror" technique and fluorescent double-immunostaining at the light microscopic level and with double-labelling using colloidal gold-conjugated antisera and immunoperoxidase reaction (diaminobenzidine) at the electron microscopic level. GABA was shown to be present in the somata of most m2-immunoreactive interneurons, as well as in the majority of m2-positive terminals in all layers. The calcium-binding protein parvalbumin was absent from practically all m2-immunoreactive cell bodies and dendrites. In contrast, many of the terminals synapsing on pyramidal cell somata and axon initial segments co-localized parvalbumin and m2, suggesting a differential distribution of m2 receptor immunoreactivity on the axonal and somadendritic membrane of parvalbumin-containing basket and axo-axonic cells. The co-existence of m2 receptors with the calcium-binding protein calbindin and the neuropeptides cholecystokinin and vasoactive intestinal polypeptide was rare throughout the

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

    SciTech Connect

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

    1990-05-01

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

  17. Atmospheric Turbulence Measurements With the Automatic Mini UAV 'M2AV Carolo'

    NASA Astrophysics Data System (ADS)

    Bange, J.; van den Kroonenberg, A. C.; Spieß, T.; Buschmann, M.; Krüger, L.; Heindorf, A.; Vörsmann, P.

    2007-05-01

    The limitations of manned airborne meteorological measurements led to the development of an autonomously operating mini aircraft, the Meteorological Mini-UAV (M2AV), at the Institute of Aerospace Systems, Technical University of Braunschweig, Germany. The task was to develop, test and verify a meteorological sensor package as payload for an already available automatic carrier aircraft, the UAV 'Carolo T200', which operates autonomously i.e. without remote control. The M2AV is a self constructed model aircraft with two electrically powered engines and a wingspan of two meters. The maximum take-off weight is 4.5~kg (the M2AV is therefore classified as an model plane which simplifies authority issues), including 1.5~kg of payload. It is hand-launched which makes operation of the aircraft easy. With an endurance of approximately 50 minutes, the range accounts for 60 km at a cruising speed of 20~m/s. The M2AV is capable of performing turbulence measurements (wind vector, temperature and humidity) within the troposphere and offers an economic component during meteorological campaigns. The meteorological sensors are mounted on a noseboom to minimise the aircraft's influence on the measurements and to position the sensors closely to each other. Wind is measured via a small five-hole probe, an inertia measurement unit and GPS. The flight mission (waypoints, altitudes, airspeed) is planned and assigned to the aircraft before the semi- automatic launch. The flight is only controlled by the on-board autopilot system which only communicates with a ground station (laptop PC) for the exchange of measured data and command updates like new waypoints etc. The talk gives details on the technical items, calibration and first missions. Results from first field experiments like the LAUNCH-2005 campaign near Berlin are used for data quality assessment by comparison with simultaneous lidar and sodar measurements. An in situ comparison with the highly accurate helicopter-borne turbulence

  18. Autoresonances of m=2 diocotron oscillations in non-neutral electron plasmas.

    PubMed

    Gomberoff, K; Higaki, H; Kaga, C; Ito, K; Okamoto, H

    2016-10-01

    The existence of autoresonances for m=2 diocotron oscillations of non-neutral electron plasmas in a uniform magnetic field was predicted by particle-in-cell simulations and it was confirmed in experiments. The obtained results show clear deviations from the standard threshold amplitude dependence on the sweep rate. The threshold amplitude approaches a constant at a lower sweep rate when there is a damping force. It was also found that the aspect ratio for the oval cross section of the confined plasma can be controlled by the frequency of the externally applied driving force.

  19. Autoresonances of m =2 diocotron oscillations in non-neutral electron plasmas

    NASA Astrophysics Data System (ADS)

    Gomberoff, K.; Higaki, H.; Kaga, C.; Ito, K.; Okamoto, H.

    2016-10-01

    The existence of autoresonances for m =2 diocotron oscillations of non-neutral electron plasmas in a uniform magnetic field was predicted by particle-in-cell simulations and it was confirmed in experiments. The obtained results show clear deviations from the standard threshold amplitude dependence on the sweep rate. The threshold amplitude approaches a constant at a lower sweep rate when there is a damping force. It was also found that the aspect ratio for the oval cross section of the confined plasma can be controlled by the frequency of the externally applied driving force.

  20. IRF5 regulates lung macrophages M2 polarization during severe acute pancreatitis in vitro

    PubMed Central

    Sun, Kang; He, Song-Bing; Qu, Jian-Guo; Dang, Sheng-Chun; Chen, Ji-Xiang; Gong, Ai-Hua; Xie, Rong; Zhang, Jian-Xin

    2016-01-01

    AIM To investigate the role of interferon regulatory factor 5 (IRF5) in reversing polarization of lung macrophages during severe acute pancreatitis (SAP) in vitro. METHODS A mouse SAP model was established by intraperitoneal (ip) injections of 20 μg/kg body weight caerulein. Pathological changes in the lung were observed by hematoxylin and eosin staining. Lung macrophages were isolated from bronchoalveolar lavage fluid. The quantity and purity of lung macrophages were detected by fluorescence-activated cell sorting and evaluated by real-time polymerase chain reaction (RT-PCR). They were treated with IL-4/IRF5 specific siRNA (IRF5 siRNA) to reverse their polarization and were evaluated by detecting markers expression of M1/M2 using RT-PCR. RESULTS SAP associated acute lung injury (ALI) was induced successfully by ip injections of caerulein, which was confirmed by histopathology. Lung macrophages expressed high levels of IRF5 as M1 phenotype during the early acute pancreatitis stages. Reduction of IRF5 expression by IRF5 siRNA reversed the action of macrophages from M1 to M2 phenotype in vitro. The expressions of M1 markers, including IRF5 (S + IRF5 siRNA vs S + PBS, 0.013 ± 0.01 vs 0.054 ± 0.047, P < 0.01), TNF-α (S + IRF5 siRNA vs S + PBS, 0.0003 ± 0.0002 vs 0.019 ± 0.018, P < 0.001), iNOS (S + IRF5 siRNA vs S + PBS, 0.0003 ± 0.0002 vs 0.026 ± 0.018, P < 0.001) and IL-12 (S + IRF5 siRNA vs S + PBS, 0.000005 ± 0.00004 vs 0.024 ± 0.016, P < 0.001), were decreased. In contrast, the expressions of M2 markers, including IL-10 (S + IRF5 siRNA vs S + PBS, 0.060 ± 0.055 vs 0.0230 ± 0.018, P < 0.01) and Arg-1 (S + IRF5 siRNA vs S + PBS, 0.910 ± 0.788 vs 0.0036 ± 0.0025, P < 0.001), were increased. IRF5 siRNA could reverse the lung macrophage polarization more effectively than IL-4. CONCLUSION Treatment with IRF5 siRNA can reverse the pancreatitis-induced activation of lung macrophages from M1 phenotype to M2 phenotype in SAP associated with ALI. PMID:27895424

  1. Seasonal modulation of M2 tide in the Northern Bay of Bengal

    NASA Astrophysics Data System (ADS)

    Tazkia, A. R.; Krien, Y.; Durand, F.; Testut, L.; Islam, AKM S.; Papa, F.; Bertin, X.

    2017-04-01

    The Northern Bay of Bengal (BoB) with its adjoining Ganges-Brahmaputra-Meghna delta (GBM) forms the largest deltaic region in the world. It is surrounded by a wide area of low-lying land (less than a few meters above mean sea level), very densely populated. It is home to a strong variability of sea level, across all timescales, with ample tides and frequent storm surges. It is also subject to extended river flooding during the monsoon season, with frequent overflows of two of the world's largest rivers (Brahmaputra and Ganges). There is thus a need to understand and predict the various mechanisms responsible for coastal and estuarine water level variability in this area. In this study, we address one of the least understood facets of this variability: the low-frequency modulation of tides. We focus on the seasonal changes of amplitude of the semi-diurnal lunar tide, M2. It is found that M2 amplitude shows marked changes between winter and summer seasons (of order 10 cm), incommensurate with most of the world's coastal ocean. We observe contrasted patterns from the open areas of the coastal ocean to the inner part of the GBM estuary. In the coastal ocean and over most of the GBM delta, M2 amplitude is stronger during summer and decreases until winter. Conversely, in the far northern part of GBM estuary, M2 amplitude is stronger during winter and weaker during summer. We make use of a hydrodynamic barotropic tidal model to decipher the processes responsible for this evolution. It is found that throughout the coastal ocean and over most of the GBM delta, this evolution is driven by frictional effects, with a seasonal modulation of bottom dissipation of tidal energy. Our simple barotropic model, however, does not capture the observed range of seasonal modulation of tides in the GBM estuary and at its mouth. Our study advocates for a careful consideration of these processes for a proper representation of the tidal dynamics as well as of the flooding hazard in the Bengal

  2. Resonant Photoemission and M_{2,3}-Absorption Spectra in Nickel Dichloride

    NASA Astrophysics Data System (ADS)

    Igarashi, J.

    Ni 3p-resonant photoemission and Ni M_{2,3}-absorption spectra are calculated in detail on a cluster of (NiCl_6)^{4-} with the use of the transition matrix elements evaluated on the Herman-Skillman potential in Ni atom. Overall spectral shape agrees well with experiment, allowing a determination of the parameters which characterize Ni 3d and Cl 3p states. Resonance behavior is discussed near the Ni 3p-core level photothreshold. The resonant enhancement is found to be larger for the peak with higher binding energy in the d^7-multiplets.

  3. The r-step Fibonacci-Hurwitz sequences in the binary polyhedral group <2, m, 2>

    NASA Astrophysics Data System (ADS)

    Deveci, Ömür; Ćiçekci, Deniz

    2016-04-01

    In [1], Deveci et al. defined the r-step Fibonacci-Hurwitz sequences from the Hurwitz matrices obtained from the characteristic polynomial of the k-step Fibonacci sequence. Also, they extended the r-step Fibonacci-Hurwitz sequences to groups. In this work, we obtain the periods of the r-step Fibonacci-Hurwitz sequences in the binary polyhedral group <2, m, 2> for generating triple {x, y, z} and generating pair {y, z} by the aid of the periods of the r-step Fibonacci-Hurwitz sequences according to modulo m.

  4. Vitamin K(3) and K(5) are inhibitors of tumor pyruvate kinase M2.

    PubMed

    Chen, Jing; Jiang, Zheng; Wang, Beibei; Wang, Yanguang; Hu, Xun

    2012-03-28

    Pyruvate kinase M2 (PKM2) is a rate-limiting enzyme of aerobic glycolysis in cancer cells and plays important roles in cancer metabolism and growth. Here we show that vitamin K(3) and K(5) (VK(3) and VK(5)) are relatively specific PKM2 inhibitors. VK(3) and VK(5) showed a significantly stronger potency to inhibit PKM2 than to inhibit PKM1 and PKL, 2 other isoforms of PK dominantly expressed in most adult tissues and liver. This study combined with previous reports supports that VK(3) and VK(5) have potential as adjuvant for cancer chemotherapy.

  5. M2 macrophages or IL-33 treatment attenuate ongoing Mycobacterium tuberculosis infection

    PubMed Central

    Piñeros, A. R.; Campos, L. W.; Fonseca, D. M.; Bertolini, T. B.; Gembre, A. F.; Prado, R. Q.; Alves-Filho, J. C.; Ramos, S. G.; Russo, M.; Bonato, V. L. D.

    2017-01-01

    The protective effects of mycobacterial infections on lung allergy are well documented. However, the inverse relationship between tuberculosis and type 2 immunity is still elusive. Although type 1 immunity is essential to protection against Mycobacterium tuberculosis it might be also detrimental to the host due to the induction of extensive tissue damage. Here, we determined whether lung type 2 immunity induced by allergen sensitization and challenge could affect the outcome of M. tuberculosis infection. We used two different protocols in which sensitization and allergen challenge were performed before or after M. tuberculosis infection. We found an increased resistance to M. tuberculosis only when allergen exposure was given after, but not before infection. Infected mice exposed to allergen exhibited lower bacterial load and cellular infiltrates in the lungs. Enhanced resistance to infection after allergen challenge was associated with increased gene expression of alternatively activated macrophages (M2 macrophages) and IL-33 levels. Accordingly, either adoptive transfer of M2 macrophages or systemic IL-33 treatment was effective in attenuating M. tuberculosis infection. Notably, the enhanced resistance induced by allergen exposure was dependent on IL-33 receptor ST2. Our work indicates that IL-33 might be an alternative therapeutic treatment for severe tuberculosis. PMID:28128217

  6. Feedback mechanisms between M2 macrophages and Th17 cells in colorectal cancer patients.

    PubMed

    Mao, Hui; Pan, Fei; Guo, Hongxia; Bu, Fangfang; Xin, Tong; Chen, Shukun; Guo, Yajun

    2016-09-01

    IL-17 and IL-22 are linked to the development of intestinal inflammation and colorectal cancer (CRC). However, the maintenance of IL-17 and IL-22 production, as well as the cell type (Th17) that mediates these cytokines in CRC patients, remains unknown. To examine this, untreated CRC patients and healthy controls were recruited in this study. We first observed that CRC patients contained significantly elevated levels of IL-17- and IL-22-producing CD4(+) T cells. The vast majority of IL-22-expressing CD4(+) T cells also expressed IL-17. We then found that the production of both IL-17 and IL-22 required support from autologous monocytes, since the depletion of monocytes significantly downregulated IL-17 and IL-22 secretion. Naive T cells from CRC patients did not secrete IL-17 or IL-22 initially, but long-term coculture with autologous monocytes significantly upregulated IL-17 and IL-22 production in an IL-6-dependent manner. Blockade of IL-6 significantly reduced the levels of both IL-17 and IL-22. We then observed that CD163(+) M2 macrophages were the main contributor of IL-6. Interestingly, incubation of monocytes with CCR4(+)CCR6(+) Th17 cells resulted in significantly higher levels of CD163(+) macrophages as well as higher IL-6 secretion, than incubation with non-Th17 CD4(+) T cells. Together, our study discovered a positive feedback mechanism between Th17 and M2 macrophages in CRC patients.

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

    PubMed Central

    Madsen, Daniel H.; Leonard, Daniel; Masedunskas, Andrius; Moyer, Amanda; Jürgensen, Henrik Jessen; Peters, Diane E.; Amornphimoltham, Panomwat; Selvaraj, Arul; Yamada, Susan S.; Brenner, David A.; Burgdorf, Sven; Engelholm, Lars H.; Behrendt, Niels; Holmbeck, Kenn; Weigert, Roberto

    2013-01-01

    Tissue remodeling processes critically depend on the timely removal and remodeling of preexisting collagen scaffolds. Nevertheless, many aspects related to the turnover of this abundant extracellular matrix component in vivo are still incompletely understood. We therefore took advantage of recent advances in optical imaging to develop an assay to visualize collagen turnover in situ and identify cell types and molecules involved in this process. Collagen introduced into the dermis of mice underwent cellular endocytosis in a partially matrix metalloproteinase–dependent manner and was subsequently routed to lysosomes for complete degradation. Collagen uptake was predominantly executed by a quantitatively minor population of M2-like macrophages, whereas more abundant Col1a1-expressing fibroblasts and Cx3cr1-expressing macrophages internalized collagen at lower levels. Genetic ablation of the collagen receptors mannose receptor (Mrc1) and urokinase plasminogen activator receptor–associated protein (Endo180 and Mrc2) impaired this intracellular collagen degradation pathway. This study demonstrates the importance of receptor-mediated cellular uptake to collagen turnover in vivo and identifies a key role of M2-like macrophages in this process. PMID:24019537

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

    PubMed

    Madsen, Daniel H; Leonard, Daniel; Masedunskas, Andrius; Moyer, Amanda; Jürgensen, Henrik Jessen; Peters, Diane E; Amornphimoltham, Panomwat; Selvaraj, Arul; Yamada, Susan S; Brenner, David A; Burgdorf, Sven; Engelholm, Lars H; Behrendt, Niels; Holmbeck, Kenn; Weigert, Roberto; Bugge, Thomas H

    2013-09-16

    Tissue remodeling processes critically depend on the timely removal and remodeling of preexisting collagen scaffolds. Nevertheless, many aspects related to the turnover of this abundant extracellular matrix component in vivo are still incompletely understood. We therefore took advantage of recent advances in optical imaging to develop an assay to visualize collagen turnover in situ and identify cell types and molecules involved in this process. Collagen introduced into the dermis of mice underwent cellular endocytosis in a partially matrix metalloproteinase-dependent manner and was subsequently routed to lysosomes for complete degradation. Collagen uptake was predominantly executed by a quantitatively minor population of M2-like macrophages, whereas more abundant Col1a1-expressing fibroblasts and Cx3cr1-expressing macrophages internalized collagen at lower levels. Genetic ablation of the collagen receptors mannose receptor (Mrc1) and urokinase plasminogen activator receptor-associated protein (Endo180 and Mrc2) impaired this intracellular collagen degradation pathway. This study demonstrates the importance of receptor-mediated cellular uptake to collagen turnover in vivo and identifies a key role of M2-like macrophages in this process.

  9. From Monocytes to M1/M2 Macrophages: Phenotypical vs. Functional Differentiation

    PubMed Central

    Italiani, Paola; Boraschi, Diana

    2014-01-01

    Studies on monocyte and macrophage biology and differentiation have revealed the pleiotropic activities of these cells. Macrophages are tissue sentinels that maintain tissue integrity by eliminating/repairing damaged cells and matrices. In this M2-like mode, they can also promote tumor growth. Conversely, M1-like macrophages are key effector cells for the elimination of pathogens, virally infected, and cancer cells. Macrophage differentiation from monocytes occurs in the tissue in concomitance with the acquisition of a functional phenotype that depends on microenvironmental signals, thereby accounting for the many and apparently opposed macrophage functions. Many questions arise. When monocytes differentiate into macrophages in a tissue (concomitantly adopting a specific functional program, M1 or M2), do they all die during the inflammatory reaction, or do some of them survive? Do those that survive become quiescent tissue macrophages, able to react as naïve cells to a new challenge? Or, do monocyte-derived tissue macrophages conserve a “memory” of their past inflammatory activation? This review will address some of these important questions under the general framework of the role of monocytes and macrophages in the initiation, development, resolution, and chronicization of inflammation. PMID:25368618

  10. Status of the secondary mirrors (M2) for the Gemini 8-m telescopes

    NASA Astrophysics Data System (ADS)

    Knohl, Ernst-Dieter; Schoeppach, Armin; Pickering, Michael A.

    1998-08-01

    The 1-m diameter lightweight secondary mirrors (M2) for the Gemini 8-m telescopes will be the largest CVD-SiC mirrors ever produced. The design and manufacture of these mirrors is a very challenging task. In this paper we will discuss the mirror design, structural and mechanical analysis, and the CVD manufacturing process used to produce the mirror blanks. The lightweight design consist of a thin faceplate (4-mm) and triangular backstructure cells with ribs of varying heights. The main drivers in the design were weight (40 kg) and manufacturing limitations imposed on the backstructure cells and mirror mounts. Finite element modeling predicts that the mirror design will meet all of the Gemini M2 requirements for weight, mechanical integrity, resonances, and optical performance. Special design considerations were necessary to avoid stress concentration in the mounting areas and to meet the requirement that the mirror survive an 8-g earthquake. The highest risk step in the mirror blank manufacturing process is the near-net-shape CVD deposition of the thin, curved faceplate. Special tooling and procedures had to be developed to produce faceplates free of fractures, cracks, and stress during the cool-down from deposition temperature (1350 C) to room temperature. Due to time delay with the CVD manufacturing process in the meantime a backup solution from Zerodur has been started. This mirror is now in the advanced polishing process. Because the design of both mirrors is very similar an excellent comparison of both solutions is possible.

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

    PubMed

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

    2014-06-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2015-03-01

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

  13. Machine to machine (M2M) technology in demand responsive commercial buildings

    SciTech Connect

    Watson, David S.; Piette, Mary Ann; Sezgen, Osman; Motegi, Naoya; ten Hope, Laurie

    2004-08-01

    Machine to Machine (M2M) is a term used to describe the technologies that enable computers, embedded processors, smart sensors, actuators and mobile devices to communicate with one another, take measurements and make decisions--often without human intervention. M2M technology was applied to five commercial buildings in a test. The goal was to reduce electric demand when a remote price signal rose above a predetermine price. In this system, a variable price signal was generated from a single source on the Internet and distributed using the meta-language, XML (Extensible Markup Language). Each of five commercial building sites monitored the common price signal and automatically shed site-specific electric loads when the price increased above predetermined thresholds. Other than price signal scheduling, which was set up in advance by the project researchers, the system was designed to operate without human intervention during the two-week test period. Although the buildings responded to the same price signal, the communication infrastructures used at each building were substantially different. This study provides an overview of the technologies used at each building site, the price generator/server, and each link in between. Network architecture, security, data visualization and site-specific system features are characterized. The results of the test are discussed, including: functionality at each site, measurement and verification techniques, and feedback from energy managers and building operators. Lessons learned from the test and potential implications for widespread rollout are provided.

  14. Decisive disappearance search at high Δ m2 with monoenergetic muon neutrinos

    NASA Astrophysics Data System (ADS)

    Axani, S.; Collin, G.; Conrad, J. M.; Shaevitz, M. H.; Spitz, J.; Wongjirad, T.

    2015-11-01

    "KPipe" is a proposed experiment which will study muon neutrino disappearance for a sensitive test of the Δ m2˜1 eV2 anomalies, possibly indicative of one or more sterile neutrinos. The experiment is to be located at the J-PARC Materials and Life Science Experimental Facility's spallation neutron source, which represents the world's most intense source of charged kaon decay-at-rest monoenergetic (236 MeV) muon neutrinos. The detector vessel, designed to measure the charged-current interactions of these neutrinos, will be 3 m in diameter and 120 m long, extending radially at a distance of 32 to 152 m from the source. This design allows a sensitive search for νμ disappearance associated with currently favored light sterile neutrino models and features the ability to reconstruct the neutrino oscillation wave within a single, extended detector. The required detector design, technology, and costs are modest. The KPipe measurements will be robust since they depend on a known energy neutrino source with low expected backgrounds. Further, since the measurements rely only on the measured rate of detected events as a function of distance, with no required knowledge of the initial flux and neutrino interaction cross section, the results will be largely free of systematic errors. The experimental sensitivity to oscillations, based on a shape-only analysis of the L /E distribution, will extend an order of magnitude beyond present experimental limits in the relevant high-Δ m2 parameter space.

  15. Subcellular redistribution of m2 muscarinic acetylcholine receptors in striatal interneurons in vivo after acute cholinergic stimulation.

    PubMed

    Bernard, V; Laribi, O; Levey, A I; Bloch, B

    1998-12-01

    The purpose of our work was to investigate how the cholinergic environment influences the targeting and the intracellular trafficking of the muscarinic receptor m2 (m2R) in vivo. To address this question, we have used immunohistochemical approaches at light and electron microscopic levels to detect the m2R in control rats and rats treated with muscarinic receptor agonists. In control animals, m2Rs were located mostly at postsynaptic sites at the plasma membrane of perikarya and dendrites of cholinergic and NPY-somatostatin interneurons as autoreceptors and heteroreceptors, respectively. Presynaptic receptors were also detected in boutons. The m2Rs were usually detected at extrasynaptic sites, but they could be found rarely in association with symmetrical synapses, suggesting that the cholinergic transmission mediated by m2R occurs via synaptic and nonsynaptic mechanisms. The stimulation of muscarinic receptors with oxotremorine provoked a dramatic alteration of m2R compartmentalization, including endocytosis with a decrease of the density of m2R at the membrane (-63%) and an increase of those associated with endosomes (+86%) in perikarya. The very strong increase of m2R associated with multivesicular bodies (+732%) suggests that oxotremorine activated degradation. The slight increase in the Golgi apparatus (+26%) suggests that the m2R stimulation had an effect on the maturation of m2R. The substance P receptor located at the membrane of the same neurons was unaffected by oxotremorine. Our data demonstrate that cholinergic stimulation dramatically influences the subcellular distribution of m2R in striatal interneurons in vivo. These events may have key roles in controlling abundance and availability of muscarinic receptors via regulation of receptor endocytosis, degradation, and/or neosynthesis. Further, the control of muscarinic receptor trafficking may influence the activity of striatal interneurons, including neurotransmitter release and/or electric activity.

  16. Stability assessment of gas mixtures containing terpenes at nominal 5 nmol/mol contained in treated aluminum gas cylinders.

    PubMed

    Rhoderick, George C

    2010-10-01

    Studies of climate change increasingly recognize the diverse influences exerted by terpenes in the atmosphere, including roles in particulates, ozone formation, and their oxidizing potential. Measurements of key terpenes suggest atmospheric concentrations ranging from low pmol/mol (parts per trillion) to nmol/mol (parts per billion), depending on location and compound. To accurately establish concentration trends, assess the role of terpenes in atmospheric chemistry, and relate measurement records from many laboratories and researchers, it is essential to have good calibration standards. The feasibility of preparing well-characterized, stable gas cylinder standards for terpenes at the nmol/mol level is not yet well established. Several of the world's National Metrology Institutes (NMIs) are researching the feasibility of developing primary and secondary reference gas standards at the nmol/mol level for terpenes. The US NMI, the National Institute of Standards and Technology, has prepared several nmol/mol mixtures, in treated aluminum gas cylinders, containing terpenes in dry nitrogen at nominal 5 nmol/mol for stability studies. Overall, 11 terpenes were studied for stability. An initial gas mixture containing nine terpenes, one oxygenate, and six aromatic compounds, including benzene as an internal standard, was prepared. Results for four of the nine terpenes in this initial mixture indicate stability in these treated aluminum gas cylinders for over 6 months and project long term (years) stability. Interesting results were seen for beta-pinene, which when using a linear equation rate decline predicts that it will reach a zero concentration level at day 416. At the same time, increases in alpha-pinene, D: -limonene (R-(+)-limonene), and p-cymene were observed, including camphene, a terpene not prepared in the gas mixture, indicating a chemical transformation of beta-pinene to these species. Additional mixtures containing combination of either alpha-pinene, camphor

  17. Inducible and constitutive expression of pMOL28-encoded nickel resistance in Alcaligenes eutrophus N9A.

    PubMed Central

    Siddiqui, R A; Schlegel, H G; Meyer, M

    1988-01-01

    The nickel and cobalt resistance plasmid pMOL28 was transferred by conjugation from its natural host Alcaligenes eutrophus CH34 to the susceptible A. eutrophus N9A. Strain N9A and its pMOL28-containing transconjugant M220 were studied in detail. At a concentration of 3.0 mM NiCl2, the wild-type N9A did not grow, while M220 started to grow at its maximum exponential growth rate after a lag of 12 to 24 h. When grown in the presence of subinhibitory concentrations (0.5 mM) of nickel salt, M220 grew actively at 3 mM NiCl2 without a lag, indicating that nickel resistance is an inducible property. Expression of nickel resistance required active growth in the presence of nickel salts at a concentration higher than 0.05 mM. Two mutants of M220 were isolated which expressed nickel resistance constitutively. When the plasmids, pMOL28.1 and pMOL28.2, carried by the mutants were transferred to strains H16 and CH34, the transconjugants expressed constitutive nickel resistance. This indicates that the mutation is plasmid located. Both mutants expressed constitutive resistance to nickel and cobalt. Physiological studies revealed the following differences between strain N9A and its pMOL28.1-harboring mutant derivatives. (i) The uptake of 63NiCl2 occurred more rapidly in the susceptible strain and reached a 30- to 60-fold-higher amount that in the pMOL28.1-harboring mutant; (ii) in intact cells of the susceptible strain N9A, the cytoplasmic hydrogenase was inhibited by 1 to 5 nM NiCl2, whereas 10 mM Ni2+ was needed to inhibit the hydrogenase of mutant cells; (iii) the minimal concentration of nickel chloride for the derepressed synthesis of cytoplasmic hydrogenase was lower in strain N9A (1 to 3 microM) than in the constitutive mutant (8 to 10 microM). PMID:3410828

  18. Speciation of [Cp*(2)M(2)O(5)] in polar and donor solvents.

    PubMed

    Sözen-Aktaş, Pelin; Del Rosal, Iker; Manoury, Eric; Demirhan, Funda; Lledós, Agustí; Poli, Rinaldo

    2013-03-18

    The speciation of compounds [Cp*2 M2 O5 ] (M=Mo, W; Cp*=pentamethylcyclopentadienyl) in different protic and aprotic polar solvents (methanol, dimethyl sulfoxide, acetone, acetonitrile), in the presence of variable amounts of water or acid/base, has been investigated by (1) H NMR spectrometry and electrical conductivity. Specific hypotheses suggested by the experimental results have been further probed by DFT calculations. The solvent (S)-assisted ionic dissociation to generate [Cp*MO2 (S)](+) and [Cp*MO3 ](-) takes place extensively for both metals only in water/methanol mixtures. Equilibrium amounts of the neutral hydroxido species [Cp*MO2 (OH)] are generated in the presence of water, with the relative amount increasing in the order MeCN≈acetoneM2 O5 ] into [Et3 NH](+) [Cp*MO3 ](-) , for which the presence of a NH⋅⋅⋅OM interaction is revealed by (1) H NMR spectroscopy in comparison with the sodium salts, Na(+) [Cp*MO3 ](-) . These are fully dissociated in DMSO and MeOH, but display a slow equilibrium between free ions and the ion pair in MeCN and acetone. Only one resonance is observed for mixtures of [Cp*MO3 ](-) and [Cp*MO2 (OH)] because of a rapid self-exchange. In the presence of extensive ionic dissociation, only one resonance is observed for mixtures of the cationic [Cp*MO2 (S)](+) product and the residual undissociated [Cp*2 M2 O5 ] because of a rapid associative exchange via the trinuclear [Cp*3 M3 O7 ](+) intermediate. In neat methanol, complex [Cp*2 W2 O5 ] reacts to yield extensive amounts of a new species, formulated as the mononuclear methoxido complex [Cp*WO2 (OMe)] on the basis of the DFT study. An equivalent product is not observed for the Mo system. The addition of increasing amounts of water results in the rapid decrease of this product in favor of [Cp*2 W2 O5 ] and [Cp*WO2 (OH)].

  19. Aft Body Closure: Predicted Strut Effects at M=2.4

    NASA Technical Reports Server (NTRS)

    Lamar, John E.; Garritz, Javier A.

    1999-01-01

    This paper reports the predicted M = 2.4 strut-interference effects on a closed aftbody with empennage for the TCA baseline model. The strut mounting technique was needed in order to assess the impact of aft-end shaping, i.e. open for a sting or closed to better represent a flight vehicle. However,this technique can potentially lead to unanticipated effects that are measured on the aft body. Therefore, a set of computations were performed in order to examine the closed aft body with and without strut present, at both zero and non-zero angles of sideslip (AOS). The work was divided into a computational task performed by Javier A. Garriz, using an inviscid (Euler) solver, and a monitoring/reporting task done by John E. Lamar. All this work was performed during FY98 at the NASA Langley Research Center.

  20. Magnetic anisotropy of S m2F e17 single crystals

    NASA Astrophysics Data System (ADS)

    Diop, L. V. B.; Kuz'min, M. D.; Skokov, K. P.; Karpenkov, D. Yu.; Gutfleisch, O.

    2016-10-01

    The previously accepted notion that the spontaneous magnetization of S m2F e17 lies in the basal plane of the crystal is true only approximately, and then only around room temperature. At low temperatures the magnetization, whose orientation is not fixed by the symmetry, is found to deviate from the basal plane by as much as 10∘. The threefold symmetry axis is a hard direction; to magnetize the crystal in this direction, a magnetic field of about 9 T is required. The hard-axis magnetization arrives at saturation discontinuously, by way of a first-order phase transition. The behavior is a general one for trigonal ferromagnets where K1<0 and the leading trigonal anisotropy constant is nonzero, K2'≠0 . Although of universal occurrence, the first-order transition is only visible at low temperatures, where it is accompanied by a magnetization anomaly of sufficient size.

  1. Development of the multi-mode external lighting system for aircraft (M2ESA)

    NASA Astrophysics Data System (ADS)

    Martin, John J.

    2005-08-01

    This paper documents the development of the Multi-Mode External Lighting System for Aircraft (M2ESA), a solid-state near-IR and visible light emitting diode-based programmable system designed to replace existing incandescent navigation lights on the exterior of military aircraft, and tailored for use with night vision goggles. Integrated systems of optics, electronics and mechanical structures were designed that were compatible with legacy aircraft systems, and which thus conformed to rigid configuration requirements and severe volume constraints. The genesis of the concept, evolution and general architecture of the system, top-level performance and environmental requirements, integration on the designated aircraft platform (the F-15), and general results of flight demonstration assessments are described.

  2. Primary structure of the human M2 mitochondrial autoantigen of primary biliary cirrhosis: Dihydrolipoamide acetyltransferase

    SciTech Connect

    Coppel, R.L.; McNeilage, L.J.; Surh, C.D.; Van De Water, J.; Spithill, T.W.; Whittingham, S.; Gershwin, M.E. )

    1988-10-01

    Primary biliary cirrhosis is a chronic, destructive autoimmune liver disease of humans. Patient sera are characterized by a high frequency of autoantibodies to a M{sub r} 70,000 mitochondrial antigen a component of the M2 antigen complex. The authors have identified a human cDNA clone encoding the complete amino acid sequence of this autoantigen. The predicted structure has significant similarity with the dihydrolipoamide acetyltransferase of the Escherichia coli pyruvate dehydrogenase multienzyme complex. The human sequence preserves the Glu-Thr-Asp-Lys-Ala motif of the lipoyl-binding site and has two potential binding sites. Expressed fragments of the cDNA react strongly with sera from patients with primary biliary cirrhosis but not with sera from patients with autoimmune chronic active hepatitis or sera from healthy subjects.

  3. M1/M2 Macrophage Polarity in Normal and Complicated Pregnancy

    PubMed Central

    Brown, Mary B.; von Chamier, Maria; Allam, Ayman B.; Reyes, Leticia

    2014-01-01

    Tissue macrophages play an important role in all stages of pregnancy, including uterine stromal remodeling (decidualization) before embryo implantation, parturition, and post-partum uterine involution. The activation state and function of utero-placental macrophages are largely dependent on the local tissue microenvironment. Thus, macrophages are involved in a variety of activities such as regulation of immune cell activities, placental cell invasion, angiogenesis, and tissue remodeling. Disruption of the uterine microenvironment, particularly during the early stages of pregnancy (decidualization, implantation, and placentation) can have profound effects on macrophage activity and subsequently impact pregnancy outcome. In this review, we will provide an overview of the temporal and spatial regulation of utero-placental macrophage activation during normal pregnancy in human beings and rodents with a focus on more recent findings. We will also discuss the role of M1/M2 dysregulation within the intrauterine environment during adverse pregnancy outcomes. PMID:25505471

  4. Gamma rays emitted in the decay of 31-year 178m2Hf

    SciTech Connect

    MB, S; PW, W; GC, B; JJ, C; PE, G; G, H; R, P; F, S; HC, S

    2003-10-15

    The spontaneous decay of the K{sup {pi}} = 16{sup +}, 31-year {sup 178m2}Hf isomer has been investigated with a 15 kBq source placed at the center of a 20-element {gamma}-ray spectrometer. High-multipolarity M4 and E5 transitions, which represent the first definitive observation of direct {gamma}-ray emission from the isomer, have been identified, together with other low-intensity transitions. Branching ratios for these other transitions have elucidated the spin dependence of the mixing between the two known K{sup {pi}} = 8{sup -} bands. The M4 and E5 {gamma}-ray decays are the first strongly K-forbidden transitions to be identified with such high multipolarities, and demonstrate a consistent extension of K-hindrance systematics, with an inhibition factor of approximately 100 per degree of K forbiddenness. Some unplaced transitions are also reported.

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

    NASA Technical Reports Server (NTRS)

    1963-01-01

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

  6. M2, S2, K1 models of the global ocean tide

    NASA Technical Reports Server (NTRS)

    Parke, M. E.; Hendershott, M. C.

    1979-01-01

    Ocean tidal signals appear in many geophysical measurements. Geophysicists need realistic tidal models to aid in interpretation of their data. Because of the closeness to resonance of dissipationless ocean tides, it is difficult for numerical models to correctly represent the actual open ocean tide. As an approximate solution to this problem, test functions derived by solving Laplace's Tidal Equations with ocean loading and self gravitation are used as a basis for least squares dynamic interpolation of coastal and island tidal data for the constituents M2, S2, and Kl. The resulting representations of the global tide are stable over at least a ?5% variation in the mean depth of the model basin, and they conserve mass. Maps of the geocentric tide, the induced free space potential, the induced vertical component of the solid earth tide, and the induced vertical component of the gravitational field for each contituent are presented.

  7. Spaceflight Effects on Hemopoiesis of Lower Vertebrates Flown on Foton-M2

    NASA Technical Reports Server (NTRS)

    Domaratskaya, E. I.; Payushina, O. V.; Butorina, M. N.; Nikonova, T. M.; Grigorian, E. N.; Mitashov, V. I.; Tairbekov, M. G.; Almeida, E.; Khrushchov, N. G.

    2006-01-01

    Intact and operated newts Pleumdeles waltl flown on Foton-M2 for 16 days were used to study the effects of spaceflight as well as tail amputation and lensectomy on their hemopoiesis. The flight did not produce noticeable changes in the peripheral blood of nonoperated newts. However, in operated animals, the number of lymphocytes increased whereas that of neutrophils decreased. There were no morphological differences in hemopoietic organs (liver and spleen) between flown non-operated and operated animals or their controls. However, in both non-operated and operated newts the liver weight and the number of hemopoietic cells in it increased. In contrast to nonoperated newts, space-flown mammals typically showed significant changes in blood cell counts. Experiments with BrdU incorporation revealed labeled cells in the hemopoietic area of the liver as well as in blood and spleen. This observation gives evidence that the BrdU label can be used to study proliferation of hemopoietic cells.

  8. 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.

  9. The Warburg Effect Mediator Pyruvate Kinase M2 Expression and Regulation in the Retina

    PubMed Central

    Rajala, Raju V. S.; Rajala, Ammaji; Kooker, Christopher; Wang, Yuhong; Anderson, Robert E.

    2016-01-01

    The tumor form of pyruvate kinase M2 (PKM2) undergoes tyrosine phosphorylation and gives rise to the Warburg effect. The Warburg effect defines a pro-oncogenic metabolism switch such that cancer cells take up more glucose than normal tissue and favor incomplete oxidation of glucose, even in the presence of oxygen. Retinal photoreceptors are highly metabolic and their energy consumption is equivalent to that of a multiplying tumor cell. In the present study, we found that PKM2 is the predominant isoform in both rod- and cone-dominant retina, and that it undergoes a light-dependent tyrosine phosphorylation. We also discovered that PKM2 phosphorylation is signaled through photobleaching of rhodopsin. Our findings suggest that phosphoinositide 3-kinase activation promotes PKM2 phosphorylation. Light and tyrosine phosphorylation appear to regulate PKM2 to provide a metabolic advantage to photoreceptor cells, thereby promoting cell survival. PMID:27883057

  10. Structure of the transmembrane region of the M2 protein H+ channel

    PubMed Central

    Wang, Junfeng; Kim, Sanguk; Kovacs, Frank; Cross, Timothy A.

    2001-01-01

    The transmembrane domain of the M2 protein from influenza A virus forms a nearly uniform and ideal helix in a liquid crystalline bilayer environment. The exposure of the hydrophilic backbone structure is minimized through uniform hydrogen bond geometry imposed by the low dielectric lipid environment. A high-resolution structure of the monomer backbone and a detailed description of its orientation with respect to the bilayer were achieved using orientational restraints from solid-state NMR. With this unique information, the tetrameric structure of this H+ channel is constrained substantially. Features of numerous published models are discussed in light of the experimental structure of the monomer and derived features of the tetrameric bundle. PMID:11604531

  11. 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.

  12. A shock tube study of OH + H(2)O(2) --> H(2)O + HO(2) and H(2)O(2) + M --> 2OH + M using laser absorption of H(2)O and OH.

    PubMed

    Hong, Zekai; Cook, Robert D; Davidson, David F; Hanson, Ronald K

    2010-05-13

    The rate constants of the reactions: (1) H2O2+M-->2OH+M, (2) OH+H2O2-->H2O+HO2 were measured in shock-heated H(2)O(2)/Ar mixtures using laser absorption diagnostics for H(2)O and OH. Time-histories of H(2)O were monitored using tunable diode laser absorption at 2550.96 nm, and time-histories of OH were achieved using ring dye laser absorption at 306 nm. Initial H(2)O(2) concentrations were also determined utilizing the H(2)O diagnostic. On the basis of simultaneous time-history measurements of OH and H(2)O, k(2) was found to be 4.6 x 10(13) exp(-2630 K/T) [cm(3) mol(-1) s(-1)] over the temperature range 1020-1460 K at 1.8 atm; additional measurements of k(2) near 1 atm showed no significant pressure dependence. Similarly, k(1) was found to be 9.5 x 10(15) exp(-21 250 K/T) [cm(3) mol(-1) s(-1)] over the same temperature and pressure range.

  13. xPyder: a PyMOL plugin to analyze coupled residues and their networks in protein structures.

    PubMed

    Pasi, Marco; Tiberti, Matteo; Arrigoni, Alberto; Papaleo, Elena

    2012-07-23

    A versatile method to directly identify and analyze short- or long-range coupled or communicating residues in a protein conformational ensemble is of extreme relevance to achieve a complete understanding of protein dynamics and structural communication routes. Here, we present xPyder, an interface between one of the most employed molecular graphics systems, PyMOL, and the analysis of dynamical cross-correlation matrices (DCCM). The approach can also be extended, in principle, to matrices including other indexes of communication propensity or intensity between protein residues, as well as the persistence of intra- or intermolecular interactions, such as those underlying protein dynamics. The xPyder plugin for PyMOL 1.4 and 1.5 is offered as Open Source software via the GPL v2 license, and it can be found, along with the installation package, the user guide, and examples, at http://linux.btbs.unimib.it/xpyder/.

  14. Microstructure and mechanical properties of hot isostatically pressed zirconia (2 mol% yttria)-reinforced tungsten disilicide composites

    SciTech Connect

    Yamaguchi, Kotaro; Yoshinaka, Masaru; Hirota, Ken; Yamaguchi, Osamu

    1995-08-01

    Dense sintered composites of ZrO{sub 2} (2 mol% Y{sub 2}O{sub 3}) and WSi{sub 2} have been fabricated by hot isostatic pressing for 2 h at 1500 C under 196 MPa. They contain a small amount of W{sub 5}Si{sub 3}; during sintering, WSi{sub 2} decomposes into W{sub 5}Si{sub 3} and amorphous Si. The ZrO{sub 2} Particles in the composites consists of only t-ZrO{sub 2}. Microstructures and mechanical properties are examined, in connection with ZrO{sub 2} content. The fracture toughness and bending strength of the composite with 40 mol% ZrO{sub 2} addition are 7.1 MPa{center_dot}m{sup 1/2} and 1,011 MPa, respectively.

  15. M2Di: Concise and efficient MATLAB 2-D Stokes solvers using the Finite Difference Method

    NASA Astrophysics Data System (ADS)

    Räss, Ludovic; Duretz, Thibault; Podladchikov, Yury Y.; Schmalholz, Stefan M.

    2017-02-01

    Recent development of many multiphysics modeling tools reflects the currently growing interest for studying coupled processes in Earth Sciences. The core of such tools should rely on fast and robust mechanical solvers. Here we provide M2Di, a set of routines for 2-D linear and power law incompressible viscous flow based on Finite Difference discretizations. The 2-D codes are written in a concise vectorized MATLAB fashion and can achieve a time to solution of 22 s for linear viscous flow on 10002 grid points using a standard personal computer. We provide application examples spanning from finely resolved crystal-melt dynamics, deformation of heterogeneous power law viscous fluids to instantaneous models of mantle flow in cylindrical coordinates. The routines are validated against analytical solution for linear viscous flow with highly variable viscosity and compared against analytical and numerical solutions of power law viscous folding and necking. In the power law case, both Picard and Newton iterations schemes are implemented. For linear Stokes flow and Picard linearization, the discretization results in symmetric positive-definite matrix operators on Cartesian grids with either regular or variable grid spacing allowing for an optimized solving procedure. For Newton linearization, the matrix operator is no longer symmetric and an adequate solving procedure is provided. The reported performance of linear and power law Stokes flow is finally analyzed in terms of wall time. All MATLAB codes are provided and can readily be used for educational as well as research purposes. The M2Di routines are available from Bitbucket and the University of Lausanne Scientific Computing Group website, and are also supplementary material to this article.

  16. A disc inside the bipolar planetary nebula M2-9

    NASA Astrophysics Data System (ADS)

    Lykou, F.; Chesneau, O.; Zijlstra, A. A.; Castro-Carrizo, A.; Lagadec, E.; Balick, B.; Smith, N.

    2011-03-01

    Aims: Bipolarity in proto-planetary and planetary nebulae is associated with events occurring in or around their cores. Past infrared observations have revealed the presence of dusty structures around the cores, many in the form of discs. Characterising those dusty discs provides invaluable constraints on the physical processes that govern the final mass expulsion of intermediate mass stars. We focus this study on the famous M2-9 bipolar nebula, where the moving lighthouse beam pattern indicates the presence of a wide binary. The compact and dense dusty core in the centre of the nebula can be studied by means of optical interferometry. Methods: M2-9 was observed with VLTI/MIDI at 39-47 m baselines with the UT2-UT3 and UT3-UT4 baseline configurations. These observations are interpreted using a dust radiative transfer Monte Carlo code. Results: A disc-like structure is detected perpendicular to the lobes, and a good fit is found with a stratified disc model composed of amorphous silicates. The disc is compact, 25 × 35 mas at 8 μm and 37 × 46 mas at 13 μm. For the adopted distance of 1.2 kpc, the inner rim of the disc is ~15 AU. The mass represents a few percent of the mass found in the lobes. The compactness of the disc puts strong constraints on the binary content of the system, given an estimated orbital period 90-120 yr. We derive masses of the binary components between 0.6-1.0 M⊙ for a white dwarf and 0.6-1.4 M⊙ for an evolved star. We present different scenarios on the geometric structure of the disc accounting for the interactions of the binary system, which includes an accretion disc as well. Based on observations collected at the European Organisation for Astronomical Research in the Southern Hemisphere, Chile, ESO N: 079.D-146.

  17. Microwave & Magnetic (M2) Proteomics of a Mouse Model of Mild Traumatic Brain Injury

    PubMed Central

    Evans, Teresa M.; Van Remmen, Holly; Purkar, Anjali; Mahesula, Swetha; Gelfond, J AL; Sabia, Marian; Qi, Wenbo; Lin, Ai-Ling; Jaramillo, Carlos A.; Haskins, William E.

    2014-01-01

    Short-term increases in oxidative stress and decreases in motor function, including debilitating effects on balance and motor control, can occur following primary mild traumatic brain injuries (mTBI). However, the long-term effects on motor unit impairment and integrity as well as the molecular mechanisms underlying secondary injuries are poorly understood. We hypothesized that changes in central nervous system-specific protein (CSP) expression might correlate to these long-term effects. To test our hypothesis, we longitudinally assessed a closed-skull mTBI mouse model, vs. sham control, at 1, 7, 30, and 120 days post-injury. Motor impairment was determined by rotarod and grip strength performance measures, while motor unit integrity was determined using electromyography. Relative protein expression was determined by microwave & magnetic (M2) proteomics of ipsilateral brain tissue, as previously described. Isoprostane measurements were performed to confirm a primary oxidative stress response. Decoding the relative expression of 476 ± 56 top-ranked proteins for each specimen revealed statistically significant changes in the expression of two well-known CSPs at 1, 7 and 30 days post-injury: P < 0.001 for myelin basic protein (MBP) and P < 0.05 for myelin associated glycoprotein (MAG). This was confirmed by Western blot. Moreover, MAG, αII-spectrin (SPNA2) and neurofilament light (NEFL) expression at 30 days post-injury were directly related to grip strength (P < 0.05). While higher-powered studies of larger cohorts merit further investigation, this study supports the proof-of-concept that M2 proteomics is a rapid method to quantify putative protein biomarkers and therapeutic targets of mTBI and suggests the feasibility of CSP expression correlations to long-term effects on motor impairment. PMID:26157646

  18. Schistosomal-derived lysophosphatidylcholine triggers M2 polarization of macrophages through PPARγ dependent mechanisms.

    PubMed

    Assunção, Leonardo Santos; Magalhães, Kelly G; Carneiro, Alan Brito; Molinaro, Raphael; Almeida, Patrícia E; Atella, Georgia C; Castro-Faria-Neto, Hugo C; Bozza, Patrícia T

    2017-02-01

    Mansonic schistosomiasis is a disease caused by the trematode Schistosoma mansoni, endemic to tropical countries. S. mansoni infection induces the formation of granulomas and potent polarization of Th2-type immune response. There is great interest in understanding the mechanisms used by this parasite that causes a modulation of the immune system. Recent studies from our group demonstrated that lipids of S. mansoni, including lysophosphatidylcholine (LPC) have immunomodulatory activity. In the present study, our aim was to investigate the role of lipids derived from S. mansoni in the activation and polarization of macrophages and to characterize the mechanisms involved in this process. Peritoneal macrophages obtained from wild type C57BL/6mice or bone marrow derived macrophages were stimulated in vitro with lipids extracted from adult worms of S. mansoni. We demonstrated that total schistosomal-derived lipids as well as purified LPC induced alternatively activated macrophages/M2 profile observed by increased expression of arginase-1, mannose receptor, Chi3l3, TGFβ and production of IL-10 and PGE2 24h after stimulation. The involvement of the nuclear receptor PPARγ in macrophage response against LPC was investigated. Through Western blot and immunofluorescence confocal microscopy we demonstrated that schistosomal-derived LPC induces increased expression of PPARγ in macrophages. The LPC-induced increased expression of arginase-1 were significantly inhibited by the PPAR-γ antagonist GW9662. Together, these results demonstrate an immunomodulatory role of schistosomal-derived LPC in activating macrophages to a profile of the type M2 through PPARγ-dependent mechanisms, indicating a novel pathway for macrophage polarization triggered by parasite-derived LPC with potential implications to disease pathogenesis.

  19. Mass-Analyzed Threshold Ionization of M_2O_2 ( M = ce and Pr)

    NASA Astrophysics Data System (ADS)

    Wu, Lu; Dangi, Beni; Rounjane, Mourad; Yang, Dong-Sheng

    2012-06-01

    M_2O_2 ( M = Ce and Pr) is produced in a pulsed laser-vaporization metal-cluster source and studied by mass-analyzed threshold ionization (MATI) spectroscopy. From the MATI spectra, the adiabatic ionization energy is determined to be 37300(5) cm-1 for Ce2O2, and 37885 (5) cm-1 for Pr2O2. Like group 3 transition metal M2O2 (M=Sc, Y, and La) clusters we reported previously, these lanthanide clusters have a D2h planer structure and the vibrational modes observed are from the in-plane motions. However, the ground and other low-energy electronic states of the lanthanide oxides have a much higher electron spin multiplicity due to the existence of 4f electrons in the Ce and Pr atoms. The 4f electron of Ce atom has significantly lower energies than the 5d or 6s electrons and remain uncoupled in Ce2O2. On the other hand, the energy differences between the 4f and 5d/6s electrons of Pr atom are relatively small, and a 4f → 5d electron promotion is required in the formation of Pr2O2. The electronic transitions responsible for the observed MATI spectra are tentatively determined to be ^4B1u ← ^5Ag for Ce2O2 and ^6B1u ← ^7B2g and ^6B1u ← ^5B1u for Pr2O2.

  20. Influenza virus M2 targets cystic fibrosis transmembrane conductance regulator for lysosomal degradation during viral infection

    PubMed Central

    Londino, James David; Lazrak, Ahmed; Noah, James W.; Aggarwal, Saurabh; Bali, Vedrana; Woodworth, Bradford A.; Bebok, Zsuzsanna; Matalon, Sadis

    2015-01-01

    We sought to determine the mechanisms by which influenza infection of human epithelial cells decreases cystic fibrosis transmembrane conductance regulator (CFTR) expression and function. We infected human bronchial epithelial (NHBE) cells and murine nasal epithelial (MNE) cells with various strains of influenza A virus. Influenza infection significantly reduced CFTR short circuit currents (Isc) and protein levels at 8 hours postinfection. We then infected CFTR expressing human embryonic kidney (HEK)-293 cells (HEK-293 CFTRwt) with influenza virus encoding a green fluorescent protein (GFP) tag and performed whole-cell and cell-attached patch clamp recordings. Forskolin-stimulated, GlyH-101-sensitive CFTR conductances, and CFTR open probabilities were reduced by 80% in GFP-positive cells; Western blots also showed significant reduction in total and plasma membrane CFTR levels. Knockdown of the influenza matrix protein 2 (M2) with siRNA, or inhibition of its activity by amantadine, prevented the decrease in CFTR expression and function. Lysosome inhibition (bafilomycin-A1), but not proteasome inhibition (lactacystin), prevented the reduction in CFTR levels. Western blots of immunoprecipitated CFTR from influenza-infected cells, treated with BafA1, and probed with antibodies against lysine 63-linked (K-63) or lysine 48-linked (K-48) polyubiquitin chains supported lysosomal targeting. These results highlight CFTR damage, leading to early degradation as an important contributing factor to influenza infection-associated ion transport defects.—Londino, J. D., Lazrak, A., Noah, J. W., Aggarwal, S., Bali, V., Woodworth, B. A., Bebok, Z., Matalon, S. Influenza virus M2 targets cystic fibrosis transmembrane conductance regulator for lysosomal degradation during viral infection. PMID:25795456

  1. nuMoM2b Sleep Disordered Breathing Study: Objectives and Methods

    PubMed Central

    Facco, Francesca L.; Parker, Corette B.; Reddy, Uma M.; Silver, Robert M.; Louis, Judette M.; Basner, Robert C.; Chung, Judith H.; Schubert, Frank P.; Pien, Grace W.; Redline, Susan; Mobley, Daniel; Koch, Matthew A.; Simhan, Hyagriv N.; Chia-Ling, Nhan-Chang; Parry, Samuel; Grobman, William A.; Haas, David M.; Wing, Deborah A.; Mercer, Brian M.; Saade, George R.; Zee, Phyllis C.

    2015-01-01

    Objective The objective of the Sleep Disordered Breathing substudy of the Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be (nuMoM2b) is to determine whether sleep disordered breathing during pregnancy is a risk factor for adverse pregnancy outcomes. Methods nuMoM2b is a prospective cohort study of 10,037 nulliparous women with singleton gestations, conducted across 8 sites, with a central Data Coordinating and Analysis Center. The Sleep Disordered Breathing substudy recruited 3702 women from the cohort to undergo objective, overnight in-home assessments of sleep disordered breathing. A standardized Level 3 home sleep test was performed between 60–150 weeks of pregnancy (Visit 1) and again between 220–310 weeks of pregnancy (Visit 3). Scorings of tests were conducted by a central Sleep Reading Center. Participants and their health care providers were notified if test results met “urgent referral” criteria based on threshold levels of apnea hypopnea indices, oxygen saturation levels or ECG abnormalities, but otherwise were not notified of test results. The primary pregnancy outcomes to be analyzed in relation to maternal sleep disordered breathing are preeclampsia, gestational hypertension, gestational diabetes, fetal growth restriction, and preterm birth. Results Objective data were obtained at Visit 1 on 3261 women, 88.1% of studies attempted; and at Visit 3 on 2511 women, 87.6% of studies attempted. Basic characteristics of the substudy cohort are reported in this methods paper. Conclusion The substudy is designed to address important questions regarding the relationship of sleep disordered breathing on the risk of preeclampsia and other outcomes of relevance to maternal and child health. PMID:25746730

  2. Plasma control of shock wave configuration in off-design mode of M = 2 inlet

    NASA Astrophysics Data System (ADS)

    Falempin, Francois; Firsov, Alexander A.; Yarantsev, Dmitry A.; Goldfeld, Marat A.; Timofeev, Konstantin; Leonov, Sergey B.

    2015-03-01

    The objective of this work was to study the steering effect of a weakly ionized plasma on a supersonic flow structure in a two-dimensional aerodynamic configuration with a three-shock compression ramp in an off-design operational mode. Experiments were performed in wind tunnel T-313 of ITAM SB RAS, with the model air inlet designed for operation at a flow of Mach number M = 2. The inlet was tested at M = 2, 2.5, and 3 and with Re = (25-36) × 106/m and an angle of attack AoA = 0°, 5°, and 8°. For the regulation of the inlet characteristics, a plasma generator with electrical power W pl = 2-10 kW was flush-mounted upstream of the compression ramp. A significant plasma effect on the shock configuration at the inlet and on the flow parameters after air compression is considered. It is shown that the main shock wave angle is controllable by means of the plasma power magnitude and, therefore, can be accurately adjusted to the cowl lip of an inlet with a fixed geometry. An additional plasma effect has been demonstrated through a notable increase in the pressure recovery coefficient in a flowpass extension behind the inlet because of an nearly isentropic pattern of flow compression with the plasma turned on. Numerical simulation brings out the details of 3D distribution of the flow structure and parameters throughout the model at thermal energy deposition in inlet near the compression surfaces. We conclude that the plasma-based technique may be a feasible method for expanding supersonic inlet operational limits.

  3. Cardiac M2 muscarinic cholinoceptor activation by human chagasic autoantibodies: association with bradycardia

    PubMed Central

    Goin, J; Borda, E; Auger, S; Storino, R; Sterin-Borda, L

    1999-01-01

    OBJECTIVE—To assess whether exposure of cardiac muscarinic acetylcholine receptors (mAChR) to activating chagasic antimyocardial immunoglobulins results in bradycardia and other dysautonomic symptoms associated with the regulation of heart rate.
METHODS—Trypanosoma cruzi infected patients with bradycardia and other abnormalities in tests of the autonomic nervous system were studied and compared with normal subjects. Antipeptide antibodies in serum were demonstrated by an enzyme linked immunosorbent assay using a synthetic 24-mer-peptide corresponding antigenically to the second extracellular loop of the human heart M2 mAChR. The functional effect of affinity purified antipeptide IgG from chagasic patients on spontaneous beating frequency and cAMP production of isolated normal rat atria was studied.
RESULTS—There was a strong association between the finding of antipeptide antibodies in chagasic patients and the presence of basal bradycardia and an altered Valsalva manoeuvre (basal bradycardia: χ2 = 37.5, p < 0.00001; Valsalva manoeuvre: χ2 = 70.0, p < 0.00001). The antipeptide autoantibodies also showed agonist activity, decreasing the rate of contraction and cAMP production. The effects on rat atria resembled the effects of the authentic agonist and those of the total polyclonal chagasic IgG, being selectively blunted by atropine and AF-DX 116, and neutralised by the synthetic peptide corresponding in amino acid sequence to the second extracellular loop of the human M2 mAChR.
CONCLUSIONS—There is an association between circulating antipeptide autoantibodies in chagasic patients and the presence of bradycardia and other dysautonomic symptoms. Thus these autoantibodies are a marker of autoimmune cardiac autonomic dysfunction. The results support the hypothesis that autoimmune mechanisms play a role in the pathogenesis of chagasic cardioneuromyopathy.


Keywords: heart rate; bradycardia; autoantibodies; chagasic cardiomyopathy PMID

  4. Coupling of G Proteins to Reconstituted Monomers and Tetramers of the M2 Muscarinic Receptor*

    PubMed Central

    Redka, Dar'ya S.; Morizumi, Takefumi; Elmslie, Gwendolynne; Paranthaman, Pranavan; Shivnaraine, Rabindra V.; Ellis, John; Ernst, Oliver P.; Wells, James W.

    2014-01-01

    G protein-coupled receptors can be reconstituted as monomers in nanodiscs and as tetramers in liposomes. When reconstituted with G proteins, both forms enable an allosteric interaction between agonists and guanylyl nucleotides. Both forms, therefore, are candidates for the complex that controls signaling at the level of the receptor. To identify the biologically relevant form, reconstituted monomers and tetramers of the purified M2 muscarinic receptor were compared with muscarinic receptors in sarcolemmal membranes for the effect of guanosine 5′-[β,γ-imido]triphosphate (GMP-PNP) on the inhibition of N-[3H]methylscopolamine by the agonist oxotremorine-M. With monomers, a stepwise increase in the concentration of GMP-PNP effected a lateral, rightward shift in the semilogarithmic binding profile (i.e. a progressive decrease in the apparent affinity of oxotremorine-M). With tetramers and receptors in sarcolemmal membranes, GMP-PNP effected a vertical, upward shift (i.e. an apparent redistribution of sites from a state of high affinity to one of low affinity with no change in affinity per se). The data were analyzed in terms of a mechanistic scheme based on a ligand-regulated equilibrium between uncoupled and G protein-coupled receptors (the “ternary complex model”). The model predicts a rightward shift in the presence of GMP-PNP and could not account for the effects at tetramers in vesicles or receptors in sarcolemmal membranes. Monomers present a special case of the model in which agonists and guanylyl nucleotides interact within a complex that is both constitutive and stable. The results favor oligomers of the M2 receptor over monomers as the biologically relevant state for coupling to G proteins. PMID:25023280

  5. Antibodies against MAEBL Ligand Domains M1 and M2 Inhibit Sporozoite Development In Vitro

    PubMed Central

    Preiser, Peter; Rénia, Laurent; Singh, Naresh; Balu, Bharath; Jarra, William; Voza, Tatiana; Kaneko, Osamu; Blair, Peter; Torii, Motomi; Landau, Irène; Adams, John H.

    2004-01-01

    MAEBL is a type 1 membrane protein that is implicated in the merozoite invasion of erythrocytes and sporozoite invasion of mosquito salivary glands. This apical organelle protein is structurally similar to the ebl erythrocyte binding proteins, such as EBA-175, except that the tandem ligand domains of MAEBL are similar to part of the extracellular domain of apical membrane antigen 1 and not the Duffy binding-like domain. Although midgut and salivary gland sporozoites are morphologically similar, salivary gland sporozoites undergo a period of new gene expression after infecting the salivary glands, display distinct phenotypic differences, and are more infectious for the mammalian host. The objectives of this project were to determine the molecular form of MAEBL in the infectious salivary gland sporozoites and whether the ligand has a role in the sporozoite development to exoerythrocytic stages in hepatocytes. We determined that MAEBL is newly expressed in salivary gland sporozoites and in a form distinct from what is present in the midgut sporozoites or present in erythrocytic stages. Both ligand domains (M1 and M2) were expressed as part of a full-length membrane form of MAEBL in the salivary gland sporozoites in contrast to the other stages that retain only the M2 ligand domain as part of the membrane form of the protein. Antisera developed against the cysteine-rich regions of the extracellular portion of MAEBL inhibited sporozoite development to exoerythrocytic forms in vitro. Together these data indicate that MAEBL has a role in this third developmental stage in the life cycle of the malaria parasite. Thus, MAEBL is another target for pre-erythrocytic-stage vaccine development against malaria parasites. PMID:15155670

  6. PyMod: sequence similarity searches, multiple sequence-structure alignments, and homology modeling within PyMOL

    PubMed Central

    2012-01-01

    Background In recent years, an exponential growing number of tools for protein sequence analysis, editing and modeling tasks have been put at the disposal of the scientific community. Despite the vast majority of these tools have been released as open source software, their deep learning curves often discourages even the most experienced users. Results A simple and intuitive interface, PyMod, between the popular molecular graphics system PyMOL and several other tools (i.e., [PSI-]BLAST, ClustalW, MUSCLE, CEalign and MODELLER) has been developed, to show how the integration of the individual steps required for homology modeling and sequence/structure analysis within the PyMOL framework can hugely simplify these tasks. Sequence similarity searches, multiple sequence and structural alignments generation and editing, and even the possibility to merge sequence and structure alignments have been implemented in PyMod, with the aim of creating a simple, yet powerful tool for sequence and structure analysis and building of homology models. Conclusions PyMod represents a new tool for the analysis and the manipulation of protein sequences and structures. The ease of use, integration with many sequence retrieving and alignment tools and PyMOL, one of the most used molecular visualization system, are the key features of this tool. Source code, installation instructions, video tutorials and a user's guide are freely available at the URL http://schubert.bio.uniroma1.it/pymod/index.html PMID:22536966

  7. Preparation of TiO2 Nanocrystallite Powders Coated with 9 mol% ZnO for Cosmetic Applications in Sunscreens

    PubMed Central

    Ko, Horng-Huey; Chen, Hui-Ting; Yen, Feng-Ling; Lu, Wan-Chen; Kuo, Chih-Wei; Wang, Moo-Chin

    2012-01-01

    The preparation of TiO2 nanocrystallite powders coated with and without 9 mol% ZnO has been studied for cosmetic applications in sunscreens by a co-precipitation process using TiCl4 and Zn(NO3)2·6H2O as starting materials. XRD results show that the phases of anatase TiO2 and rutile TiO2 coexist for precursor powders without added ZnO (T-0Z) and calcined at 523 to 973 K for 2 h. When the T-0Z precursor powders are calcined at 1273 K for 2 h, only the rutile TiO2 appears. In addition, when the TiO2 precursor powders contain 9 mol% ZnO (T-9Z) are calcined at 873 to 973 K for 2 h, the crystallized samples are composed of the major phase of rutile TiO2 and the minor phases of anatase TiO2 and Zn2Ti3O8. The analyses of UV/VIS/NIR spectra reveal that the absorption of the T-9Z precursor powders after being calcined has a red-shift effect in the UV range with increasing calcination temperature. Therefore, the TiO2 nanocrystallite powders coated with 9 mol% ZnO can be used as the attenuate agent in the UV-A region for cosmetic applications in sunscreens. PMID:22408415

  8. Observational data and orbits of the asteroids discovered at the Molėtai Observatory in 2005-2007

    NASA Astrophysics Data System (ADS)

    Černis, K.; Wlodarczyk, I.; Zdanavičius, J.

    The paper presents statistics of the asteroids observed and discovered at the Molėtai Observatory, Lithuania, in 2005-2007 within the project for astrometric observations of the near-Earth objects (NEOs), the main belt asteroids and comets. CCD observations of asteroids were obtained with the 35/51 cm Maksutov-type meniscus telescope and the 1.65 m Ritchey-Chretien reflector. In the Minor Planet Circulars and the Minor Planet Electronic Circulars (2005-2007) we published 17 003 astrometric positions of 2980 asteroids. Among them 112 were new normal asteroids and one NEO (2006 SF77) discovered at Molėtai; a few NEOs were found by our team independently. For the asteroids discovered at Molėtai their precise orbits were calculated. Because of short observational arc, a few asteroids have low-precision orbits and some asteroids have been lost. For three of them with low-precision orbital elements (NEO 2006 SF77 and two Mars crossers - 2006 SN368 and 2007 VM315), we present their ephemerides for 2016-2018.

  9. Preparation of TiO₂ nanocrystallite powders coated with 9 mol% ZnO for cosmetic applications in sunscreens.

    PubMed

    Ko, Horng-Huey; Chen, Hui-Ting; Yen, Feng-Ling; Lu, Wan-Chen; Kuo, Chih-Wei; Wang, Moo-Chin

    2012-01-01

    The preparation of TiO(2) nanocrystallite powders coated with and without 9 mol% ZnO has been studied for cosmetic applications in sunscreens by a co-precipitation process using TiCl(4) and Zn(NO(3))(2)·6H(2)O as starting materials. XRD results show that the phases of anatase TiO(2) and rutile TiO(2) coexist for precursor powders without added ZnO (T-0Z) and calcined at 523 to 973 K for 2 h. When the T-0Z precursor powders are calcined at 1273 K for 2 h, only the rutile TiO(2) appears. In addition, when the TiO(2) precursor powders contain 9 mol% ZnO (T-9Z) are calcined at 873 to 973 K for 2 h, the crystallized samples are composed of the major phase of rutile TiO(2) and the minor phases of anatase TiO(2) and Zn(2)Ti(3)O(8). The analyses of UV/VIS/NIR spectra reveal that the absorption of the T-9Z precursor powders after being calcined has a red-shift effect in the UV range with increasing calcination temperature. Therefore, the TiO(2) nanocrystallite powders coated with 9 mol% ZnO can be used as the attenuate agent in the UV-A region for cosmetic applications in sunscreens.

  10. Efectos de la irradiación iónica en hielos de moléculas carbonadas

    NASA Astrophysics Data System (ADS)

    Satorre, M. A.

    En Astrofísica podemos encontrar numerosos contextos en los cuales se observan moléculas en estado sólido que, en condiciones estándar de presión y temperatura, se encontrarían como gases o líquidos. Dichas moléculas se denominan hielos y han sido observadas en nubes densas del medio interestelar, en envolturas circumestelares, en satélites del Sistema Solar, en cometas, etc. Los hielos pueden ser alterados en su composición química debido a diversos factores como por ejemplo variaciones de temperatura o aportes energéticos por parte de la irradiación, ya sea tanto de fotones ultravioleta como de iones. Dependiendo del escenario astrofísico que analicemos, unos factores cobran más importancia que otros. Los experimentos de laboratorio muestran el efecto que produce sobre la composición de los hielos la irradiación iónica, en particular sobre los que contenían alguna molécula con átomos de carbono. Dicha composición se analiza con espectroscopía IR en el rango de 2 a ˜ 25μ m. La aplicabilidad de los resultados de los experimentos es distinta dependiendo de la composición química inicial de los hielos, del tipo de ion utilizado y de la dosis total de irradiación. Existen efectos generales de la irradiación sobre la materia en los experimentos de relevancia astrofísica como son: - la formación de nuevas moléculas, que pueden incluir o no el ion incidente; - la progresiva pérdida de hidrógeno (carbonización) cuando irradiamos muestras que originalmente contienen una determinada relación carbono/hidrógeno; - la variación de la temperatura de sublimación que presentan algunos hielos. Esto puede suceder tanto en hielos que estaban presentes antes de la irradiación como en hielos formados por ésta. Se presentará el papel del ion en la formación de nuevas moléculas a partir de las que originalmente se encontraban en el hielo. Al penetrar en él, el ion provoca distintos procesos como rotura de enlaces y excitaciones electr

  11. M2 occlusions as targets for endovascular therapy: comprehensive analysis of diffusion/perfusion MRI, angiography, and clinical outcomes

    PubMed Central

    Sheth, Sunil A; Yoo, Bryan; Saver, Jeffrey L; Starkman, Sidney; Ali, Latisha K; Kim, Doojin; Gonzalez, Nestor R; Jahan, Reza; Tateshima, Satoshi; Duckwiler, Gary; Vinuela, Fernando; Liebeskind, David S

    2014-01-01

    Background The ideal population of patients for endovascular therapy (ET) in acute ischemic stroke remains undefined. Recent ET trials have moved towards selecting patients with proximal middle cerebral artery (MCA) or internal carotid artery occlusions, which will likely leave a gap in our understanding of the treatment outcomes of M2 occlusions. Objective and methods To examine the presentation, treatment, and outcomes of M2 compared with M1 MCA occlusions in patients undergoing ET by assessing comprehensive MRI, angiography, and clinical data. Results We found that M2 occlusions can lead to massive strokes defined by hypoperfused and infarcted volumes as well as death or moderate to severe disability in nearly 50% of patients at discharge. Compared with M1 occlusions, M2 occlusions achieved similar Thrombolysis in Cerebral Infarction (TICI) 2b/3 recanalization rates, with significantly less hemorrhage. M2 occlusions presented with smaller infarct and hypoperfused volumes and had smaller final infarct volumes regardless of recanalization. TICI 2b/3 recanalization of M2 occlusions was associated with smaller infarct volumes compared with TICI 0–2a recanalization, as well as less infarct expansion, in patients who received IV tissue plasminogen activator as well as those that did not. Successful reperfusion of M2 occlusions was associated with improved discharge modified Rankin scale. Conclusions If suitable as targets of ET, M2 occlusions should be given the same consideration as M1 occlusions. PMID:24821842

  12. Human eosinophil major basic protein is an endogenous allosteric antagonist at the inhibitory muscarinic M2 receptor.

    PubMed Central

    Jacoby, D B; Gleich, G J; Fryer, A D

    1993-01-01

    The effect of human eosinophil major basic protein (MBP) as well as other eosinophil proteins, on binding of [3H]N-methyl-scopolamine ([3H]NMS: 1 x 10(-10) M) to muscarinic M2 receptors in heart membranes and M3 receptors in submandibular gland membranes was studied. MBP inhibited specific binding of [3H]NMS to M2 receptors but not to M3 receptors. MBP also inhibited atropine-induced dissociation of [3H]NMS-receptor complexes in a dose-dependent fashion, demonstrating that the interaction of MBP with the M2 muscarinic receptor is allosteric. This effect of MBP suggests that it may function as an endogenous allosteric inhibitor of agonist binding to the M2 muscarinic receptor. Inhibition of [3H]NMS binding by MBP was reversible by treatment with heparin, which binds and neutralizes MBP. Eosinophil peroxidase (EPO) also inhibited specific binding of [3H]NMS to M2 receptors but not to M3 receptors and inhibited atropine-induced dissociation of [3H]NMS-receptor complexes. On a molar basis, EPO is less potent than MBP. Neither eosinophil cationic protein nor eosinophil-derived neurotoxin affected binding of [3H]NMS to M2 receptors. Thus both MBP and EPO are selective allosteric antagonists at M2 receptors. The effects of these proteins may be important causes of M2 receptor dysfunction and enhanced vagally mediated bronchoconstriction in asthma. Images PMID:8473484

  13. Molecular dynamics simulation of the M2 helices within the nicotinic acetylcholine receptor transmembrane domain: structure and collective motions.

    PubMed

    Hung, Andrew; Tai, Kaihsu; Sansom, Mark S P

    2005-05-01

    Multiple nanosecond duration molecular dynamics simulations were performed on the transmembrane region of the Torpedo nicotinic acetylcholine receptor embedded within a bilayer mimetic octane slab. The M2 helices and M2-M3 loop regions were free to move, whereas the outer (M1, M3, M4) helix bundle was backbone restrained. The M2 helices largely retain their hydrogen-bonding pattern throughout the simulation, with some distortions in the helical end and loop regions. All of the M2 helices exhibit bending motions, with the hinge point in the vicinity of the central hydrophobic gate region (corresponding to residues alphaL251 and alphaV255). The bending motions of the M2 helices lead to a degree of dynamic narrowing of the pore in the region of the proposed hydrophobic gate. Calculations of Born energy profiles for various structures along the simulation trajectory suggest that the conformations of the M2 bundle sampled correspond to a closed conformation of the channel. Principal components analyses of each of the M2 helices, and of the five-helix M2 bundle, reveal concerted motions that may be relevant to channel function. Normal mode analyses using the anisotropic network model reveal collective motions similar to those identified by principal components analyses.

  14. Precipitation Kinetics of M2C Carbide in Severely Ausformed 13Co-8Ni Secondary Hardening Steels

    NASA Astrophysics Data System (ADS)

    Cho, Ki Sub; Park, Sung Soo; Kim, Hong Kyu; Song, Young Beum; Kwon, Hoon

    2015-04-01

    With continuous heating calorimetric data as a basis, the kinetics of M2C formation during isothermal aging was modeled in severely ausformed 13Co-8Ni steels using the Johnson-Mehl-Avrami theory coupled with a variation of effective activation energy with respect to the degree of transformation. These results were compared with small-angle neutron scattering measurements and discussed in terms of variations in the thermodynamic and kinetic behavior of M2C precipitation. In particular, the M2C carbides in the deformed samples contained more Fe content compared with the non-deformed samples. As this can be ascribed to the ausforming effect increasing the driving force for M2C nucleation, it consequently leads to the decrease of the growth/coarsening rate for M2C carbides at over-aged conditions.

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

    PubMed

    Ren, Junping; Liu, Guangliang; Go, Jonathan; Kolli, Deepthi; Zhang, Guanping; Bao, Xiaoyong

    2014-01-01

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

  16. CODA METHOD AT HIGH FREQUENCIES: RETRIEVING SOURCE PARAMETERS OF SMALL (M1-M2) EARTHQUAKES

    NASA Astrophysics Data System (ADS)

    Viegas, G.; Abercrombie, R. E.; Mayeda, K. M.

    2009-12-01

    We calculate source parameters of small earthquakes from coda derived source spectrum ratios, extending the coda method to higher frequencies and smaller crustal volumes. To validate our high frequency results, we compare our source parameters estimates to the ones obtained with a direct wave study for the same set of earthquakes. We investigate earthquake source scaling relationships using local and regional good quality recordings of the M5 2002 Au Sable Forks, NY, mainshock and aftershocks sequence (M4-M1), and regional recordings of other moderate Eastern North America (ENA) earthquakes. We successfully retrieve spectral ratios, with a clear corner frequency and omega squared fall off, for the small (M2) Au Sable Forks aftershocks recorded locally (~3 km to 12 km epicentral distances) at a high sampling rate (200 sps). The local data have maximum coda duration of 15 s after the S wave onset (triggered recording). We investigate if the records are long enough, by first testing the method with Parkfield, CA, earthquakes, a dataset with similar dimensions in terms of station epicentral distances, earthquake magnitudes, and instrument sampling rate, for which records with long codas are available. The method holds for both datasets at high frequencies (up to 80 Hz), with a small increase of inter-station coda amplitude instability (0.5 standard deviation), expected for smaller earthquakes. We obtain in average higher corner frequencies and stress drops estimates (factor of 1.7 for corner frequency and 4.3 for stress drop) for the small (~M2) locally recorded Au Sable Forks earthquakes, than the values obtained with a direct wave study, and in average lower corner frequencies and stress drops for the moderate regionally recorded earthquakes (factor of 0.7 for corner frequency and 0.4 for stress drop). The corner frequencies of the mainshock and M3 earthquakes are close to the usable band limit and so uncertainties in the estimates of corner frequency and stress drop

  17. 43 CFR 10.8 - Summaries.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... REGULATIONS Human Remains, Funerary Objects, Sacred Objects, or Objects of Cultural Patrimony in Museums and... religious leaders that the Indian tribe or Native Hawaiian organization thinks should be consulted...

  18. 43 CFR 10.8 - Summaries.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... REGULATIONS Human Remains, Funerary Objects, Sacred Objects, or Objects of Cultural Patrimony in Museums and... religious leaders that the Indian tribe or Native Hawaiian organization thinks should be consulted...

  19. 43 CFR 10.8 - Summaries.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... REGULATIONS Human Remains, Funerary Objects, Sacred Objects, or Objects of Cultural Patrimony in Museums and... religious leaders that the Indian tribe or Native Hawaiian organization thinks should be consulted...

  20. 43 CFR 10.8 - Summaries.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... REGULATIONS Human Remains, Funerary Objects, Sacred Objects, or Objects of Cultural Patrimony in Museums and... religious leaders that the Indian tribe or Native Hawaiian organization thinks should be consulted...

  1. 43 CFR 10.8 - Summaries.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... REGULATIONS Human Remains, Funerary Objects, Sacred Objects, or Objects of Cultural Patrimony in Museums and... religious leaders that the Indian tribe or Native Hawaiian organization thinks should be consulted...

  2. 17 CFR 10.8 - Presiding officers.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... Presiding Officer who is not an Administrative Law Judge, all provisions of this part that refer to and grant authority to or impose obligations upon an Administrative Law Judge shall be read as referring to... proceedings within the scope of this part shall be assigned to an Administrative Law Judge for hearing. If...

  3. 15 CFR 10.8 - Standing Committee.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... general interest groups such as municipal, State, and Federal agencies. When requested by the Standing... technology that might affect the standard; (2) Provide the Department with interpretations of provisions...

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

    NASA Technical Reports Server (NTRS)

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

    2015-01-01

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

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

    SciTech Connect

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

    2012-08-26

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

  6. SH2 domain-containing phosphatase 1 regulates pyruvate kinase M2 in hepatocellular carcinoma

    PubMed Central

    Tai, Wei-Tien; Hung, Man-Hsin; Chu, Pei-Yi; Chen, Yao-Li; Chen, Li-Ju; Tsai, Ming-Hsien; Chen, Min-Husan; Shiau, Chung-Wai; Boo, Yin-Pin; Chen, Kuen-Feng

    2016-01-01

    Pyruvate kinase M2 (PKM2) is known to promote tumourigenesis through dimer formation of p-PKM2Y105. Here, we investigated whether SH2-containing protein tyrosine phosphatase 1 (SHP-1) decreases p-PKM2Y105 expression and, thus, determines the sensitivity of sorafenib through inhibiting the nuclear-related function of PKM2. Immunoprecipitation and immunoblot confirmed the effect of SHP-1 on PKM2Y105 dephosphorylation. Lactate production was assayed in cells and tumor samples to determine whether sorafenib reversed the Warburg effect. Clinical hepatocellular carcinoma (HCC) tumor samples were assessed for PKM2 expression. SHP-1 directly dephosphorylated PKM2 at Y105 and further decreased the proliferative activity of PKM2; similar effects were found in sorafenib-treated HCC cells. PKM2 was also found to determine the sensitivity of targeted drugs, such as sorafenib, brivanib, and sunitinib, by SHP-1 activation. Significant sphere-forming activity was found in HCC cells stably expressing PKM2. Clinical findings suggest that PKM2 acts as a predicting factor of early recurrence in patients with HCC, particularly those without known risk factors (63.6%). SHP-1 dephosphorylates PKM2 at Y105 to inhibit nuclear function of PKM2 and determines the efficacy of targeted drugs. Targeting PKM2 by SHP-1 might provide new therapeutic insights for patients with HCC. PMID:26959741

  7. Desuccinylation of pyruvate kinase M2 by SIRT5 contributes to antioxidant response and tumor growth

    PubMed Central

    linping, Gu; Yunhua, Xu; Ziming, Li; Yongfeng, Yu; Zhiwei, Chen; Shun, Lu

    2017-01-01

    Tumor cells trends to express high level of pyruvate kinase M2 (PKM2). The inhibition of PKM2 activity is needed for antioxidant response by diverting glucose flux into the pentose phosphate pathway and thus generating sufficient reducing potential. Here we report that PKM2 is succinylated at lysine 498 (K498) and succinylation increases its activity. SIRT5 binds to, desuccinylates and inhibits PKM2 activity. Increased level of reactive oxygen species (ROS) decreases both the succinylation and activity of PKM2 by increasing its binding to SIRT5. Substitution of endogenous PKM2 with a succinylation mimetic mutant K498E decreases cellular NADPH production and inhibits cell proliferation and tumor growth. Moreover, inhibition of SIRT5 suppresses tumor cell proliferation through desuccinylation of PKM2 K498. These results reveal a new mechanism of PKM2 modification, a new function of SIRT5 in response to oxidative stress which stimulates cell proliferation and tumor growth, and also a potential target for clinical cancer research. PMID:28036303

  8. Two-dimensional topological insulators in group-11 chalcogenide compounds: M2Te (M =Cu ,Ag )

    NASA Astrophysics Data System (ADS)

    Ma, Yandong; Kou, Liangzhi; Dai, Ying; Heine, Thomas

    2016-06-01

    Two-dimensional (2D) topological insulators (TIs) are recently recognized states of quantum matter that are highly interesting for lower-power-consuming electronic devices owing to their nondissipative transport properties protected from backscattering. So far, only few 2D TIs, suffering from small bulk band gap (<10 meV ), have been experimentally confirmed. Here, through first-principles calculations, we propose a family of 2D TIs in group-11 chalcogenide 2D crystals, M2Te (M =Cu ,Ag ) . The nontrivial topological states in C u2Te and A g2Te 2D crystals, identified by topological invariant and edge state calculations, exhibit sizeable bulk gaps of 78 and 150 meV, respectively, suggesting that they are candidates for room-temperature applications. Moreover, strain engineering leads to effective control of the nontrivial gaps of C u2Te and A g2Te , and a topological phase transition can be realized in C u2Te , while the nontrivial phase in A g2Te is stable against strain. Their dynamic and thermal stabilities are further confirmed by employing phonon calculations and ab initio molecular dynamic simulations.

  9. 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.

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

    NASA Astrophysics Data System (ADS)

    Jakubík, Jan; Randáková, Alena; Doležal, Vladimír

    2013-06-01

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

  11. Pyruvate kinase isoenzyme M2 is a therapeutic target of gemcitabine-resistant pancreatic cancer cells.

    PubMed

    Kim, Dong Joon; Park, Young Soo; Kang, Min Gu; You, Yeon-Mi; Jung, Yuri; Koo, Han; Kim, Jung-Ae; Kim, Mi-Ju; Hong, Seung-Mo; Lee, Kyong Bun; Jang, Ja-June; Park, Kyung Chan; Yeom, Young Il

    2015-08-01

    Despite its wide use as a first-line therapeutic agent, gemcitabine has shown limited efficacy in advanced pancreatic cancer due to chemoresistance by as yet unidentified mechanisms. Our goal here was to identify molecular features involved in gemcitabine chemoresistance. Pyruvate kinase M2 (PKM2), a key enzyme of aerobic glycolysis, has recently emerged as an important therapeutic target for cancer treatment. It is involved in the metabolic reprogramming of cancer cells and has previously unexpected non-metabolic functions that are heavily involved in tumor growth and survival. Herein, we report that the chemoresistance of pancreatic cancer to gemcitabine was dependent on PKM2 expression and its non-metabolic function. Knocking-down of PKM2 significantly enhanced gemcitabine-induced cell apoptosis through the activation of caspase 3/7 and PARP cleavage, and this inhibitory activity was associated with p38-mediated activation of p53 phosphorylation at serine 46. Our findings support the potential of PKM2 as a novel target for gemcitabine chemoresistance and suggest the feasibility of combining gemcitabine and PKM2 inhibition for the improved chemotherapy of pancreatic cancer.

  12. FAST, LOW-IONIZATION EMISSION REGIONS OF THE PLANETARY NEBULA M2-42

    SciTech Connect

    Danehkar, A.; Parker, Q. A.; Steffen, W.

    2016-02-15

    Spatially resolved observations of the planetary nebula M2-42 (PN G008.2−04.8) obtained with the Wide Field Spectrograph on the Australian National University 2.3 m telescope have revealed the remarkable features of bipolar collimated jets emerging from its main structure. Velocity-resolved channel maps derived from the [N ii] λ6584 emission line disentangle different morphological components of the nebula. This information is used to develop a three-dimensional morpho-kinematic model, which consists of an equatorial dense torus and a pair of asymmetric bipolar outflows. The expansion velocity of about 20 km s{sup −1} is measured from the spectrum integrated over the main shell. However, the deprojected velocities of the jets are found to be in the range of 80–160 km s{sup −1} with respect to the nebular center. It is found that the mean density of the collimated outflows, 595 ± 125 cm{sup −3}, is five times lower than that of the main shell, 3150 cm{sup −3}, whereas their singly ionized nitrogen and sulfur abundances are about three times higher than those determined from the dense shell. The results indicate that the features of the collimated jets are typical of fast, low-ionization emission regions.

  13. Cross section for inelastic neutron ''acceleration'' by {sup 178}Hf{sup m2}

    SciTech Connect

    Karamian, S. A.; Carroll, J. J.

    2011-02-15

    The scattering of thermal neutrons from isomeric nuclei may include events in which the outgoing neutrons have increased kinetic energy. This process has been called inelastic neutron acceleration, or INNA, and occurs when the final nucleus, after emission of the neutron, is left in a state with lower energy than that of the isomer. The result, therefore, is an induced depletion of the isomer to the ground state. A cascade of several {gamma}'s must accompany the neutron emission to release the high angular momentum of the initial isomeric state. INNA was previously observed in a few cases, and the measured cross sections were only in modest agreement with theoretical estimates. The most recent measurement of an INNA cross section was {sigma}{sub INNA}=258{+-}58 b for neutron scattering by {sup 177}Lu{sup m}. In the present work, an INNA cross section of {sigma}{sub INNA}=168 {+-} 33 b was deduced from measurements of the total burnup of the high-spin, four-quasiparticle isomer {sup 178}Hf{sup m2} during irradiation by thermal neutrons. Statistical estimates for the probability of different reaction channels past neutron absorption were used in the analysis, and the deduced {sigma}{sub INNA} was compared to the theoretically predicted cross section.

  14. The transglutaminase type 2 and pyruvate kinase isoenzyme M2 interplay in autophagy regulation.

    PubMed

    Altuntas, Sara; Rossin, Federica; Marsella, Claudia; D'Eletto, Manuela; Diaz-Hidalgo, Laura; Farrace, Maria Grazia; Campanella, Michelangelo; Antonioli, Manuela; Fimia, Gian Maria; Piacentini, Mauro

    2015-12-29

    Autophagy is a self-degradative physiological process by which the cell removes worn-out or damaged components. Constant at basal level it may become highly active in response to cellular stress. The type 2 transglutaminase (TG2), which accumulates under stressful cell conditions, plays an important role in the regulation of autophagy and cells lacking this enzyme display impaired autophagy/mitophagy and a consequent shift their metabolism to glycolysis. To further define the molecular partners of TG2 involved in these cellular processes, we analysed the TG2 interactome under normal and starved conditions discovering that TG2 interacts with various proteins belonging to different functional categories. Herein we show that TG2 interacts with pyruvate kinase M2 (PKM2), a rate limiting enzyme of glycolysis which is responsible for maintaining a glycolytic phenotype in malignant cells and displays non metabolic functions, including transcriptional co-activation and protein kinase activity. Interestingly, the ablation of PKM2 led to the decrease of intracellular TG2's transamidating activity paralleled by an increase of its tyrosine phosphorylation. Along with this, a significant decrease of ULK1 and Beclin1 was also recorded, thus suggesting a block in the upstream regulation of autophagosome formation. These data suggest that the PKM2/TG2 interplay plays an important role in the regulation of autophagy in particular under cellular stressful conditions such as those displayed by cancer cells.

  15. A role for coenzyme M (2-mercaptoethanesulfonic acid) in a bacterial pathway of aliphatic epoxide carboxylation

    PubMed Central

    Allen, Jeffrey R.; Clark, Daniel D.; Krum, Jonathan G.; Ensign, Scott A.

    1999-01-01

    The bacterial metabolism of short-chain aliphatic alkenes occurs via oxidation to epoxyalkanes followed by carboxylation to β-ketoacids. Epoxyalkane carboxylation requires four enzymes (components I–IV), NADPH, NAD+, and a previously unidentified nucleophilic thiol. In the present work, coenzyme M (2-mercaptoethanesulfonic acid), a compound previously found only in the methanogenic Archaea where it serves as a methyl group carrier and activator, has been identified as the thiol and central cofactor of aliphatic epoxide carboxylation in the Gram-negative bacterium Xanthobacter strain Py2. Component I catalyzed the addition of coenzyme M to epoxypropane to form a β-hydroxythioether, 2-(2-hydroxypropylthio)ethanesulfonate. Components III and IV catalyzed the NAD+-dependent stereoselective dehydrogenation of R- and S-enantiomers of 2-(2-hydroxypropylthio)ethanesulfonate to form 2-(2-ketopropylthio)ethanesulfonate. Component II catalyzed the NADPH-dependent cleavage and carboxylation of the β-ketothioether to form acetoacetate and coenzyme M. These findings evince a newfound versatility for coenzyme M as a carrier and activator of alkyl groups longer in chain-length than methane, a function for coenzyme M in a catabolic pathway of hydrocarbon oxidation, and the presence of coenzyme M in the bacterial domain of the phylogenetic tree. These results serve to unify bacterial and Archaeal metabolism further and showcase diverse biological functions for an elegantly simple organic molecule. PMID:10411892

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

    NASA Astrophysics Data System (ADS)

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

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

  17. Efficient Plasma Production in Low Background Neutral Pressures with the M2P2 Prototype

    NASA Technical Reports Server (NTRS)

    Ziemba, T.; Euripides, P.; Winglee, R.; Slough, J.; Giersch, L.

    2003-01-01

    Mini-Magnetospheric Plasma Propulsion (M2P2) seeks the creation of a large-scale (10 km radius) magnetic wall or bubble (i.e. a magnetosphere) by the electromagnetic inflation of a small-scale (20 cm radius) dipole magnet. The inflated magnetosphere will intercept the solar wind and thereby provide high-speed propulsion with modest power and fuel requirements due to the gain provided by the ambient medium. Magnetic field inflation is produced by the injection of plasma onto the dipole magnetic field eliminating the need for large mechanical structures and added material weight at launch. For successful inflation of the magnetic bubble a beta near unity must be achieved along the imposed dipole field. This is dependent on the plasma parameters that can be achieved with a plasma source that provide continuous operation at the desired power levels of 1 to 2 kilowatts. Over the last two years we have been developing a laboratory prototype to demonstrate the inflation of the magnetic field under space-like conditions. In this paper we will present some of the latest results from the prototype development at the University of Washington and show that the prototype can produce high ionization efficiencies while operating in near space like neutral background pressures producing electron temperatures of a few tens of electron volts. This allows for operation with propellant expenditures lower than originally estimated.

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

    PubMed

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

    2016-08-25

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

  19. Desensitization of human muscarinic acetylcholine receptor m2 subtypes is caused by their sequestration/internalization.

    PubMed

    Tsuga, H; Kameyama, K; Haga, T

    1998-10-01

    Desensitization of human muscarinic acetylcholine receptor m2 subtypes (hm2 receptors) stably expressed in chinese hamster ovary cells was measured as decreases in the carbamylcholine-stimulated [35S]GTPgammaS binding activity in membrane preparations after pre-treatment of cells with carbamylcholine. The extent of carbamylcholine-stimulated [35S]GTPgammaS binding activity was found to decrease to 64% following pretreatment of cells with 10 microM carbamylcholine for 30 min, and under the same conditions 51-59% of hm2 receptors were sequestered/internalized as assessed by decreases in the [3H]N-methylscopolamine binding activity on the cell surface. A similar reduction in the carbamylcholine-stimulated [35S]GTPgammaS binding activity was observed by pretreatment of cells with 5 nM propylbenzylylcholine mustard, which irreversibly bound to and inactivated 58% of the hm2 receptors. When the cells were pretreated with 10 microM carbamylcholine in the presence of 0.32 M sucrose, which is known to inhibit clathrin-mediated endocytosis, no sequestration/internalization of hm2 receptors was observed, and the extent of carbamylcholine-stimulated [35S]GTPgammaS binding activity did not change. These results indicate that desensitization of hm2 receptors may be caused by reduction of receptor number on the cell surface through sequestration/internalization rather than by loss of the function of receptors.

  20. Inhibitory and Activating Effects of Some Flavonoid Derivatives on Human Pyruvate Kinase Isoenzyme M2.

    PubMed

    Adem, Sevki; Aslan, Abdulselam; Ahmed, Ishtiaq; Krohn, Karsten; Guler, Caglar; Comaklı, Veysel; Demirdag, Ramazan; Kuzu, Muslum

    2016-02-01

    Pyruvate kinase isoenzyme M2 (PKM2) is expressed excessively in many different cancer types and it plays an important role in the control of glucose metabolism. Thus, it is evaluated as an important target in the development of medication for cancer. The flavonoids comprise a large group of natural products with variable phenolic structures and occur mainly in plants. They are of great interest due to their biological properties. In this study, the effects of various flavonoid derivatives on the PKM2 enzyme activity were analyzed in vitro. The flavonoid derivatives 1 and 2 showed inhibition effect with IC50 values of <60 μM. IC50 values of compounds 3-8 were calculated as 134, 415, 145, 163, 295 μM, and 3.5 mM, respectively. The molecules 9-12 showed an activation effect with values of AC50 of less than 90 μM. The IC50 values of the derivatives 13-17 were calculated as 115, 150, 200, 221, and 275 μM, respectively. The results show that catechin derivatives can be probably used as lead compounds for the design of PKM2 enzyme activators and inhibitors.

  1. Experiment "Regeneration" Performed Aboard the Russian Spacecraft Foton-M2 in 2005

    NASA Technical Reports Server (NTRS)

    Grigoryan, Elonora; Almeida, Eduardo; Domaratskaya, Elena; Poplinskaya, Valentina; Aleinikova, Karina; Tairbekov, Murad; Mitashov, Victor

    2006-01-01

    The experiments on the newts performed earlier aboard Russian biosate llites showed that the rate of lens and tail regeneration in space wa s greater than on the ground. In parallel it was found that the numbe r of cells in S-phase was greater in space-flown animals than in the ground controls. However, it was unclear whether cell proliferation stimulation was induced by micro-g per se. Molecular mechanisms under lying the change also remained obscure. These issues were addressed b y the joint Russian-American experiment "Regeneration" flown on Foton -M2 in 2005. The method for in-flight delivering DNA precursor BrdU was developed. The experiment showed that during the flight the numbe r of S-phase cells in the regenerating eyes and tails increased. Thes e data together with those obtained earlier suggest that cell prolife ration increases in response to the effects of both micro-g and 1-g a fter return to Earth. The expression of bFGF in regenerating tissues of "flown" newts and ground controls was examined using immuno-histo chemistry. Obtained results suggest that this growth factor is a part icipant of the promotional effect of space flight upon cell prolifera tion in lens and tail regenerates.

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

    NASA Technical Reports Server (NTRS)

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

    2006-01-01

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

  3. First passage times in M2[X ]|G |1 |R queue with hysteretic overload control policy

    NASA Astrophysics Data System (ADS)

    Pechinkin, Alexander V.; Razumchik, Rostislav R.; Zaryadov, Ivan S.

    2016-06-01

    One of the reported approaches towards the solution of overload problem in networks of SIP servers is the implementation of multi-level hysteretic control of arrivals in SIP servers. Each level, being the parameter of the policy, specifies operation mode of SIP server i.e. it implicitly indicates what SIP server must do with the arriving packets. The choice of parameters' values is not guided by standards and is usually left for the network owner. In general, all operation modes of the considered policy can be grouped into two groups: normal mode (when all arriving packets are accepted) and congested mode (when part or all arriving packets are being dropped). Such grouping may serve as the criteria for choosing parameters' values of the policy: pick those values which minimize SIP server sojourn time in congested mode. In this short note we propose some analytical results which facilitate the solution of stated minimization problem. The considered mathematical model of SIP server is the queueing system M2[X ]|G |1 |R with batch arrivals and bi-level hysteretic control policy, which specifies three operation modes: normal (customers both flows are accepted), overload (only customers from one flow are accepted), discard (customers from both flows are blocked/lost)). The switching between modes can occur only on service completions. Analytical method allowing computation of stationary sojourn times in different operation modes (as well as first passage times between modes) is presented in brief. Numerical example is given.

  4. Inhibition of Pyruvate Kinase M2 Markedly Reduces Chemoresistance of Advanced Bladder Cancer to Cisplatin

    PubMed Central

    Wang, Xing; Zhang, Fenglin; Wu, Xue-Ru

    2017-01-01

    Chemoresistance to cisplatin is a principal cause of treatment failure and mortality of advanced bladder cancer (BC). The underlying mechanisms remain unclear, which hinders the development of preventive strategies. Recent data indicate that pyruvate kinase M2 (PKM2), a glycolytic enzyme for Warburg effect, is strongly upregulated in BC. This study explores the role of PKM2 in chemoresistance and whether inhibiting PKM2 augments the chemosensitivity to cisplatin and reduces BC growth and progression. We found that Shikonin binds PKM2 and inhibits BC cell survival in a dose-dependent but pyruvate kinase activity-independent manner. Down-regulation of PKM2 by shRNA blunts cellular responses to shikonin but enhances the responses to cisplatin. Shikonin and cisplatin together exhibit significantly greater inhibition of proliferation and apoptosis than when used alone. Induced cisplatin-resistance is strongly associated with PKM2 overexpression, and cisplatin-resistant cells respond sensitively to shikonin. In syngeneic mice, shikonin and cisplatin together, but not as single-agents, markedly reduces BC growth and metastasis. Based on these data, we conclude that PKM2 overexpression is a key mechanism of chemoresistance of advanced BC to cisplatin. Inhibition of PKM2 via RNAi or chemical inhibitors may be a highly effective approach to overcome chemoresistance and improve the outcome of advanced BC. PMID:28378811

  5. Activation and Proton Transport Mechanism in Influenza A M2 Channel

    PubMed Central

    Wei, Chenyu; Pohorille, Andrew

    2013-01-01

    Molecular dynamics trajectories 2 μs in length have been generated for the pH-activated, tetrameric M2 proton channel of the influenza A virus in all protonation states of the pH sensor located at the His37 tetrad. All simulated structures are in very good agreement with high-resolution structures. Changes in the channel caused by progressive protonation of His37 provide insight into the mechanism of proton transport. The channel is closed at both His37 and Trp41 sites in the singly and doubly protonated states, but it opens at Trp41 upon further protonation. Anions access the charged His37 and by doing so stabilize the protonated states of the channel. The narrow opening at the His37 site, further blocked by anions, is inconsistent with the water-wire mechanism of proton transport. Instead, conformational interconversions of His37 correlated with hydrogen bonding to water molecules indicate that these residues shuttle protons in high-protonation states. Hydrogen bonds between charged and uncharged histidines are rare. The valve at Val27 remains on average quite narrow in all protonation states but fluctuates sufficiently to support water and proton transport. A proton transport mechanism in which the channel, depending on pH, opens at either the histidine or valine gate is only partially supported by the simulations. PMID:24209848

  6. Rates of E1, E2, M1, and M2 transitions in Ni II

    NASA Astrophysics Data System (ADS)

    Cassidy, C. M.; Hibbert, A.; Ramsbottom, C. A.

    2016-03-01

    Aims: We present rates for all E1, E2, M1, and M2 transitions among the 295 fine-structure levels of the configurations 3d9, 3d84s, 3d74s2, 3d84p, and 3d74s4p, determined through an extensive configuration interaction calculation. Methods: The CIV3 code developed by Hibbert and coworkers is used to determine for these levels configuration interaction wave functions with relativistic effects introduced through the Breit-Pauli approximation. Results: Two different sets of calculations have been undertaken with different 3d and 4d functions to ascertain the effect of such variation. The main body of the text includes a representative selection of data, chosen so that key points can be discussed. Some analysis to assess the accuracy of the present data has been undertaken, including comparison with earlier calculations and the more limited range of experimental determinations. The full set of transition data is given in the supplementary material as it is very extensive. Conclusions: We believe that the present transition data are the best currently available. Full Table 4 and Tables 5-8 are only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/587/A107

  7. The transglutaminase type 2 and pyruvate kinase isoenzyme M2 interplay in autophagy regulation

    PubMed Central

    Altuntas, Sara; Rossin, Federica; Marsella, Claudia; D'Eletto, Manuela; Hidalgo, Laura Diaz; Farrace, Maria Grazia; Campanella, Michelangelo; Antonioli, Manuela; Fimia, Gian Maria; Piacentini, Mauro

    2015-01-01

    Autophagy is a self-degradative physiological process by which the cell removes worn-out or damaged components. Constant at basal level it may become highly active in response to cellular stress. The type 2 transglutaminase (TG2), which accumulates under stressful cell conditions, plays an important role in the regulation of autophagy and cells lacking this enzyme display impaired autophagy/mitophagy and a consequent shift their metabolism to glycolysis. To further define the molecular partners of TG2 involved in these cellular processes, we analysed the TG2 interactome under normal and starved conditions discovering that TG2 interacts with various proteins belonging to different functional categories. Herein we show that TG2 interacts with pyruvate kinase M2 (PKM2), a rate limiting enzyme of glycolysis which is responsible for maintaining a glycolytic phenotype in malignant cells and displays non metabolic functions, including transcriptional co-activation and protein kinase activity. Interestingly, the ablation of PKM2 led to the decrease of intracellular TG2's transamidating activity paralleled by an increase of its tyrosine phosphorylation. Along with this, a significant decrease of ULK1 and Beclin1 was also recorded, thus suggesting a block in the upstream regulation of autophagosome formation. These data suggest that the PKM2/TG2 interplay plays an important role in the regulation of autophagy in particular under cellular stressful conditions such as those displayed by cancer cells. PMID:26702927

  8. Reduction of the linear reflex gain explained from the M1-M2 refractory period.

    PubMed

    Klomp, Asbjorn; de Vlugt, Erwin; Meskers, Carel G M; de Groot, Jurriaan H; Arendzen, J Hans; van der Helm, Frans C T

    2013-06-01

    Linear system identification methods combined with neuromechanical modeling enable the quantification of reflex gains from recorded joint angular perturbation, torque, and/or electromyography (EMG). However, the stretch reflex response as recorded by EMG consists of multiple consecutive activation volleys (M1 and M2 responses) separated by a period of reduced activity and is nonlinearly related to joint perturbation. The goal of this study is to assess to what extent linear assumptions hold when quantifying these reflexive responses. Series of ramp-and-hold angular perturbations with fixed velocity but different ramp durations (and, therefore, different amplitudes) were applied to the wrist joint of seven healthy volunteers. Evoked EMG responses were compared to the reflex response estimated from a common linear reflex model relating EMG to perturbation velocity. Model fits described the measured EMG responses best when the perturbation and M1 response durations were equivalent. With increasing perturbation duration, i.e., amplitude, EMG response increased but reflex gain decreased due to the inert period after M1, which is believed to be related to alignment of the refractory period of the motoneurons. For angular joint perturbations exceeding the M1 duration (coinciding with 2 (°) of wrist joint rotation in this study), reflex gain variation may be largely explained from a shortcoming of the linear model in describing the nonlinear reflex response, and in particular the period of low reflexive activity after M1.

  9. Tumour cell conditioned medium reveals greater M2 skewing of macrophages in the absence of properdin

    PubMed Central

    Al‐Rayahi, Izzat A.M.; Browning, Michael J.

    2017-01-01

    Abstract Introduction The tumour microenvironment is shaped by the interaction of immune, non immune, and tumour cells present in close proximity. Tumour cells direct the development of a locally immune suppressed state, affecting the activity of anti tumour T cells and preparing the escape phase of tumour development. Macrophages in the tumour typically develop into so‐called tumour associated macrophages with a distinct profile of activities which lead to a reduction in inflammation and antigen presentation. The direct impact of tumour cell conditioned medium on the activity profile of macrophages in dependence of their complement component expression has not yet been investigated. Methods In our in vitro study, macrophages differentiated from bone marrows of properdin deficient and wildtype mice were stimulated with conditioned medium of a syngeneic tumour cell line, B16F10, a mouse melanoma subline. Results In comparison with macrophages from wildtype mice, those from congenic properdin deficient mice showed skewing towards M2 profile, encompassing mRNA expression for genes involved in arginine metabolism, production of type 2 cytokines, and relatively lower surface expression of molecules needed for antigen presentation. Conclusions These data suggest that properdin insufficiency promotes a tumour environment that helps the tumour evade the immune response. PMID:28250926

  10. Insulin regulates glucose consumption and lactate production through reactive oxygen species and pyruvate kinase M2.

    PubMed

    Li, Qi; Liu, Xue; Yin, Yu; Zheng, Ji-Tai; Jiang, Cheng-Fei; Wang, Jing; Shen, Hua; Li, Chong-Yong; Wang, Min; Liu, Ling-Zhi; Jiang, Bing-Hua

    2014-01-01

    Although insulin is known to regulate glucose metabolism and closely associate with liver cancer, the molecular mechanisms still remain to be elucidated. In this study, we attempt to understand the mechanism of insulin in promotion of liver cancer metabolism. We found that insulin increased pyruvate kinase M2 (PKM2) expression through reactive oxygen species (ROS) for regulating glucose consumption and lactate production, key process of glycolysis in hepatocellular carcinoma HepG2 and Bel7402 cells. Interestingly, insulin-induced ROS was found responsible for the suppression of miR-145 and miR-128, and forced expression of either miR-145 or miR-128 was sufficient to abolish insulin-induced PKM2 expression. Furthermore, the knockdown of PKM2 expression also inhibited cancer cell growth and insulin-induced glucose consumption and lactate production, suggesting that PKM2 is a functional downstream effecter of insulin. Taken together, this study would provide a new insight into the mechanism of insulin-induced glycolysis.

  11. NREL National Wind Technology Center (NWTC): M2 Tower; Boulder, Colorado (Data)

    DOE Data Explorer

    Jager, D.; Andreas, A.

    1996-09-24

    The National Wind Technology Center (NWTC), located at the foot of the Rocky Mountains near Boulder, Colorado, is a world-class research facility managed by NREL for the U.S. Department of Energy. NWTC researchers work with members of the wind energy industry to advance wind power technologies that lower the cost of wind energy through research and development of state-of-the-art wind turbine designs. NREL's Measurement and Instrument Data Center provides data from NWTC's M2 tower which are derived from instruments mounted on or near an 82 meter (270 foot) meteorological tower located at the western edge of the NWTC site and about 11 km (7 miles) west of Broomfield, and approximately 8 km (5 miles) south of Boulder, Colorado. The data represent the mean value of readings taken every two seconds and averaged over one minute. The wind speed and direction are measured at six heights on the tower and air temperature is measured at three heights. The dew point temperature, relative humidity, barometric pressure, totalized liquid precipitation, and global solar radiation are also available.

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

    PubMed Central

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

    2012-01-01

    Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. PKM2 interaction with phosphotyrosine-containing proteins inhibits enzyme activity and increases availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small molecule PKM2 activators inhibit growth of xenograft tumors. Structural studies reveal that small molecule activators bind PKM2 at the subunit interaction interface, a site distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small molecule activation of PKM2 can interfere with anabolic metabolism. PMID:22922757

  13. Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2.

    PubMed

    Chen, J; Xie, J; Jiang, Z; Wang, B; Wang, Y; Hu, X

    2011-10-20

    We recently reported that shikonin and its analogs were a class of necroptotic inducers that could bypass cancer drug resistance. However, the molecular targets of shikonin are not known. Here, we showed that shikonin and its analogs are inhibitors of tumor-specific pyruvate kinase-M2 (PKM2), among which shikonin and its enantiomeric isomer alkannin were the most potent and showed promising selectivity, that is, shikonin and alkannin at concentrations that resulted in over 50% inhibition of PKM2 activity did not inhibit PKM1 and pyruvate kinase-L (PKL). Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x(L) and A549) that primarily express PKM2. HeLa cells transfected with PKM1 showed reduced sensitivity to shikonin- or alkannin-induced cell death. To the best of our knowledge, shikonin and alkannin are the most potent and specific inhibitors to PKM2 reported so far. As PKM2 universally expresses in cancer cells and dictates the last rate-limiting step of glycolysis vital for cancer cell proliferation and survival, enantiomeric shikonin and alkannin may have potential in future clinical application.

  14. Pentraxin-3 Attenuates Renal Damage in Diabetic Nephropathy by Promoting M2 Macrophage Differentiation.

    PubMed

    Sun, Huaibin; Tian, Jun; Xian, Wanhua; Xie, Tingting; Yang, Xiangdong

    2015-10-01

    As one of the most important long-term complications of diabetes, diabetic nephropathy (DN) is the major cause of end-stage renal disease and high mortality in diabetic patients. The long pentraxin 3 (Ptx3) is a member of a superfamily of conserved proteins characterized by a cyclic multimeric structure and a conserved C-terminal domain. Several clinical investigations have demonstrated that elevated plasma Ptx3 levels are associated with cardiovascular and chronic kidney diseases (CKD). However, the therapeutic effect of Ptx3 on DN has never been investigated. In our current study, we showed a crucial role for Ptx3 in attenuating renal damage in DN. In our mouse hyperglycemia-induced nephropathy model, Ptx3 treatment showed significantly increased expression of nephrin, acetylated nephrin, and Wilm's tumor-1 protein (WT-1) when compared with control. The number of CD4(+) T cells, CD8(+) T cells, Ly6G(+) neutrophils, and CD11b(+) macrophages were all significantly lower in the Ptx3-treated group than that in the control group in DN. The IL-4 and IL-13 levels in the Ptx3-treated group were markedly higher than that in the control group in DN. Correspondingly, the Ptx3-treated group showed increased numbers of Arg1- or CD206-expressing macrophages compared with the control group. Furthermore, inhibition of Ptx3-treated macrophages abrogated the alleviated renal damage induced by Ptx3 treatment. In conclusion, Ptx3 attenuates renal damage in DN by promoting M2 macrophage differentiation.

  15. Orientation relationships between M2C carbide and the austenite matrix in an Fe-Mn-AI-Mo-C alloy

    NASA Astrophysics Data System (ADS)

    Peng, Shang-Wen; Chou, Chang-Pin

    1993-05-01

    M2C carbides were observed to precipitate within the austenite matrix of an Fe-24.6Mn-6.6Al-3. IMo-1.0C alloy after quenching from 1200 °C and aging at 750 °C. By means of transmission electron microscopy (TEM) and diffraction techniques, the orientation relationships between M2C (p) and the austenite (γ) matrix were determined to be: (0001)p//(111)γ, (11- bar 20)p// (1 bar 10)γ, ( bar 1100)p//(11 bar 2)γ. M2C carbide has been reported by many researchers to precipitate from the ferrite matrix or along austenite/ferrite boundaries in alloy steels containing Mo. However, little information concerning the formation of M2C in the austenite matrix has been provided. This investigation presents the first evidence for the existence of M2C carbide wholly within the austenite matrix and its relationship to the austenite. The energy-dispersive spectrometry (EDS) analyses were performed on M2C carbides, and the results indicate that the solubility of the M2C carbide for foreign atoms other than Mo is very limited.

  16. Discovery of potential M2 channel inhibitors based on the amantadine scaffold via virtual screening and pharmacophore modeling.

    PubMed

    Tran, Linh; Choi, Sy Bing; Al-Najjar, Belal O; Yusuf, Muhammad; Wahab, Habibah A; Le, Ly

    2011-12-08

    The M2 channel protein on the influenza A virus membrane has become the main target of the anti-flu drugs amantadine and rimantadine. The structure of the M2 channel proteins of the H3N2 (PDB code 2RLF) and 2009-H1N1 (Genbank accession number GQ385383) viruses may help researchers to solve the drug-resistant problem of these two adamantane-based drugs and develop more powerful new drugs against influenza A virus. In the present study, we searched for new M2 channel inhibitors through a combination of different computational methodologies, including virtual screening with docking and pharmacophore modeling. Virtual screening was performed to calculate the free energies of binding between receptor M2 channel proteins and 200 new designed ligands. After that, pharmacophore analysis was used to identify the important M2 protein-inhibitor interactions and common features of top binding compounds with M2 channel proteins. Finally, the two most potential compounds were determined as novel leads to inhibit M2 channel proteins in both H3N2 and 2009-H1N1 influenza A virus.

  17. Modulation of M(2) muscarinic receptor-receptor interaction by immunoglobulin G antibodies from Chagas' disease patients.

    PubMed

    Beltrame, S P; Auger, S R; Bilder, C R; Waldner, C I; Goin, J C

    2011-05-01

    Circulating immunoglobulin (Ig)G antibodies against M(2) muscarinic acetylcholine receptors (M(2) mAChR) have been implicated in Chagas' disease (ChD) pathophysiology. These antibodies bind to and activate their target receptor, displaying agonist-like activity through an unclear mechanism. This study tested the ability of serum anti-M(2) mAChR antibodies from chronic ChD patients to modulate M(2) muscarinic receptor-receptor interaction by bioluminescence resonance energy transfer (BRET). Human embryonic kidney (HEK) 293 cells co-expressing fusion proteins M(2) mAChR-Renilla luciferase (RLuc) and M(2) mAChR-yellow fluorescent protein (YFP) were exposed to the serum IgG fraction from ChD patients, and BRET between RLuc and YFP was assessed by luminometry. Unlike serum IgG from healthy subjects and conventional muscarinic ligands, ChD IgG promoted a time- and concentration-dependent increase in the BRET signal. This effect neither required cellular integrity nor occurred as a consequence of receptor activation. Enhancement of M(2) receptor-receptor interaction by ChD IgG was receptor subtype-specific and mediated by the recognition of the second extracellular loop of the M(2) mAChR. The monovalent Fab fragment derived from ChD IgG was unable to reproduce the effect of the native immunoglobulin. However, addition of ChD Fab in the presence of anti-human Fab IgG restored BRET-enhancing activity. These data suggest that the modulatory effect of ChD IgG on M(2) receptor-receptor interaction results from receptor cross-linking by bivalent antibodies.

  18. Identification of M2 macrophages in anterior pituitary glands of normal rats and rats with estrogen-induced prolactinoma.

    PubMed

    Fujiwara, Ken; Yatabe, Megumi; Tofrizal, Alimuddin; Jindatip, Depicha; Yashiro, Takashi; Nagai, Ryozo

    2017-01-24

    Macrophages are present throughout the anterior pituitary gland. However, the features and function of macrophages in the gland are poorly understood. Recent studies have indicated that there are two main macrophage classes: M1 (classically activated) and M2 (alternatively activated). In this study, we examine whether both M1 and M2 macrophages are present in the anterior pituitary gland of rats. Our findings indicate that macrophages that are positive for CD68 (a pan-macrophage marker) were localized near capillaries in rat anterior pituitary gland. These macrophages were positive for iNOS or mannose receptor (MR), which are markers of M1 and M2 macrophages, respectively. To determine the morphological characteristics of M2 macrophages under pathological conditions, diethylstilbestrol (DES)-treated rats were used as an animal model of prolactinoma. After 2 weeks of DES treatment, a number of MR-immunopositive cells were present in the gland. Immunoelectron microscopy revealed that MR-immunopositive M2 macrophages had many small vesicles and moderately large vacuoles in cytoplasm. Phagosomes were sometimes present in cytoplasm. Interestingly, M2 macrophages in prolactinoma tissues did not usually exhibit distinct changes or differences during the normal, hyperplasia and adenoma stages. This study is the first to confirm that both M1 and M2 macrophages are present in the anterior pituitary gland of rats. Moreover, the number of M2 macrophages was greatly increased in rats with DES-induced prolactinoma. Future studies should attempt to characterize the functional role of M2 macrophages in the gland.

  19. Immunogenicity and protective efficacy of the norovirus P particle-M2e chimeric vaccine in chickens.

    PubMed

    Elaish, M; Kang, K I; Xia, M; Ali, A; Shany, S A S; Wang, L; Jiang, X; Lee, C W

    2015-09-11

    The ectodomain of the influenza matrix protein 2 (M2e) is highly conserved across strains and has been shown to be a promising candidate for universal influenza vaccine in the mouse model. In this study, we tested immune response and protective efficacy of a chimeric norovirus P particle containing the avian M2e protein against challenges with three avian influenza (AI) viruses (H5N2, H6N2, H7N2) in chickens. Two-week-old specific pathogen free chickens were vaccinated 3 times with an M2e-P particle (M2e-PP) vaccine via the subcutaneous (SQ) route with oil adjuvant, and transmucosal routes (intranasal, IN; eye drop, ED; microspray, MS) without adjuvant. M2e-PP vaccination via the SQ route induced significant IgG antibody responses which were increased by each booster vaccination. In groups vaccinated via IN, ED or MS, neither IgG nor IgA responses were detected from sera or nasal washes of immunized birds. The M2e-PP vaccination via the SQ route significantly reduced the virus shedding in the trachea and the cloaca for all three challenge viruses. Despite the absence of detectable IgG and IgA responses in birds vaccinated with the M2e-PP via intranasal routes, a similar level of reduction in virus shedding was observed in the IN group compared to the SQ group. Our results supports that the universal vaccine approach using M2e-based vaccine can provide cross-protection against challenge viruses among different HA subtypes although the efficacy of the vaccine should be enhanced further to be practical. Better understanding of the protective immune mechanism will be critical for the development of an M2e-based vaccine in chickens.

  20. Novel feedback loop between M2 macrophages/microglia and regulatory B cells in estrogen-protected EAE mice.

    PubMed

    Benedek, Gil; Zhang, Jun; Nguyen, Ha; Kent, Gail; Seifert, Hilary; Vandenbark, Arthur A; Offner, Halina

    2017-04-15

    Immunoregulatory sex hormones, including estrogen and estriol, may prevent relapses in multiple sclerosis during pregnancy. Our previous studies have demonstrated that regulatory B cells are crucial for estrogen-mediated protection against experimental autoimmune encephalomyelitis (EAE). Herein, we demonstrate an estrogen-dependent induction of alternatively activated (M2) macrophages/microglia that results in an increased frequency of regulatory B cells in the spinal cord of estrogen treated mice with EAE. We further demonstrate that cultured M2-polarized microglia promote the induction of regulatory B cells. Our study suggests that estrogen neuroprotection induces a regulatory feedback loop between M2 macrophages/microglia and regulatory B cells.

  1. Loss of M2 muscarine receptors in the cerebral cortex in Alzheimer's disease and experimental cholinergic denervation.

    PubMed

    Mash, D C; Flynn, D D; Potter, L T

    1985-05-31

    Cerebral cortex samples from patients with Alzheimer's disease and from rats after experimental cholinergic denervation of the cerebral cortex exhibited reductions in the presynaptic marker choline acetyltransferase activity and in the number of M2 muscarine receptors, with no change in the number of M1 receptors. These results are in keeping with evidence that M2 receptors function in cholinergic nerve terminals to regulate the release of acetylcholine, whereas M1 receptors are located on postsynaptic cells and facilitate cellular excitation. New M1-selective agonists and M2-selective antagonists directed at post- or presynaptic sites deserve consideration as potential agents for the treatment of the disease.

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

    PubMed Central

    Bi, Jia; Zeng, Xianxin; Zhao, Lin; Wei, Qian; Yu, Lifeng; Wang, Xinnan; Yu, Zhaojin; Cao, Yaming; Shan, Fengping; Wei, Minjie

    2016-01-01

    Macrophages can acquire a variety of polarization status and functions: classically activated macrophages (M1 macrophages); alternatively activated macrophages (M2 macrophages). However, the molecular basis of the process is still unclear. Here, this study addresses that microRNA-181a (miR-181a) is a key molecule controlling macrophage polarization. We found that miR-181a is overexpressed in M2 macrophages than in M1 macrophages. miR-181a expression was decreased when M2 phenotype converted to M1, whereas it increased when M1 phenotype converted to M2. Overexpression of miR-181a in M1 macrophages diminished M1 phenotype expression while promoting polarization to the M2 phenotype. In contrast, knockdown of miR-181a in M2 macrophages promoted M1 polarization and diminished M2 phenotype expression. Mechanistically, Bioinformatic analysis revealed that Kruppel-like factor 6 (KLF6) and CCAAT/enhancer binding protein-α (C/EBPα) is a potential target of miR-181a and luciferase assay confirmed that KLF6 and C/EBPα translation is suppressed by miR-181a through interaction with the 3′UTR of KLF6 and C/EBPα mRNA. Further analysis showed that induction of miR-181a suppressed KLF6 and C/EBPα protein expression. Importantly, miR-181a also diminishes M2 macrophages-mediated migration and invasion capacity of tumor cells. Collectively, our results suggest that miR-181a plays a significant role in regulating macrophage polarization through directly target KLF6 and C/EBPα. PMID:27673564

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

    NASA Technical Reports Server (NTRS)

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

    2002-01-01

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

  4. Molecular cloning, characterization, and expression of Cuc m 2, a major allergen in Cucumis melo

    PubMed Central

    Sankian, Mojtaba; Mahmoudi, Mahmoud; Varasteh, Abdol-Reza

    2013-01-01

    Background: Several studies reported the clinical features of IgE-mediated hypersensitivity after ingestion of melon. Melon allergy is a common IgE-mediated fruit allergy in Iran. This prompted us to investigate immunochemical and molecular properties of the major allergen in melon fruit, to compare the IgE-binding capacity of the natural protein with the recombinant allergen, and to determine cross-reactivity of the major allergen with closely-related allergens from other plants displaying clinical cross-reactivity with melon. Methods: Identification and molecular characterization of the major melon allergen were performed using IgE immunoblotting, allergen-specific ELISA, affinity-based purifications, cross-inhibition assays, cloning, and expression of the allergen in Escherichia coli. Results: Melon profilin was identified and isolated as a major IgE-binding component and designated as Cuc m 2. Sequencing corresponding cDNA revealed an open reading frame of 363 bp coding for 131 amino acid residues and two fragments of 171 bp and 383 bps for the 5’and 3’ UTRs, respectively. Significant cross-reactivity was found between melon profilin and Cynodon dactylon, tomato, peach, and grape profilins in cross-inhibition assays. Although the highest degree of amino acid identity was revealed with watermelon profilin, there was no significant cross-reactivity between melon and watermelon profilins. Conclusion: Melon profilin is the major IgE-binding component in melon extract, and the recombinant and natural forms exhibited similar IgE-binding capacities. A part of the fruit-fruit and pollen-fruit cross-reactions could be explained by the presence of this conserved protein; however, sequence homology provides insufficient information to predict IgE cross-reactivity of profilins. PMID:26989709

  5. 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.

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

    NASA Technical Reports Server (NTRS)

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

    2002-01-01

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

  7. mTORC2 signalling regulates M2 macrophage differentiation in response to helminth infection and adaptive thermogenesis

    PubMed Central

    Hallowell, R. W.; Collins, S. L.; Craig, J. M.; Zhang, Y.; Oh, M.; Illei, P. B.; Chan-Li, Y.; Vigeland, C. L.; Mitzner, W.; Scott, A. L.; Powell, J. D.; Horton, M. R.

    2017-01-01

    Alternatively activated macrophages (M2) have an important function in innate immune responses to parasitic helminths, and emerging evidence also indicates these cells are regulators of systemic metabolism. Here we show a critical role for mTORC2 signalling in the generation of M2 macrophages. Abrogation of mTORC2 signalling in macrophages by selective conditional deletion of the adaptor molecule Rictor inhibits the generation of M2 macrophages while leaving the generation of classically activated macrophages (M1) intact. Selective deletion of Rictor in macrophages prevents M2 differentiation and clearance of a parasitic helminth infection in mice, and also abrogates the ability of mice to regulate brown fat and maintain core body temperature. Our findings define a role for mTORC2 in macrophages in integrating signals from the immune microenvironment to promote innate type 2 immunity, and also to integrate systemic metabolic and thermogenic responses. PMID:28128208

  8. WebMolCS: A Web-Based Interface for Visualizing Molecules in Three-Dimensional Chemical Spaces.

    PubMed

    Awale, Mahendra; Probst, Daniel; Reymond, Jean-Louis

    2017-03-30

    The concept of chemical space provides a convenient framework to analyze large collections of molecules by placing them in property spaces where distances represent similarities. Here we report webMolCS, a new type of web-based interface visualizing up to 5000 user-defined molecules in six different three-dimensional (3D) chemical spaces obtained by principal component analysis or similarity mapping of multidimensional property spaces describing composition (MQN: 42D molecular quantum numbers, SMIfp: 34D SMILES fingerprint), shapes and pharmacophores (APfp: 20D atom pair fingerprint, Xfp: 55D category extended atom pair fingerprint), and substructures (Sfp: 1024D binary substructure fingerprint, ECfp4:1024D extended connectivity fingerprint). Each molecule is shown as a sphere, and its structure appears on mouse over. The sphere is color-coded by similarity to the first compound in the list, by the list rank, or by a user-defined value, which reveals the relationship between any property encoded by these values and structural similarities. WebMolCS is freely available at www.gdb.unibe.ch .

  9. Observational data and orbits of the asteroids discovered at the Molėtai observatory in 2008-2009

    NASA Astrophysics Data System (ADS)

    Černis, K.; Wlodarczyk, I.; Zdanavičius, J.

    We present the statistics of the asteroids observed and discovered at the Molėtai Observatory, Lithuania, in 2008-2009 within the project for astrometric observations of the near-Earth objects (NEOs), the main belt asteroids and comets. CCD observations of the asteroids were obtained with the 35/51-cm Maksutov-type meniscus telescope. In the Minor Planet Circulars and the Minor Planet Electronic Circulars (2008-2009), 11 900 astrometric positions of 2522 asteroids were published. Among them 95 were new asteroids, including four belonging to the Trojan group: (352655) 2008QX28, 2008 SE8, (353194) 2009 SM100 and (264068) 2009 SQ148. For the asteroids discovered at Molėtai their precise orbits are calculated. Because of short observational arc, a few asteroids have low-precision orbits and some asteroids are considered lost. For the three Main Belt asteroids with low-precision orbital elements, 2008 QP32, 2008 SD8 and 2008 SG150, we present their ephemerides for 2017. They can be brighter than 20 mag.

  10. Busulfan 12 mg/kg plus melphalan 140 mg/m2 versus melphalan 200 mg/m2 as conditioning regimens for autologous transplantation in newly diagnosed multiple myeloma patients included in the PETHEMA/GEM2000 study

    PubMed Central

    Lahuerta, Juan José; Mateos, Maria Victoria; Martínez-López, Joaquin; Grande, Carlos; de la Rubia, Javier; Rosiñol, Laura; Sureda, Anna; García-Laraña, José; Díaz-Mediavilla, Joaquín; Hernández-García, Miguel T.; Carrera, Dolores; Besalduch, Joan; de Arriba, Felipe; Oriol, Albert; Escoda, Lourdes; García-Frade, Javier; Rivas-González, Concepción; Alegre, Adrían; Bladé, Joan; San Miguel, Jesús F.

    2010-01-01

    Background The aim of this study was to compare the long-term safety and efficacy of oral busulfan 12 mg/kg plus melphalan 140 mg/m2 and melphalan 200 mg/m2 as conditioning regimens for autologous stem cell transplantation in newly diagnosed patients with multiple myeloma in the GEM2000 study. Design and Methods The first 225 patients received oral busulfan 12 mg/kg plus melphalan 140 mg/m2; because of a high frequency of veno-occlusive disease, the protocol was amended and a further 542 patients received melphalan 200 mg/m2. Results Engraftment and hospitalization times were similar in both groups. Oral busulfan 12 mg/kg plus melphalan 140 mg/m2 resulted in higher transplant-related mortality (8.4% versus 3.5%; P=0.002) due to the increased frequency of veno-occlusive disease in this group. Response rates were similar in both arms. With respective median follow-ups of 72 and 47 months, the median progression-free survival was significantly longer with busulfan plus melphalan (41 versus 31 months; P=0.009), although survival was similar to that in the melphalan 200 mg/m2 group. However, access to novel agents as salvage therapy after relapse/progression was significantly lower for patients receiving busulfan plus melphalan (43%) than for those receiving melphalan 200 mg/m2 (58%; P=0.01). Conclusions Conditioning with oral busulfan 12 mg/kg plus melphalan 140 mg/m2 was associated with longer progression-free survival but equivalent survival to that achieved with melphalan 200 mg/m2 but this should be counterbalanced against the higher frequency of veno-occlusive disease-related deaths. This latter fact together with the limited access to novel salvage therapies in patients conditioned with oral busulfan 12 mg/kg plus melphalan 140 mg/m2 may explain the absence of a survival difference. Oral busulfan was used in the present study; use of the intravenous formulation may reduce toxicity and result in greater efficacy, and warrants further investigation in myeloma

  11. 3d-modelling workflows for trans-nationally shared geological models - first approaches from the project GeoMol

    NASA Astrophysics Data System (ADS)

    Rupf, Isabel

    2013-04-01

    To meet the EU's ambitious targets for carbon emission reduction, renewable energy production has to be strongly upgraded and made more efficient for grid energy storage. Alpine Foreland Basins feature a unique geological inventory which can contribute substantially to tackle these challenges. They offer a geothermal potential and storage capacity for compressed air, as well as space for underground storage of CO2. Exploiting these natural subsurface resources will strongly compete with existing oil and gas claims and groundwater issues. The project GeoMol will provide consistent 3-dimensional subsurface information about the Alpine Foreland Basins based on a holistic and transnational approach. Core of the project GeoMol is a geological framework model for the entire Northern Molasse Basin, complemented by five detailed models in pilot areas, also in the Po Basin, which are dedicated to specific questions of subsurface use. The models will consist of up to 13 litho-stratigraphic horizons ranging from the Cenozoic basin fill down to Mesozoic and late Paleozoic sedimentary rocks and the crystalline basement. More than 5000 wells and 28 000 km seismic lines serve as input data sets for the geological subsurface model. The data have multiple sources and various acquisition dates, and their interpretations have gone through several paradigm changes. Therefore, it is necessary to standardize the data with regards to technical parameters and content prior to further analysis (cf. Capar et al. 2013, EGU2013-5349). Each partner will build its own geological subsurface model with different software solutions for seismic interpretation and 3d-modelling. Therefore, 3d-modelling follows different software- and partner-specific workflows. One of the main challenges of the project is to ensure a seamlessly fitting framework model. It is necessary to define several milestones for cross border checks during the whole modelling process. Hence, the main input data set of the

  12. The M2 macrophages induce autophagic vascular disorder and promote mouse sensitivity to urethane-related lung carcinogenesis.

    PubMed

    Li, G-G; Guo, Z-Z; Ma, X-F; Cao, N; Geng, S-N; Zheng, Y-Q; Meng, M-J; Lin, H-H; Han, G; Du, G-J

    2016-06-01

    Tumor vessels are known to be abnormal, with typically aberrant, leaky and disordered vessels. Here, we investigated whether polarized macrophage phenotypes are involved in tumor abnormal angiogenesis and what is its mechanism. We found that there was no difference in chemotaxis of polarized M1 and M2 macrophages to lewis lung carcinoma (LLC) cells and that either M1 or M2 macrophage-conditioned media had no effect on LLC cell proliferation. Unexpectedly, the M2 but not M1 macrophage-conditioned media promoted the proliferation of human umbilical vein endothelial cells (HUVECs) and simultaneously increased endothelial cell permeability in vitro and angiogenic index in the chick embryo chorioallantoic membrane (CAM). The treatment with M2 but not M1 macrophage-conditioned media increased autophagosomes as well as microtubule-associated protein light chain 3B (LC3-B) expression (a robust marker of autophagosomes) but decreased p62 protein expression (a selective autophagy substrate) in HUVECs, the treatment with chloroquine that blocked autophagy abrogated the abnormal angiogenic efficacy of M2 macrophage-conditioned media. These results were confirmed in urethane-induced lung carcinogenic progression. Urethane-induced lung carcinogenesis led to more M2 macrophage phenotype and increased abnormal angiogenesis concomitant with the upregulation of LC3-B and the downregulation of p62. Clodronate liposome-induced macrophage depletion, chloroquine-induced autophagic prevention or salvianolic acid B-induced vascular protection decreased abnormal angiogenesis and lung carcinogenesis. In addition, we found that the tendency of age-related M2 macrophage polarization also promoted vascular permeability and carcinogenesis in urethane carcinogenic progression. These findings indicate that the M2 macrophages induce autophagic vascular disorder to promote lung cancer progression, and the autophagy improvement represents an efficacious strategy for abnormal angiogenesis and cancer

  13. Free-Energy Profiles of Membrane Insertion of the M2 Transmembrane Peptide from Influenza A Virus

    DTIC Science & Technology

    2008-12-01

    16,17). Recently, Stouffer et al. (18) determined the high-resolution structure of the M2-TMP in the presence of an amantadine -like inhibitors with x...However, they also show significant differences in structural details related to the amantadine inhibition mechanism. Further structural studies need...influenza-A M2 protein forms amantadine -sensitive proton channels in planar lipid bilayers. Virology. 190:485–489. 18. Stouffer, A. L., R. Acharya, D

  14. Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10.

    PubMed

    Ambade, Aditya; Satishchandran, Abhishek; Saha, Banishree; Gyongyosi, Benedek; Lowe, Patrick; Kodys, Karen; Catalano, Donna; Szabo, Gyongyi

    2016-01-01

    Obesity-related inflammation promotes cancer development. Tissue resident macrophages affect tumor progression and the tumor micro-environment favors polarization into alternatively activated macrophages (M2) that facilitate tumor invasiveness. Here, we dissected the role of western diet-induced NASH in inducing macrophage polarization in a carcinogen initiated model of hepatocellular carcinoma (HCC). Adult C57BL/6 male mice received diethyl nitrosamine (DEN) followed by 24 weeks of high fat-high cholesterol-high sugar diet (HF-HC-HSD). We assessed liver MRI and histology, serum ALT, AFP, liver triglycerides, and cytokines. Macrophage polarization was determined by IL-12/TNFα (M1) and CD163/CD206 (M2) expression using flow cytometry. Role of hif-1α-induced IL-10 was dissected in hepatocyte specific hif-1αKO and hif-1αdPA (over-expression) mice. The western diet-induced features of NASH and accelerated HCC development after carcinogen exposure. Liver fibrosis and serum AFP were significantly increased in DEN + HF-HC-HSD mice compared to controls. Western diet resulted in macrophage (F4/80(+)CD11b(+)) infiltration to liver and DEN + HF-HC-HSD mice showed preferential increase in M2 macrophages. Isolated hepatocytes from western diet fed mice showed significant upregulation of the hypoxia-inducible transcription factor, hif-1α, and livers from hif-1α over-expressing mice had increased proportion of M2 macrophages. Primary hepatocytes from wild-type mice treated with DEN and palmitic acid in vitro showed activation of hif-1α and induction of IL-10, a M2 polarizing cytokine. IL-10 neutralization in hepatocyte-derived culture supernatant prevented M2 macrophage polarization and silencing hif-1α in macrophages blocked their M2 polarization. Therefore, our data demonstrate that NASH accelerates HCC progression via upregulation of hif-1α mediated IL-10 polarizing M2 macrophages.

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

    PubMed

    Leblond, Anne-Laure; Klinkert, Kerstin; Martin, Kenneth; Turner, Elizebeth C; Kumar, Arun H; Browne, Tara; Caplice, Noel M

    2015-01-01

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

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

    PubMed

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

    2012-01-01

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

  17. M2-like tumor-associated macrophages drive vasculogenic mimicry through amplification of IL-6 expression in glioma cells

    PubMed Central

    Zhang, Lin; Xu, Yangyang; Sun, Jintang; Chen, Weiliang; Zhao, Lei; Ma, Chao; Wang, Qingjie; Sun, Jia; Huang, Bin; Zhang, Yun; Li, Xingang; Qu, Xun

    2017-01-01

    Vasculogenic mimicry (VM) has offered a new horizon for understanding tumor angiogenesis, but the mechanisms of VM in glioma progression have not been studied explicitly until now. As a significant component of immune infiltration in tumor microenvironment, macrophages have been demonstrated to play an important role in tumor growth and angiogenesis. However, whether macrophages could play a potential key role in glioma VM is still poorly understood. Herein we reported that both VM and CD163+ cells were associated with WHO grade and reduced patient survival, and VM channel counting was correlated to the number of infiltrated CD163+ cells in glioma specimens. In vitro studies of glioma cell lines implicated that M2-like macrophages (M2) promoted glioma VM. We found that conditional medium derived from M2 amplified IL-6 expression in glioma cells. Furthermore, our data indicated that IL-6 could promote glioma VM, as blocking IL-6 with neutralizing antibodies abrogated M2-mediated VM enhancement. In addition, the potent PKC inhibitor bisindolylmaleimide I could prevent M2-induced IL-6 upregulation and further inhibited glioma VM facilitation. Taken together, our results suggested that M2-like macrophages drove glioma VM through amplifying IL-6 secretion in glioma cells via PKC pathway. PMID:27903982

  18. On use of the variable Zagreb vM2 index in QSPR: boiling points of benzenoid hydrocarbons.

    PubMed

    Nikolić, Sonja; Milicević, Ante; Trinajstić, Nenad; Jurić, Albin

    2004-12-31

    The variable Zagreb (v)M(2) index is introduced and applied to the structure-boiling point modeling of benzenoid hydrocarbons. The linear model obtained (the standard error of estimate for the fit model S(fit)=6.8 degrees C) is much better than the corresponding model based on the original Zagreb M2 index (S(fit)=16.4 degrees C). Surprisingly,the model based on the variable vertex-connectivity index (S(fit)=6.8 degrees C) is comparable to the model based on (v)M2 index. A comparative study with models based on the vertex-connectivity index, edge-connectivity index and several distance indices favours models based on the variable Zagreb (v)M2 index and variable vertex-connectivity index.However, the multivariate regression with two-, three- and four-descriptors gives improved models, the best being the model with four-descriptors (but (v)M2 index is not among them) with S(fit)=5 degrees C, though the four-descriptor model contaning (v)M2 index is only slightly inferior (S(fit)=5.3 degrees C).

  19. Cholesterol dependent conformational exchange of the C-terminal domain of the influenza A M2 protein

    PubMed Central

    Kim, Sangwoo S.; Upshur, Mary Alice; Saotome, Kei; Sahu, Indra D.; McCarrick, Robert M.; Feix, Jimmy B.; Lorigan, Gary A.; Howard, Kathleen P.

    2016-01-01

    The C-terminal amphipathic helix of the influenza A M2 protein plays a critical cholesterol dependent role in viral budding. To provide atomic-level detail on the impact cholesterol has on the conformation of M2 protein, we spin-labeled sites right before and within the C-terminal amphipathic helix of the M2 protein. We studied the spin-labeled M2 proteins in membranes both with and without cholesterol. We used a multipronged site-directed spin-label electron paramagnetic resonance (SDSL-EPR) approach and collected data on line shapes, relaxation rates, accessibility of sites to the membrane, and distances between symmetry related sites within the tetrameric protein. We demonstrate that the C-terminal amphipathic helix of M2 populates at least two conformations in POPC/POPG 4:1 bilayers. Furthermore, we show that the conformational state that becomes more populated in the presence of cholesterol is less dynamic, less membrane buried, and more tightly packed than the other state. Cholesterol dependent changes in M2 could be attributed to the changes cholesterol induces in bilayer properties and/or direct binding of cholesterol to the protein. We propose a model consistent with all our experimental data that suggests that the predominant conformation we observe in the presence of cholesterol is relevant for the understanding of viral budding. PMID:26569023

  20. Purification of the 22000- and 20000-mol.wt. forms of human somatotropin and characterization of their binding to liver and mammary binding sites.

    PubMed Central

    Closset, J; Smal, J; Gomez, F; Hennen, G

    1983-01-01

    Quantitative data concerning the binding of 22000-mol.wt. human somatotropin and its 20000-mol.wt. variant are described using pregnant-rabbit liver and mammary-gland receptors. The purification and the complete chemical characterization of both human somatotropin and its 20000-mol.wt. variant is also presented. Contamination of the 20000-mol.wt.-variant preparation by 22000-mol.wt. hormone was found to be 0.5% by weight as measured in radioimmunoassay using monoclonal antibody. Labelling of human somatotropin and its 20000-mol.wt. variant using the Iodogen method is described as well as the characterization of the binding to pregnant-rabbit liver and mammary-gland receptor preparations. The maximum binding capacity of the 125I-labelled human somatotropin was between 50 and 60% to liver particulate receptor, whereas that of the 20000-mol.wt. variant was 30%. The specificity of binding of both forms to rabbit hepatic and mammary-gland receptor was found to be similar for both proteins in the same system. The affinity constants and capacity were respectively 0.7 X 10(10)M-1 and 815 fmol/mg of protein for human somatotropin and 0.6 X 10(10)M-1 and 1.250 fmol/mg of protein for the 20000-mol.wt. variant. These data suggest that both proteins behave as partial agonists to the receptors studied. PMID:6312965

  1. PREFACE: 10th International Conference on Materials and Mechanisms of Superconductivity (M2S-X)

    NASA Astrophysics Data System (ADS)

    Greene, L. H.; Zhu, J.-X.; Wang, H.; Meen, J.; Lorenz, B.; Dong, X. L.; dela Cruz, C. R.; Carlson, E.; Bud'ko, S. L.; Bauer, E.; Paglione, J.

    2013-07-01

    The 2012 Materials and Mechanisms of Superconductivity Conference (M2S 2012), which occurs every three years, brought together world experts and young scientists to discuss open questions in the fundamental physics and applications of superconductors, and to disseminate the latest theoretical and experimental research results in superconductors and related novel materials. This conference of 600 participants acted as a valuable training ground in this technologically important area. We focused on key unanswered questions in high-temperature cuprate superconductors, high-temperature iron-based superconductors, topological superconductors, organic superconductors, and heavy-electron superconductors. The discovery of new materials and novel technological applications for electronic devices and for energy transmission and storage was emphasized. There were special sessions on superconductivity and energy, and outreach sessions, and an evening public lecture. There were also junior researcher symposia interspersed within the conference, thus providing an ideal environment for advanced graduate students and postdoctoral researchers to explore the latest theoretical and experimental methods used to investigate challenging questions in the physics of materials as it relates to both fundamental science and technological applications. These proceedings are an archival testament to the excitement in the field and provide a valuable snapshot of the cutting-edge research of 2012. We hope this will be a valuable resource to active researchers in the field as well as an encouraging volume to excite new researchers to the ever-growing, multifaceted field of superconductivity. We thank Bernd Lorenz and his Publications Committee for their tremendously creative and diligent work in putting this volume together. This Conference would not have been possible without the tireless work of our Program Committee, Chaired by Rick Greene and Co-Chaired by Mike Norman. Becky McDuffee, our

  2. M-M bond-stretching energy landscapes for M2(dimen)4(2+) (M = Rh, Ir; dimen = 1,8-diisocyanomenthane) complexes.

    PubMed

    Hunter, Bryan M; Villahermosa, Randy M; Exstrom, Christopher L; Hill, Michael G; Mann, Kent R; Gray, Harry B

    2012-06-18

    Isomers of Ir(2)(dimen)(4)(2+) (dimen = 1,8-diisocyanomenthane) exhibit different Ir-Ir bond distances in a 2:1 MTHF/EtCN solution (MTHF = 2-methyltetrahydrofuran). Variable-temperature absorption data suggest that the isomer with the shorter Ir-Ir distance is favored at room temperature [K = ∼8; ΔH° = -0.8 kcal/mol; ΔS° = 1.44 cal mol(-1) K(-1)]. We report calculations that shed light on M(2)(dimen)(4)(2+) (M = Rh, Ir) structural differences: (1) metal-metal interaction favors short distances; (2) ligand deformational-strain energy favors long distances; (3) out-of-plane (A(2u)) distortion promotes twisting of the ligand backbone at short metal-metal separations. Calculated potential-energy surfaces reveal a double minimum for Ir(2)(dimen)(4)(2+) (∼4.1 Å Ir-Ir with 0° twist angle and ∼3.6 Å Ir-Ir with ±12° twist angle) but not for the rhodium analogue (∼4.5 Å Rh-Rh with no twisting). Because both the ligand strain and A(2u) distortional energy are virtually identical for the two complexes, the strength of the metal-metal interaction is the determining factor. On the basis of the magnitude of this interaction, we obtain the following results: (1) a single-minimum (along the Ir-Ir coordinate), harmonic potential-energy surface for the triplet electronic excited state of Ir(2)(dimen)(4)(2+) (R(e,Ir-Ir) = 2.87 Å; F(Ir-Ir) = 0.99 mdyn Å(-1)); (2) a single-minimum, anharmonic surface for the ground state of Rh(2)(dimen)(4)(2+) (R(e,Rh-Rh) = 3.23 Å; F(Rh-Rh) = 0.09 mdyn Å(-1)); (3) a double-minimum (along the Ir-Ir coordinate) surface for the ground state of Ir(2)(dimen)(4)(2+) (R(e,Ir-Ir) = 3.23 Å; F(Ir-Ir) = 0.16 mdyn Å(-1)).

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

    NASA Technical Reports Server (NTRS)

    1966-01-01

    NASA research pilot Milt Thompson sits in the M2-F2 'heavyweight' lifting body research vehicle before a 1966 test flight. The M2-F2 and the other lifting-body designs were all attached to a wing pylon on NASA's B-52 mothership and carried aloft. The vehicles were then drop-launched and, at the end of their flights, glided back to wheeled landings on the dry lake or runway at Edwards AFB. The lifting body designs influenced the design of the Space Shuttle and were also reincarnated in the design of the X-38 in the 1990s. NASA B-52, Tail Number 008, is an air launch carrier aircraft, 'mothership