Superconductivity as a probe of magnetic switching and ferromagnetic stability in Nb/Ni multilayers

The temperature and field dependences of the AC and DC magnetic moment of superconducting and ferromagnetic Nb/Ni multilayers were measured using a SQUID magnetometer with magnetic field applied parallel to the multilayer plane. Periodic kinks in the superconducting upper critical field are evidence for nucleation of a hierarchy of Abrikosov vortex lattices aligned parallel to the multilayer. Small cusps in the low-field, isothermal DC magnetization are evidence that supercurrents are sensitive to extremely small changes in the Ni layer magnetization. Smooth ferromagnetic hysteresis is observed in the normal state, but is supplanted below the superconducting transition by two reproducible discontinuities that indicate magnetic switching of the Ni layers is tightly coupled to the supercurrents. The discontinuities are attributed to the non-dipole character of the moment near switching fields and, therefore, cannot be analyzed by standard magnetometer software. Ferromagnetic resonance spectra were measured in parallel and perpendicular DC magnetic fields at room temperature and 4.2 K, and resulting data suggest that Ni layers interact magnetically in the superconducting state

Two Chromatin Remodeling Activities Cooperate during Activation of Hormone Responsive Promoters

Steroid hormones regulate gene expression by interaction of their receptors with hormone responsive elements (HREs) and recruitment of kinases, chromatin remodeling complexes, and coregulators to their target promoters. Here we show that in breast cancer cells the BAF, but not the closely related PBAF complex, is required for progesterone induction of several target genes including MMTV, where it catalyzes localized displacement of histones H2A and H2B and subsequent NF1 binding. PCAF is also needed for induction of progesterone target genes and acetylates histone H3 at K14, an epigenetic mark that interacts with the BAF subunits by anchoring the complex to chromatin. In the absence of PCAF, full loading of target promoters with hormone receptors and BAF is precluded, and induction is compromised. Thus, activation of hormone-responsive promoters requires cooperation of at least two chromatin remodeling activities, BAF and PCAF

A polymeric nanomedicine diminishes inflammatory events in renal tubular cells

The polyglutamic acid/peptoid 1 (QM56) nanoconjugate inhibits apoptosis by interfering with Apaf-1 binding to procaspase-9. We now describe anti-inflammatory properties of QM56 in mouse kidney and renal cell models. In cultured murine tubular cells, QM56 inhibited the inflammatory response to Tweak, a non-apoptotic stimulus. Tweak induced MCP-1 and Rantes synthesis through JAK2 kinase and NF-kB activation. Similar to JAK2 kinase inhibitors, QM56 inhibited Tweak-induced NF-kB transcriptional activity and chemokine expression, despite failing to inhibit NF-kB-p65 nuclear translocation and NF-kB DNA binding. QM56 prevented JAK2 activation and NF-kB-p65(Ser536) phosphorylation. The anti-inflammatory effect and JAK2 inhibition by QM56 were observed in Apaf-12/2 cells. In murine acute kidney injury, QM56 decreased tubular cell apoptosis and kidney inflammation as measured by downmodulations of MCP-1 and Rantes mRNA expression, immune cell infiltration and activation of the JAK2-dependent inflammatory pathway. In conclusion, QM56 has an anti-inflammatory activity which is independent from its role as inhibitor of Apaf-1 and apoptosis and may have potential therapeutic relevance.This work was supported by grants from the Instituto de Salud Carlos III (www.isciii.es), FIS: PI07/0020, CP08/1083, PS09/00447 and ISCIII-RETICS REDINREN RD 06/0016; Sociedad Española de Nefrología (www.senefro.org). Álvaro Ucero, Sergio Berzal and Carlos Ocaña supported by Fundacion Conchita Rabago (www.fundacionconchitarabago.net), Alberto Ortiz by the Programa de Intensificación de la Actividad Investigadora in the Sistema Nacional de Salud of the Instituto de Salud Carlos III and the Agencia ‘‘Pedro Lain Entralgo’’ of the Comunidad de Madrid and CIFRA S-BIO 0283/2006 www.madrid.org/lainentralgo) and Adrián Ramos, by FIS (Programa Miguel Servet)

Optimization of atmospheric plasma treatment of LDPE films: Influence on adhesive properties and ageing behavior

One of the major disadvantages of low density polyethylene (LDPE) films is their poor adhesive properties. Therefore, LDPE films have been treated with atmospheric pressure air plasma in order to improve their surface properties. So as to simulate the possible conditions in an industrial process, the samples have been treated with two different sample distances (6 and 10 mm), and treatment rates between 100 and 1000 mm s-1. The different sample distances are the distance of the sample from the plasma source. The variation of the surface properties and adhesion characteristics of the films were investigated for different aging times after plasma exposure (up to 21 days) using contact angle measurement, atomic force microscopy, weight loss measurements and shear test. Results show that the treatment increases the polar component () and these changes improve adhesive properties of the material. After the twenty-first day, the ageing process causes a decrease of wettability and adhesive properties of the LDPE films (up to 60%).Fombuena Borrás, V.; García Sanoguera, D.; Sánchez Nacher, L.; Balart Gimeno, RA.; Boronat Vitoria, T. (2014). Optimization of atmospheric plasma treatment of LDPE films: Influence on adhesive properties and ageing behavior. Journal of Adhesion Science and Technology. 28(1):97-113. doi:10.1080/01694243.2013.847045S97113281Achilias, D. S., Roupakias, C., Megalokonomos, P., Lappas, A. A., & Antonakou, Ε. V. (2007). Chemical recycling of plastic wastes made from polyethylene (LDPE and HDPE) and polypropylene (PP). Journal of Hazardous Materials, 149(3), 536-542. doi:10.1016/j.jhazmat.2007.06.076Friedman, M., & Walsh, G. (2002). High performance films: Review of new materials and trends. Polymer Engineering & Science, 42(8), 1756-1788. doi:10.1002/pen.11069Wiles, D. M., & Scott, G. (2006). Polyolefins with controlled environmental degradability. Polymer Degradation and Stability, 91(7), 1581-1592. doi:10.1016/j.polymdegradstab.2005.09.010Gao, J., Lei, J., Li, Q., & Ye, S. (2004). Functionalized low-density polyethylene via a novel photografting method and its adhesion properties. Journal of Adhesion Science and Technology, 18(2), 195-203. doi:10.1163/156856104772759403Shenton, M. J., Lovell-Hoare, M. C., & Stevens, G. C. (2001). Adhesion enhancement of polymer surfaces by atmospheric plasma treatment. Journal of Physics D: Applied Physics, 34(18), 2754-2760. doi:10.1088/0022-3727/34/18/307Belgacem, M. N., Salon-Brochier, M. C., Krouit, M., & Bras, J. (2011). Recent Advances in Surface Chemical Modification of Cellulose Fibres. Journal of Adhesion Science and Technology, 25(6-7), 661-684. doi:10.1163/016942410x525867Friedrich, J., Unger, W., & Lippitz, A. (1995). Plasma modification of polymer surfaces. Macromolecular Symposia, 100(1), 111-115. doi:10.1002/masy.19951000118Ladizesky, N. H., & Ward, I. M. (1989). The adhesion behaviour of high modulus polyethylene fibres following plasma and chemical treatment. Journal of Materials Science, 24(10), 3763-3773. doi:10.1007/bf02385768Nardin, M., & Ward, I. M. (1987). Influence of surface treatment on adhesion of polyethylene fibres. Materials Science and Technology, 3(10), 814-826. doi:10.1179/mst.1987.3.10.814Villagra Di Carlo, B., Gottifredi, J. C., & Habert, A. C. (2010). Synthesis and characterization of composite membrane by deposition of acrylic acid plasma polymer onto pre-treated polyethersulfone support. Journal of Materials Science, 46(6), 1850-1856. doi:10.1007/s10853-010-5012-4Matsunaga, M., & Whitney, P. J. (2000). Surface changes brought about by corona discharge treatment of polyethylene film and the effect on subsequent microbial colonisation. Polymer Degradation and Stability, 70(3), 325-332. doi:10.1016/s0141-3910(00)00105-1Novák, I., Pollák, V., & Chodák, I. (2006). Study of Surface Properties of Polyolefins Modified by Corona Discharge Plasma. Plasma Processes and Polymers, 3(4-5), 355-364. doi:10.1002/ppap.200500163Arpagaus, C., Rossi, A., & Rudolf von Rohr, P. (2005). Short-time plasma surface modification of HDPE powder in a Plasma Downer Reactor – process, wettability improvement and ageing effects. Applied Surface Science, 252(5), 1581-1595. doi:10.1016/j.apsusc.2005.02.099Morra, M., Occhiello, E., Marola, R., Garbassi, F., Humphrey, P., & Johnson, D. (1990). On the aging of oxygen plasma-treated polydimethylsiloxane surfaces. Journal of Colloid and Interface Science, 137(1), 11-24. doi:10.1016/0021-9797(90)90038-pKim, K. S., Ryu, C. M., Park, C. S., Sur, G. S., & Park, C. E. (2003). Investigation of crystallinity effects on the surface of oxygen plasma treated low density polyethylene using X-ray photoelectron spectroscopy. Polymer, 44(20), 6287-6295. doi:10.1016/s0032-3861(03)00674-8Kim, S. H., Ha, H. J., Ko, Y. K., Yoon, S. J., Rhee, J. M., Kim, M. S., … Khang, G. (2007). Correlation of proliferation, morphology and biological responses of fibroblasts on LDPE with different surface wettability. Journal of Biomaterials Science, Polymer Edition, 18(5), 609-622. doi:10.1163/156856207780852514Borcia, G., Anderson, C. A., & Brown, N. M. D. (2004). The surface oxidation of selected polymers using an atmospheric pressure air dielectric barrier discharge. Part I. Applied Surface Science, 221(1-4), 203-214. doi:10.1016/s0169-4332(03)00879-1Pascual, M., Calvo, O., Sanchez-Nácher, L., Bonet, M. A., Garcia-Sanoguera, D., & Balart, R. (2009). Optimization of adhesive joints of low density polyethylene (LDPE) composite laminates with polyolefin foam using corona discharge plasma. Journal of Applied Polymer Science, 114(5), 2971-2977. doi:10.1002/app.30906Encinas, N., Díaz-Benito, B., Abenojar, J., & Martínez, M. A. (2010). Extreme durability of wettability changes on polyolefin surfaces by atmospheric pressure plasma torch. Surface and Coatings Technology, 205(2), 396-402. doi:10.1016/j.surfcoat.2010.06.069Takke, V., Behary, N., Perwuelz, A., & Campagne, C. (2009). Studies on the atmospheric air-plasma treatment of PET (polyethylene terephtalate) woven fabrics: Effect of process parameters and of aging. Journal of Applied Polymer Science, 114(1), 348-357. doi:10.1002/app.30618Awaja, F., Gilbert, M., Kelly, G., Fox, B., & Pigram, P. J. (2009). Adhesion of polymers. Progress in Polymer Science, 34(9), 948-968. doi:10.1016/j.progpolymsci.2009.04.007Garcia, D., Sanchez, L., Fenollar, O., Lopez, R., & Balart, R. (2008). Modification of polypropylene surface by CH4–O2 low-pressure plasma to improve wettability. Journal of Materials Science, 43(10), 3466-3473. doi:10.1007/s10853-007-2322-2Guimond, S., & Wertheimer, M. R. (2004). Surface degradation and hydrophobic recovery of polyolefins treated by air corona and nitrogen atmospheric pressure glow discharge. Journal of Applied Polymer Science, 94(3), 1291-1303. doi:10.1002/app.21134Pascual, M., Balart, R., Sánchez, L., Fenollar, O., & Calvo, O. (2008). Study of the aging process of corona discharge plasma effects on low density polyethylene film surface. Journal of Materials Science, 43(14), 4901-4909. doi:10.1007/s10853-008-2712-0Sanchis, R., Fenollar, O., García, D., Sánchez, L., & Balart, R. (2008). Improved adhesion of LDPE films to polyolefin foams for automotive industry using low-pressure plasma. International Journal of Adhesion and Adhesives, 28(8), 445-451. doi:10.1016/j.ijadhadh.2008.04.002Fresnais, J., Chapel, J. P., Benyahia, L., & Poncin-Epaillard, F. (2009). Plasma-Treated Superhydrophobic Polyethylene Surfaces: Fabrication, Wetting and Dewetting Properties. Journal of Adhesion Science and Technology, 23(3), 447-467. doi:10.1163/156856108x370127Abenojar, J., Colera, I., Martínez, M. A., & Velasco, F. (2010). Study by XPS of an Atmospheric Plasma-Torch Treated Glass: Influence on Adhesion. Journal of Adhesion Science and Technology, 24(11-12), 1841-1854. doi:10.1163/016942410x507614Lommatzsch, U., Pasedag, D., Baalmann, A., Ellinghorst, G., & Wagner, H.-E. (2007). Atmospheric Pressure Plasma Jet Treatment of Polyethylene Surfaces for Adhesion Improvement. Plasma Processes and Polymers, 4(S1), S1041-S1045. doi:10.1002/ppap.200732402Balu, B., Berry, A. D., Patel, K. T., Breedveld, V., & Hess, D. W. (2011). Directional Mobility and Adhesion of Water Drops on Patterned Superhydrophobic Surfaces. Journal of Adhesion Science and Technology, 25(6-7), 627-642. doi:10.1163/016942410x525849Bhattacharya, S., Singh, R. K., Mandal, S., Ghosh, A., Bok, S., Korampally, V., … Gangopadhyay, S. (2010). Plasma Modification of Polymer Surfaces and Their Utility in Building Biomedical Microdevices. Journal of Adhesion Science and Technology, 24(15-16), 2707-2739. doi:10.1163/016942410x511105Das, S., Neogi, S., Chainy, G. B. N., & Guha, S. K. (2011). A Novel Two-Step Procedure for Plasma Surface Modification of Low-Density Polyethylene for Improved Drug Adhesion in Intra Uterine Devices (IUDs). Journal of Adhesion Science and Technology, 25(1-3), 151-167. doi:10.1163/016942410x503285Schulz, U., Munzert, P., & Kaiser, N. (2010). Plasma Surface Modification of PMMA for Optical Applications. Journal of Adhesion Science and Technology, 24(7), 1283-1289. doi:10.1163/016942409x12561252292026Silverstein, M. S., Breuer, O., & Dodiuk, H. (1994). Surface modification of UHMWPE fibers. Journal of Applied Polymer Science, 52(12), 1785-1795. doi:10.1002/app.1994.070521213Inagaki, N., Narushim, K., Tuchida, N., & Miyazaki, K. (2004). Surface characterization of plasma-modified poly(ethylene terephthalate) film surfaces. Journal of Polymer Science Part B: Polymer Physics, 42(20), 3727-3740. doi:10.1002/polb.20234Nakamatsu, J., Delgado-Aparicio, L. F., Da Silva, R., & Soberon, F. (1999). Ageing of plasma-treated poly(tetrafluoroethylene) surfaces. Journal of Adhesion Science and Technology, 13(7), 753-761. doi:10.1163/156856199x00983Yun, Y. I., Kim, K. S., Uhm, S.-J., Khatua, B. B., Cho, K., Kim, J. K., & Park, C. E. (2004). Aging behavior of oxygen plasma-treated polypropylene with different crystallinities. Journal of Adhesion Science and Technology, 18(11), 1279-1291. doi:10.1163/1568561041588200Morent, R., De Geyter, N., Leys, C., Gengembre, L., & Payen, E. (2007). Study of the ageing behaviour of polymer films treated with a dielectric barrier discharge in air, helium and argon at medium pressure. Surface and Coatings Technology, 201(18), 7847-7854. doi:10.1016/j.surfcoat.2007.03.018Zhao, B., & Kwon, H. J. (2011). Adhesion of Polymers in Paper Products from the Macroscopic to Molecular Level — An Overview. Journal of Adhesion Science and Technology, 25(6-7), 557-579. doi:10.1163/016942410x52582

Use of 1H and 31P HRMAS to evaluate the relationship between quantitative alterations in metabolite concentrations and tissue features in human brain tumour biopsies

[EN] Quantitative multinuclear high-resolution magic angle spinning (HRMAS) was performed in order to determine the tissue pH values of and the absolute metabolite concentrations in 33 samples of human brain tumour tissue. Metabolite concentrations were quantified by 1D 1 H and 31P HRMAS using the electronic reference to in vivo concentrations (ERETIC) synthetic signal. 1 H–1 H homonuclear and 1 H–31P heteronuclear correlation experiments enabled the direct assessment of the 1 H–31P spin systems for signals that suffered from overlapping in the 1D 1 H spectra, and linked the information present in the 1D 1 H and 31P spectra. Afterwards, the main histological features were determined, and high heterogeneity in the tumour content, necrotic content and nonaffected tissue content was observed. The metabolite profiles obtained by HRMAS showed characteristics typical of tumour tissues: rather low levels of energetic molecules and increased concentrations of protective metabolites. Nevertheless, these characteristics were more strongly correlated with the total amount of living tissue than with the tumour cell contents of the samples alone, which could indicate that the sampling conditions make a significant contribution aside from the effect of tumour development in vivo. The use of methylene diphosphonic acid as a chemical shift and concentration reference for the 31P HRMAS spectra of tissues presented important drawbacks due to its interaction with the tissue. Moreover, the pH data obtained from 31P HRMAS enabled us to establish a correlation between the pH and the distance between the N(CH3)3 signals of phosphocholine and choline in 1 H spectra of the tissue in these tumour samples.The authors acknowledge the SCSIE-University of Valencia Microscopy Service for the histological preparations. They also acknowledge Martial Piotto (Bruker BioSpin, France) for providing the ERETIC synthetic signal. Furthermore, they acknowledge financial support from the Spanish Government project SAF2007-6547, the Generalitat Valenciana project GVACOMP2009-303, and the E.U.'s VI Framework Programme via the project "Web accessible MR decision support system for brain tumor diagnosis and prognosis, incorporating in vivo and ex vivo genomic and metabolomic data" (FP6-2002-LSH 503094). CIBER-BBN is an initiative funded by the VI National R&D&D&i Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions, and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund.Esteve Moya, V.; Celda, B.; Martínez Bisbal, MC. (2012). Use of 1H and 31P HRMAS to evaluate the relationship between quantitative alterations in metabolite concentrations and tissue features in human brain tumour biopsies. Analytical and Bioanalytical Chemistry. 403:2611-2625. https://doi.org/10.1007/s00216-012-6001-zS26112625403Cheng LL, Chang IW, Louis DN, Gonzalez RG (1998) Cancer Res 58:1825–1832Opstad KS, Bell BA, Griffiths JR, Howe FA (2008) Magn Reson Med 60:1237–1242Sjobakk TE, Johansen R, Bathen TF, Sonnewald U, Juul R, Torp SH, Lundgren S, Gribbestad IS (2008) NMR Biomed 21:175–185Martinez-Bisbal MC, Marti-Bonmati L, Piquer J, Revert A, Ferrer P, Llacer JL, Piotto M, Assemat O, Celda B (2004) NMR Biomed 17:191–205Erb G, Elbayed K, Piotto M, Raya J, Neuville A, Mohr M, Maitrot D, Kehrli P, Namer IJ (2008) Magn Reson Med 59:959–965Wilson M, Davies NP, Brundler MA, McConville C, Grundy RG, Peet AC (2009) Mol Cancer 8:6Martinez-Bisbal MC, Monleon D, Assemat O, Piotto M, Piquer J, Llacer JL, Celda B (2009) NMR Biomed 22:199–206Martínez-Granados B, Monleón D, Martínez-Bisbal MC, Rodrigo JM, del Olmo J, Lluch P, Ferrández A, Martí-Bonmatí L, Celda B (2006) NMR Biomed 19:90–100Hubesch B, Sappey-Marinier D, Roth K, Meyerhoff DJ, Matson GB, Weiner MW (1990) Radiology 174:401–409Albers MJ, Krieger MD, Gonzalez-Gomez I, Gilles FH, McComb JG, Nelson MD Jr, Bluml S (2005) Magn Reson Med 53:22–29Wijnen JP, Scheenen TW, Klomp DW, Heerschap A (2010) NMR Biomed 23:968–976Podo F (1999) NMR Biomed 12:413–439Griffiths JR, Cady E, Edwards RH, McCready VR, Wilkie DR, Wiltshaw E (1983) Lancet 1:1435–1436Robitaille PL, Robitaille PA, Gordon Brown G, Brown GG (1991) J Magn Reson 92:73–84, 1969Griffiths JR (1991) Br J Cancer 64:425–427Payne GS, Troy H, Vaidya SJ, Griffiths JR, Leach MO, Chung YL (2006) NMR Biomed 19:593–598De Silva SS, Payne GS, Thomas V, Carter PG, Ind TE, deSouza NM (2009) NMR Biomed 22:191–198Wang Y, Cloarec O, Tang H, Lindon JC, Holmes E, Kochhar S, Nicholson JK (2008) Anal Chem 80:1058–1066Lehnhardt FG, Rohn G, Ernestus RI, Grune M, Hoehn M (2001) NMR Biomed 14:307–317Srivastava NK, Pradhan S, Gowda GA, Kumar R (2010) NMR Biomed 23:113–122Akoka S, Barantin L, Trierweiler M (1999) Anal Chem 71:2554–2557Albers MJ, Butler TN, Rahwa I, Bao N, Keshari KR, Swanson MG, Kurhanewicz J (2009) Magn Reson Med 61:525–532Ben Sellem D, Elbayed K, Neuville A, Moussallieh FM, Lang-Averous G, Piotto M, Bellocq JP, Namer IJ (2011) J Oncol 2011:174019Bourne R, Dzendrowskyj T, Mountford C (2003) NMR Biomed 16:96–101Martinez-Bisbal MC, Esteve V, Martinez-Granados B, Celda B (2011) J Biomed Biotechnol 2011:763684, Epub 2010 Sep 5Celda B, Montelione GT (1993) J Magn Reson B 101:189–193Esteve V, Celda B (2008) Magn Reson Mater Phys MAGMA 21:484–484Collins TJ (2007) Biotechniques 43:25–30Govindaraju V, Young K, Maudsley AA (2000) NMR Biomed 13:129–153Fan TW-M (1996) Prog Nucl Magn Reson Spectrosc 28:161–219Ulrich EL, Akutsu H, Doreleijers JF, Harano Y, Ioannidis YE, Lin J, Livny M, Mading S, Maziuk D, Miller Z, Nakatani E, Schulte CF, Tolmie DE, Kent Wenger R, Yao H, Markley JL (2008) Nucleic Acids Res 36:D402–D408Kriat M, Vion-Dury J, Confort-Gouny S, Favre R, Viout P, Sciaky M, Sari H, Cozzone PJ (1993) J Lipid Res 34:1009–1019Subramanian A, Shankar Joshi B, Roy AD, Roy R, Gupta V, Dang RS (2008) NMR Biomed 21:272–288Daykin CA, Corcoran O, Hansen SH, Bjornsdottir I, Cornett C, Connor SC, Lindon JC, Nicholson JK (2001) Anal Chem 73:1084–1090Griffin JL, Lehtimaki KK, Valonen PK, Grohn OH, Kettunen MI, Yla-Herttuala S, Pitkanen A, Nicholson JK, Kauppinen RA (2003) Cancer Res 63:3195–3201Petroff OAC, Prichard JW (1995) In: Kraicer J, Dixon SJ (eds) Methods in neurosciences. Academic, San DiegoBarton S, Howe F, Tomlins A, Cudlip S, Nicholson J, Anthony Bell B, Griffiths J (1999) Magn Reson Mater Phys Biol Med 8:121–128Sitter B, Sonnewald U, Spraul M, Fjosne HE, Gribbestad IS (2002) NMR Biomed 15:327–337Coen M, Hong YS, Cloarec O, Rhode CM, Reily MD, Robertson DG, Holmes E, Lindon JC, Nicholson JK (2007) Anal Chem 79:8956–8966Russell D, Rubinstein LJ (1998) Russel and Rubinstein's pathology of tumors of the nervous system. Arnold, LondonTynkkynen T, Tiainen M, Soininen P, Laatikainen R (2009) Anal Chim Acta 648:105–112Kjaergaard M, Brander S, Poulsen F (2011) J Biomol NMR 49:139–149Robert O, Sabatier J, Desoubzdanne D, Lalande J, Balayssac S, Gilard V, Martino R, Malet-Martino M (2011) Anal Bioanal Chem 399:987–999Chadzynski GL, Bender B, Groeger A, Erb M, Klose U (2011) J Magn Reson 212:55–63Weljie AM, Jirik FR (2011) Int J Biochem Cell Biol 43:981–989Barba I, Cabanas ME, Arus C (1999) Cancer Res 59:1861–1868Liimatainen T, Hakumaki JM, Kauppinen RA, Ala-Korpela M (2009) NMR Biomed 22:272–279Opstad KS, Bell BA, Griffiths JR, Howe FA (2008) NMR Biomed 21:677–685Schmitz JE, Kettunen MI, Hu D, Brindle KM (2005) Magn Reson Med 54:43–50Glunde K, Artemov D, Penet MF, Jacobs MA, Bhujwalla ZM (2010) Chem Rev 110:3043–3059Hertz L (2008) Neuropharmacology 55:289–309Takahashi T, Otsuguro K, Ohta T, Ito S (2010) Br J Pharmacol 161:1806–181

Striatal Pre- and Postsynaptic Profile of Adenosine A2A Receptor Antagonists

Striatal adenosine A2A receptors (A2ARs) are highly expressed in medium spiny neurons (MSNs) of the indirect efferent pathway, where they heteromerize with dopamine D2 receptors (D2Rs). A2ARs are also localized presynaptically in cortico-striatal glutamatergic terminals contacting MSNs of the direct efferent pathway, where they heteromerize with adenosine A1 receptors (A1Rs). It has been hypothesized that postsynaptic A2AR antagonists should be useful in Parkinson's disease, while presynaptic A2AR antagonists could be beneficial in dyskinetic disorders, such as Huntington's disease, obsessive-compulsive disorders and drug addiction. The aim or this work was to determine whether selective A2AR antagonists may be subdivided according to a preferential pre- versus postsynaptic mechanism of action. The potency at blocking the motor output and striatal glutamate release induced by cortical electrical stimulation and the potency at inducing locomotor activation were used as in vivo measures of pre- and postsynaptic activities, respectively. SCH-442416 and KW-6002 showed a significant preferential pre- and postsynaptic profile, respectively, while the other tested compounds (MSX-2, SCH-420814, ZM-241385 and SCH-58261) showed no clear preference. Radioligand-binding experiments were performed in cells expressing A2AR-D2R and A1R-A2AR heteromers to determine possible differences in the affinity of these compounds for different A2AR heteromers. Heteromerization played a key role in the presynaptic profile of SCH-442416, since it bound with much less affinity to A2AR when co-expressed with D2R than with A1R. KW-6002 showed the best relative affinity for A2AR co-expressed with D2R than co-expressed with A1R, which can at least partially explain the postsynaptic profile of this compound. Also, the in vitro pharmacological profile of MSX-2, SCH-420814, ZM-241385 and SCH-58261 was is in accordance with their mixed pre- and postsynaptic profile. On the basis of their preferential pre- versus postsynaptic actions, SCH-442416 and KW-6002 may be used as lead compounds to obtain more effective antidyskinetic and antiparkinsonian compounds, respectively

Potassium Starvation in Yeast: Mechanisms of Homeostasis Revealed by Mathematical Modeling

The intrinsic ability of cells to adapt to a wide range of environmental conditions is a fundamental process required for survival. Potassium is the most abundant cation in living cells and is required for essential cellular processes, including the regulation of cell volume, pH and protein synthesis. Yeast cells can grow from low micromolar to molar potassium concentrations and utilize sophisticated control mechanisms to keep the internal potassium concentration in a viable range. We developed a mathematical model for Saccharomyces cerevisiae to explore the complex interplay between biophysical forces and molecular regulation facilitating potassium homeostasis. By using a novel inference method (“the reverse tracking algorithm”) we predicted and then verified experimentally that the main regulators under conditions of potassium starvation are proton fluxes responding to changes of potassium concentrations. In contrast to the prevailing view, we show that regulation of the main potassium transport systems (Trk1,2 and Nha1) in the plasma membrane is not sufficient to achieve homeostasis

Chilling-Dependent Release of Seed and Bud Dormancy in Peach Associates to Common Changes in Gene Expression

Reproductive meristems and embryos display dormancy mechanisms in specialized structures named respectively buds and seeds that arrest the growth of perennial plants until environmental conditions are optimal for survival. Dormancy shows common physiological features in buds and seeds. A genotype-specific period of chilling is usually required to release dormancy by molecular mechanisms that are still poorly understood. In order to find common transcriptional pathways associated to dormancy release, we analyzed the chilling-dependent expression in embryos of certain genes that were previously found related to dormancy in flower buds of peach. We propose the presence of short and long-term dormancy events affecting respectively the germination rate and seedling development by independent mechanisms. Short periods of chilling seem to improve germination in an abscisic acid-dependent manner, whereas the positive effect of longer cold treatments on physiological dwarfing coincides with the accumulation of phenylpropanoids in the seed

Insights on Glucocorticoid Receptor Activity Modulation through the Binding of Rigid Steroids

Background: The glucocorticoid receptor (GR) is a transcription factor that regulates gene expression in a ligand-dependent fashion. This modular protein is one of the major pharmacological targets due to its involvement in both cause and treatment of many human diseases. Intense efforts have been made to get information about the molecular basis of GR activity. Methodology/Principal Findings: Here, the behavior of four GR-ligand complexes with different glucocorticoid and antiglucocorticoid properties were evaluated. The ability of GR-ligand complexes to oligomerize in vivo was analyzed by performing the novel Number and Brightness assay. Results showed that most of GR molecules form homodimers inside the nucleus upon ligand binding. Additionally, in vitro GR-DNA binding analyses suggest that ligand structure modulates GRDNA interaction dynamics rather than the receptor's ability to bind DNA. On the other hand, by coimmunoprecipitation studies we evaluated the in vivo interaction between the transcriptional intermediary factor 2 (TIF2) coactivator and different GR-ligand complexes. No correlation was found between GR intranuclear distribution, cofactor recruitment and the homodimerization process. Finally, Molecular determinants that support the observed experimental GR LBD-ligand/TIF2 interaction were found by Molecular Dynamics simulation. Conclusions/Significance: The data presented here sustain the idea that in vivo GR homodimerization inside the nucleus can be achieved in a DNA-independent fashion, without ruling out a dependent pathway as well. Moreover, since at least one GR-ligand complex is able to induce homodimer formation while preventing TIF2 coactivator interaction, results suggest that these two events might be independent from each other. Finally, 21-hydroxy-6,19-epoxyprogesterone arises as a selective glucocorticoid with potential pharmacological interest. Taking into account that GR homodimerization and cofactor recruitment are considered essential steps in the receptor activation pathway, results presented here contribute to understand how specific ligands influence GR behavior. © 2010 Presman et al.Fil:Presman, D.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Alvarez, L.D. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Levi, V. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Martí, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Veleiro, A.S. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Burton, G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Pecci, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina

Targeting Angiogenesis-Dependent Calcified Neoplasms Using Combined Polymer Therapeutics

There is an immense clinical need for novel therapeutics for the treatment of angiogenesis-dependent calcified neoplasms such as osteosarcomas and bone metastases. We developed a new therapeutic strategy to target bone metastases and calcified neoplasms using combined polymer-bound angiogenesis inhibitors. Using an advanced "living polymerization" technique, the reversible addition-fragmentation chain transfer (RAFT), we conjugated the aminobisphosphonate alendronate (ALN), and the potent anti-angiogenic agent TNP-470 with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer through a Glycine-Glycine-Proline-Norleucine linker, cleaved by cathepsin K, a cysteine protease overexpressed at resorption sites in bone tissues. In this approach, dual targeting is achieved. Passive accumulation is possible due to the increase in molecular weight following polymer conjugation of the drugs, thus extravasating from the tumor leaky vessels and not from normal healthy vessels. Active targeting to the calcified tissues is achieved by ALN's affinity to bone mineral.The anti-angiogenic and antitumor potency of HPMA copolymer-ALN-TNP-470 conjugate was evaluated both in vitro and in vivo. We show that free and conjugated ALN-TNP-470 have synergistic anti-angiogenic and antitumor activity by inhibiting proliferation, migration and capillary-like tube formation of endothelial and human osteosarcoma cells in vitro. Evaluation of anti-angiogenic, antitumor activity and body distribution of HPMA copolymer-ALN-TNP-470 conjugate was performed on severe combined immunodeficiency (SCID) male mice inoculated with mCherry-labeled MG-63-Ras human osteosarcoma and by modified Miles permeability assay. Our targeted bi-specific conjugate reduced VEGF-induced vascular hyperpermeability by 92% and remarkably inhibited osteosarcoma growth in mice by 96%.This is the first report to describe a new concept of a narrowly-dispersed combined polymer therapeutic designed to target both tumor and endothelial compartments of bone metastases and calcified neoplasms at a single administration. This new approach of co-delivery of two synergistic drugs may have clinical utility as a potential therapy for angiogenesis-dependent cancers such as osteosarcoma and bone metastases