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105 results on '"Thompson, L. M."'

2. Amapari Marker Band, Gale Crater, Mars: Event Horizon With Highest Bedrock Iron and Zinc Concentrations Detected by Curiosity's Alpha Particle X‐Ray Spectrometer.

Author

Thompson, L. M., Spray, J. G., VanBommel, S. J., O'Connell‐Cooper, C. D., Berger, J. A., Gellert, R., Vasavada, A. R., Gupta, S., Yen, A. S., McCraig, M. A., and Boyd, N. I.

Abstract

Alpha Particle X‐ray spectrometer (APXS) analyses of the distinct Amapari Marker Band (AMB), Gale crater, Mars reveal the highest, in situ, FeO and Zn abundances (47.51, 2.23 wt%), and elevated MnO associated with a lower rippled unit. APXS analyses also reveal a marked shift in provenance, to a generally basaltic composition, compared to the underlying Mg‐sulfate‐bearing strata, which persists into the overlying stratigraphy. The AMB also records perturbation in the MgSO4‐forming conditions present above and below. AMB chemistry could be consistent with a volcanic ash source; high metal concentrations resulting from volatile reactions within an ash cloud. Alternatively, syn‐ and/or post‐depositional precipitation processes within a primary lake setting and/or a later diagenetic event or events may have played a role. Ongoing and future work will aim to further constrain processes responsible for deposition of the AMB, the high metal concentrations and its regional and global implications. Plain Language Summary: The Amapari Marker Band (AMB) at Gale crater forms a distinct, dark‐toned, resistant horizon identified from orbit within rock layers of the Mg‐sulfate‐bearing, central mound. Curiosity recently investigated the AMB and found a lower rippled layer, consistent with a shallow lake, contrasting with windblown sediment deposition above and below it. Analysis of the AMB by the Alpha Particle X‐ray spectrometer also revealed a marked change in the chemistry of the rocks, with the highest in situ FeO and Zn abundances measured on Mars, elevated MnO, and a composition consistent with input of different sediment compared to underlying rocks. The change in bulk chemistry persists into the overlying rocks indicating that the AMB marks a significant event in the evolution of Gale crater, and possibly beyond. The AMB may record deposition of basaltic volcanic ash into a lake; the high metal concentrations resulting from gas reactions within an ash cloud. Alternatively, the high metals may be the result of water/sediment interactions: either in the lake, and/or after deposition and possibly after becoming a solid rock. Ongoing and future work will aim to further constrain processes responsible for deposition of the AMB, the high metal concentrations and its regional and global implications. Key Points: APXS analysis reveals a marked change in chemistry and provenance associated with the Amapari Marker Band, Gale craterHighest in situ iron and zinc, and elevated manganese detected by APXS within the Amapari Marker BandThe Amapari Marker Bands marks a significant event in the evolution of Gale crater, and possibly beyond [ABSTRACT FROM AUTHOR]

Published
2024
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5. Identification of combinatorial drug regimens for treatment of Huntington's disease using Drosophila

Author

Agrawal, N, Pallos, J, Slepko, N, Apostol, B L, Bodai, L, Chang, L W, Chiang, A S, Thompson, L M, and Marsh, J L

Subjects
combinatorial treatments, neurodegeneration
Abstract

We explore the hypothesis that pathology of Huntington's disease involves multiple cellular mechanisms whose contributions to disease are incrementally additive or synergistic. We provide evidence that the photoreceptor neuron degeneration seen in flies expressing mutant human huntingtin correlates with widespread degenerative events in the Drosophila CNS. We use a Drosophila Huntington's disease model to establish dose regimens and protocols to assess the effectiveness of drug combinations used at low threshold concentrations. These proof of principle studies identify at least two potential combinatorial treatment options and illustrate a rapid and cost-effective paradigm for testing and optimizing combinatorial drug therapies while reducing side effects for patients with neurodegenerative disease. The potential for using prescreening in Drosophila to inform combinatorial therapies that are most likely to be effective for testing in mammals is discussed.

Published
2005

6. A cell-based assay for aggregation inhibitors as therapeutics of polyglutamine-repeat disease and validation in Drosophila

Author

Apostol, B L, Kazantsev, A, Raffioni, S, Illes, K, Pallos, J, Bodai, L, Slepko, N, Bear, J E, Gertler, F B, Hersch, S, Housman, D E, Marsh, J L, and Thompson, L M

Abstract

The formation of polyglutamine-containing aggregates and inclusions are hallmarks of pathogenesis in Huntington's disease that can be recapitulated in model systems. Although the contribution of inclusions to pathogenesis is unclear, cell-based assays can be used to screen for chemical compounds that affect aggregation and may provide therapeutic benefit. We have developed inducible PC12 cell-culture models to screen for loss of visible aggregates. To test the validity of this approach, compounds that inhibit aggregation in the PC12 cell-based screen were tested in a Drosophila model of polyglutamine-repeat disease. The disruption of aggregation in PC12 cells strongly correlates with suppression of neuronal degeneration in Drosophila. Thus, the engineered PC12 cells coupled with the Drosophila model provide a rapid and effective method to screen and validate compounds.

Published
2003

8. Evidence for a Diagenetic Origin of Vera Rubin Ridge, Gale Crater, Mars:Summary and Synthesis of Curiosity's Exploration Campaign

Author

Fraeman, A. A., Edgar, L. A., Rampe, E. B., Thompson, L. M., Frydenvang, J., Fedo, C. M., Catalano, J. G., Dietrich, W. E., Gabriel, T. S.J., Vasavada, A. R., Grotzinger, J. P., L'Haridon, J., Mangold, N., Sun, V. Z., House, C. H., Bryk, A. B., Hardgrove, C., Czarnecki, S., Stack, K. M., Morris, R. V., Arvidson, R. E., Banham, S. G., Bennett, K. A., Bridges, J. C., Edwards, C. S., Fischer, W. W., Fox, V. K., Gupta, S., Horgan, B. H.N., Jacob, S. R., Johnson, J. R., Johnson, S. S., Rubin, D. M., Salvatore, M. R., Schwenzer, S. P., Siebach, K. L., Stein, N. T., Turner, S. M.R., Wellington, D. F., Wiens, R. C., Williams, A. J., David, G., Wong, G. M., Fraeman, A. A., Edgar, L. A., Rampe, E. B., Thompson, L. M., Frydenvang, J., Fedo, C. M., Catalano, J. G., Dietrich, W. E., Gabriel, T. S.J., Vasavada, A. R., Grotzinger, J. P., L'Haridon, J., Mangold, N., Sun, V. Z., House, C. H., Bryk, A. B., Hardgrove, C., Czarnecki, S., Stack, K. M., Morris, R. V., Arvidson, R. E., Banham, S. G., Bennett, K. A., Bridges, J. C., Edwards, C. S., Fischer, W. W., Fox, V. K., Gupta, S., Horgan, B. H.N., Jacob, S. R., Johnson, J. R., Johnson, S. S., Rubin, D. M., Salvatore, M. R., Schwenzer, S. P., Siebach, K. L., Stein, N. T., Turner, S. M.R., Wellington, D. F., Wiens, R. C., Williams, A. J., David, G., and Wong, G. M.

Abstract

This paper provides an overview of the Curiosity rover's exploration at Vera Rubin ridge (VRR) and summarizes the science results. VRR is a distinct geomorphic feature on lower Aeolis Mons (informally known as Mount Sharp) that was identified in orbital data based on its distinct texture, topographic expression, and association with a hematite spectral signature. Curiosity conducted extensive remote sensing observations, acquired data on dozens of contact science targets, and drilled three outcrop samples from the ridge, as well as one outcrop sample immediately below the ridge. Our observations indicate that strata composing VRR were deposited in a predominantly lacustrine setting and are part of the Murray formation. The rocks within the ridge are chemically in family with underlying Murray formation strata. Red hematite is dispersed throughout much of the VRR bedrock, and this is the source of the orbital spectral detection. Gray hematite is also present in isolated, gray-colored patches concentrated toward the upper elevations of VRR, and these gray patches also contain small, dark Fe-rich nodules. We propose that VRR formed when diagenetic event(s) preferentially hardened rocks, which were subsequently eroded into a ridge by wind. Diagenesis also led to enhanced crystallization and/or cementation that deepened the ferric-related spectral absorptions on the ridge, which helped make them readily distinguishable from orbit. Results add to existing evidence of protracted aqueous environments at Gale crater and give new insight into how diagenesis shaped Mars' rock record.

Published
2020

10. POST-TRANSLATIONAL MODIFICATION OF HTT WITHIN ITS FIRST 17 AMINO ACIDS REGULATES ITS STABILITY, AGGREGATION, CELLULAR LOCALIZATION AND TOXICITY

Author

Steffan, J S, OʼRourke, J G, Aiken, C T, Kaltenbach, L S, Agrawal, N, Illes, K, Pallos, J, Khoshnan, A, Martinez-Vincente, M, Arrasate, M, Lukacsovich, T, Dasso, M, Hayden, M R, Zeitlin, S O, Wanker, E E, Lima, C D, Finkbeiner, S, Huang, L, Lo, D C, Patterson, P H, Cuervo, A M, Marsh, J L, and Thompson, L M

Published
2009
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11. NF-κB2 signalling in enteroids modulates enterocyte responses to secreted factors from bone marrow-derived dendritic cells

Author

Jones, L G, Vaisa, A, Thompson, L M, Ikuomola, F I, Caamaño, J H, Burkitt, M D, Miyajima, F, Williams, J M, Campbell, B J, Pritchard, D M, and Duckworth, C A

Abstract

Alternative pathway NF-κB signalling regulates susceptibility towards developing inflammatory bowel disease (IBD), colitis-associated cancer and sepsis-associated intestinal epithelial cell apoptosis and shedding. However, the cell populations responsible for the perturbed alternative pathway NF-κB signalling in intestinal mucosal pathology remain unclear. In order to investigate the contribution of the epithelial compartment, we have tested whether NF-κB2 regulated transcription in intestinal epithelial cells controls the intestinal epithelial response to cytokines that are known to disrupt intestinal barrier permeability. Enteroids were generated from the proximal, middle and distal regions of small intestine (SI) from C57BL/6J wild-type mice and displayed region-specific morphology that was maintained during sub-culture. Enteroids treated with 100 ng/mL TNF were compared with corresponding regions of SI from C57BL/6J mice treated systemically with 0.33 mg/kg TNF for 1.5 h. TNF-induced apoptosis in all regions of the intestine in vitro and in vivo but resulted in Paneth cell degranulation only in proximal tissue-derived SI and enteroids. TNF also resulted in increased enteroid sphericity (quantified as circularity from two-dimensional bright field images). This response was dose and time-dependent and correlated with active caspase-3 immunopositivity. Proximal tissue-derived enteroids generated from Nfκb2−/− mice showed a significantly blunted circularity response following the addition of TNF, IFNγ, lipopolysaccharide (LPS) activated C57BL/6J-derived bone marrow-derived dendritic cells (BMDC) and secreted factors from LPS-activated BMDCs. However, Nfκb1−/− mouse-derived enteroids showed no significant changes in response to these stimuli. In conclusion, the selection of SI region is important when designing enteroid studies as region-specific identity and response to stimuli such as TNF are maintained in culture. Intestinal epithelial cells are at least partially responsible for regulating their own fate by modulating NF-κB2 signalling in response to stimuli known to be involved in multiple intestinal and systemic diseases. Future studies are warranted to investigate the therapeutic potential of intestinal epithelial NF-κB2 inhibition.

Published
2019

13. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author

Nicolas, A., Kenna, K. P., Renton, A. E., Ticozzi, N., Faghri, F., Chia, R., Dominov, J. A., Kenna, B. J., Nalls, M. A., Keagle, P., Rivera, A. M., van Rheenen, W., Murphy, N. A., van Vugt, J. J. F. A., Geiger, J. T., Van der Spek, R. A., Pliner, H. A., Shankaracharya, Smith, B. N., Marangi, Giuseppe, Topp, S. D., Abramzon, Y., Gkazi, A. S., Eicher, J. D., Kenna, A., Logullo, F. O., Simone, I. L., Logroscino, Giandomenico, Salvi, F., Bartolomei, I., Borghero, G., Murru, M. R., Costantino, E., Pani, C., Puddu, R., Caredda, C., Piras, V., Tranquilli, S., Cuccu, S., Corongiu, D., Melis, M., Milia, A., Marrosu, F., Marrosu, M. G., Floris, G., Cannas, A., Capasso, Monica, Caponnetto, C., Mancardi, G., Origone, P., Mandich, P., Conforti, F. L., Cavallaro, S., Mora, G., Marinou, K., Sideri, R., Penco, S., Mosca, Luigi, Lunetta, C., Pinter, G. L., Corbo, M., Riva, N., Carrera, P., Volanti, P., Mandrioli, J., Fini, N., Fasano, Alfonso, Tremolizzo, L., Arosio, A., Ferrarese, C., Trojsi, F., Tedeschi, G., Monsurro, M. R., Piccirillo, G., Femiano, C., Ticca, A., Ortu, E., La Bella, V., Spataro, R., Colletti, T., Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Santarelli, M., Petrucci, A., Pugliatti, M., Pirisi, A., Parish, L. D., Occhineri, P., Giannini, F., Battistini, S., Ricci, C., Benigni, M., Cau, T. B., Loi, D., Calvo, A., Moglia, C., Brunetti, M., Barberis, M., Restagno, G., Casale, F., Marrali, G., Fuda, G., Ossola, I., Cammarosano, S., Canosa, A., Ilardi, A., Manera, U., Grassano, M., Tanel, R., Pisano, F., Mazzini, L., Messina, S., D'Alfonso, Sandra, Corrado, L., Ferrucci, L., Harms, M. B., Goldstein, D. B., Shneider, N. A., Goutman, S. A., Simmons, Z., Miller, T. M., Chandran, S., Pal, S., Manousakis, G., Appel, S. H., Simpson, E., Wang, L., Baloh, R. H., Gibson, S. B., Bedlack, R., Lacomis, D., Sareen, D., Sherman, A., Bruijn, L., Penny, M., Moreno, C. D. A. M., Kamalakaran, S., Allen, A. S., Boone, B. E., Brown, R. H., Carulli, J. P., Chesi, A., Chung, W. K., Cirulli, E. T., Cooper, G. M., Couthouis, J., Day-Williams, A. G., Dion, P. A., Gitler, A. D., Glass, J. D., Han, Y., Harris, T., Hayes, S. D., Jones, A. L., Keebler, J., Krueger, B. J., Lasseigne, B. N., Levy, S. E., Lu, Y. -F., Maniatis, T., McKenna-Yasek, D., Myers, R. M., Petrovski, S., Pulst, S. M., Raphael, A. R., Ravits, J. M., Ren, Z., Rouleau, G. A., Sapp, P. C., Sims, K. B., Staropoli, J. F., Waite, L. L., Wang, Quanquan, Wimbish, J. R., Xin, W. W., Phatnani, H., Kwan, J., Broach, J., Arcila-Londono, X., Lee, E. B., Van Deerlin, V. M., Fraenkel, E., Ostrow, L. W., Baas, F., Zaitlen, N., Berry, J. D., Malaspina, A., Fratta, P., Cox, G. A., Thompson, L. M., Finkbeiner, S., Dardiotis, E., Hornstein, E., Macgowan, D. J. L., Heiman-Patterson, T., Hammell, M. G., Patsopoulos, N. A., Dubnau, J., Nath, A., Musunuri, R. L., Evani, U. S., Abhyankar, A., Zody, M. C., Kaye, J., Wyman, S. K., Lenail, A., Lima, L., Rothstein, J. D., Svendsen, C. N., Van Eyk, J. E., Maragakis, N. J., Kolb, S. J., Cudkowicz, M., Baxi, E., Benatar, M., Taylor, J. P., Wu, G., Rampersaud, E., Wuu, J., Rademakers, R., Zuchner, S., Schule, R., Mccauley, J., Hussain, S., Cooley, A., Wallace, M., Clayman, C., Barohn, R., Statland, J., Swenson, A., Jackson, C., Trivedi, J., Khan, S., Katz, J., Jenkins, L., Burns, T., Gwathmey, K., Caress, J., Mcmillan, C., Elman, L., Pioro, E. P., Heckmann, J., So, Y., Walk, D., Maiser, S., Zhang, J., Silani, V., Gellera, C., Ratti, A., Taroni, F., Lauria, G., Verde, F., Fogh, I., Tiloca, C., Comi, G. P., Soraru, G., Cereda, C., De Marchi, F., Corti, S., Ceroni, M., Siciliano, Giovanni, Filosto, M., Inghilleri, M., Peverelli, S., Colombrita, C., Poletti, B., Maderna, L., Del Bo, R., Gagliardi, S., Querin, G., Bertolin, C., Pensato, V., Castellotti, B., Camu, W., Mouzat, K., Lumbroso, S., Corcia, P., Meininger, V., Besson, G., Lagrange, E., Clavelou, P., Guy, N., Couratier, P., Vourch, P., Danel, V., Bernard, E., Lemasson, G., Laaksovirta, H., Myllykangas, L., Jansson, L., Valori, Vanna Maria, Ealing, J., Hamdalla, H., Rollinson, S., Pickering-Brown, S., Orrell, R. W., Sidle, K. C., Hardy, J., Singleton, A. B., Johnson, J. O., Arepalli, S., Polak, M., Asress, S., Al-Sarraj, S., King, A., Troakes, C., Vance, C., de Belleroche, J., ten Asbroek, A. L. M. A., Munoz-Blanco, J. L., Hernandez, D. G., Ding, J., Gibbs, J. R., Scholz, S. W., Floeter, M. K., Campbell, R. H., Landi, Francesco, Bowser, R., Kirby, J., Pamphlett, R., Gerhard, G., Dunckley, T. L., Brady, C. B., Kowall, N. W., Troncoso, J. C., Le Ber, I., Heiman-Patterson, T. D., Kamel, F., Van Den Bosch, L., Strom, T. M., Meitinger, T., Shatunov, A., Van Eijk, K. R., de Carvalho, M., Kooyman, M., Middelkoop, B., Moisse, M., Mclaughlin, R. L., Van Es, M. A., Weber, M., Boylan, K. B., Van Blitterswijk, M., Morrison, K. E., Basak, A. N., Mora, J. S., Drory, V. E., Shaw, P. J., Turner, M. R., Talbot, K., Hardiman, O., Williams, K. L., Fifita, J. A., Nicholson, G. A., Blair, I. P., Esteban-Perez, J., Garcia-Redondo, A., Al-Chalabi, A., Al Kheifat, A., Andersen, P. M., Chio, A., Cooper-Knock, J., Dekker, A., Redondo, A. G., Gotkine, M., Hide, W., Iacoangeli, A., Kiernan, M., Landers, J. E., Mill, J., Neto, M. M., Pardina, J. M., Newhouse, S., Pinto, S., Pulit, S., Robberecht, W., Shaw, C., Sproviero, W., Tazelaar, G., Van Damme, P., van den Berg, L. H., van Vugt, J., Veldink, J. H., Zatz, M., Bauer, D. C., Twine, N. A., Rogaeva, E., Zinman, L., Brice, A., Feldman, E. L., Ludolph, A. C., Weishaupt, J. H., Trojanowski, J. Q., Stone, D. J., Tienari, P., Shaw, C. E., Traynor, B. J., Marangi G. (ORCID:0000-0002-6898-8882), Logroscino G. (ORCID:0000-0003-1301-5343), Capasso M., Mosca L. (ORCID:0000-0003-4641-0841), Fasano A., Sabatelli M. (ORCID:0000-0001-6635-4985), Zollino M. (ORCID:0000-0003-4871-9519), Conte A., Luigetti M. (ORCID:0000-0001-7539-505X), Lattante S. (ORCID:0000-0003-2891-0340), D'Alfonso S., Siciliano G., Valori M., Landi F. (ORCID:0000-0002-3472-1389), Nicolas, A., Kenna, K. P., Renton, A. E., Ticozzi, N., Faghri, F., Chia, R., Dominov, J. A., Kenna, B. J., Nalls, M. A., Keagle, P., Rivera, A. M., van Rheenen, W., Murphy, N. A., van Vugt, J. J. F. A., Geiger, J. T., Van der Spek, R. A., Pliner, H. A., Shankaracharya, Smith, B. N., Marangi, Giuseppe, Topp, S. D., Abramzon, Y., Gkazi, A. S., Eicher, J. D., Kenna, A., Logullo, F. O., Simone, I. L., Logroscino, Giandomenico, Salvi, F., Bartolomei, I., Borghero, G., Murru, M. R., Costantino, E., Pani, C., Puddu, R., Caredda, C., Piras, V., Tranquilli, S., Cuccu, S., Corongiu, D., Melis, M., Milia, A., Marrosu, F., Marrosu, M. G., Floris, G., Cannas, A., Capasso, Monica, Caponnetto, C., Mancardi, G., Origone, P., Mandich, P., Conforti, F. L., Cavallaro, S., Mora, G., Marinou, K., Sideri, R., Penco, S., Mosca, Luigi, Lunetta, C., Pinter, G. L., Corbo, M., Riva, N., Carrera, P., Volanti, P., Mandrioli, J., Fini, N., Fasano, Alfonso, Tremolizzo, L., Arosio, A., Ferrarese, C., Trojsi, F., Tedeschi, G., Monsurro, M. R., Piccirillo, G., Femiano, C., Ticca, A., Ortu, E., La Bella, V., Spataro, R., Colletti, T., Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Santarelli, M., Petrucci, A., Pugliatti, M., Pirisi, A., Parish, L. D., Occhineri, P., Giannini, F., Battistini, S., Ricci, C., Benigni, M., Cau, T. B., Loi, D., Calvo, A., Moglia, C., Brunetti, M., Barberis, M., Restagno, G., Casale, F., Marrali, G., Fuda, G., Ossola, I., Cammarosano, S., Canosa, A., Ilardi, A., Manera, U., Grassano, M., Tanel, R., Pisano, F., Mazzini, L., Messina, S., D'Alfonso, Sandra, Corrado, L., Ferrucci, L., Harms, M. B., Goldstein, D. B., Shneider, N. A., Goutman, S. A., Simmons, Z., Miller, T. M., Chandran, S., Pal, S., Manousakis, G., Appel, S. H., Simpson, E., Wang, L., Baloh, R. H., Gibson, S. B., Bedlack, R., Lacomis, D., Sareen, D., Sherman, A., Bruijn, L., Penny, M., Moreno, C. D. A. M., Kamalakaran, S., Allen, A. S., Boone, B. E., Brown, R. H., Carulli, J. P., Chesi, A., Chung, W. K., Cirulli, E. T., Cooper, G. M., Couthouis, J., Day-Williams, A. G., Dion, P. A., Gitler, A. D., Glass, J. D., Han, Y., Harris, T., Hayes, S. D., Jones, A. L., Keebler, J., Krueger, B. J., Lasseigne, B. N., Levy, S. E., Lu, Y. -F., Maniatis, T., McKenna-Yasek, D., Myers, R. M., Petrovski, S., Pulst, S. M., Raphael, A. R., Ravits, J. M., Ren, Z., Rouleau, G. A., Sapp, P. C., Sims, K. B., Staropoli, J. F., Waite, L. L., Wang, Quanquan, Wimbish, J. R., Xin, W. W., Phatnani, H., Kwan, J., Broach, J., Arcila-Londono, X., Lee, E. B., Van Deerlin, V. M., Fraenkel, E., Ostrow, L. W., Baas, F., Zaitlen, N., Berry, J. D., Malaspina, A., Fratta, P., Cox, G. A., Thompson, L. M., Finkbeiner, S., Dardiotis, E., Hornstein, E., Macgowan, D. J. L., Heiman-Patterson, T., Hammell, M. G., Patsopoulos, N. A., Dubnau, J., Nath, A., Musunuri, R. L., Evani, U. S., Abhyankar, A., Zody, M. C., Kaye, J., Wyman, S. K., Lenail, A., Lima, L., Rothstein, J. D., Svendsen, C. N., Van Eyk, J. E., Maragakis, N. J., Kolb, S. J., Cudkowicz, M., Baxi, E., Benatar, M., Taylor, J. P., Wu, G., Rampersaud, E., Wuu, J., Rademakers, R., Zuchner, S., Schule, R., Mccauley, J., Hussain, S., Cooley, A., Wallace, M., Clayman, C., Barohn, R., Statland, J., Swenson, A., Jackson, C., Trivedi, J., Khan, S., Katz, J., Jenkins, L., Burns, T., Gwathmey, K., Caress, J., Mcmillan, C., Elman, L., Pioro, E. P., Heckmann, J., So, Y., Walk, D., Maiser, S., Zhang, J., Silani, V., Gellera, C., Ratti, A., Taroni, F., Lauria, G., Verde, F., Fogh, I., Tiloca, C., Comi, G. P., Soraru, G., Cereda, C., De Marchi, F., Corti, S., Ceroni, M., Siciliano, Giovanni, Filosto, M., Inghilleri, M., Peverelli, S., Colombrita, C., Poletti, B., Maderna, L., Del Bo, R., Gagliardi, S., Querin, G., Bertolin, C., Pensato, V., Castellotti, B., Camu, W., Mouzat, K., Lumbroso, S., Corcia, P., Meininger, V., Besson, G., Lagrange, E., Clavelou, P., Guy, N., Couratier, P., Vourch, P., Danel, V., Bernard, E., Lemasson, G., Laaksovirta, H., Myllykangas, L., Jansson, L., Valori, Vanna Maria, Ealing, J., Hamdalla, H., Rollinson, S., Pickering-Brown, S., Orrell, R. W., Sidle, K. C., Hardy, J., Singleton, A. B., Johnson, J. O., Arepalli, S., Polak, M., Asress, S., Al-Sarraj, S., King, A., Troakes, C., Vance, C., de Belleroche, J., ten Asbroek, A. L. M. A., Munoz-Blanco, J. L., Hernandez, D. G., Ding, J., Gibbs, J. R., Scholz, S. W., Floeter, M. K., Campbell, R. H., Landi, Francesco, Bowser, R., Kirby, J., Pamphlett, R., Gerhard, G., Dunckley, T. L., Brady, C. B., Kowall, N. W., Troncoso, J. C., Le Ber, I., Heiman-Patterson, T. D., Kamel, F., Van Den Bosch, L., Strom, T. M., Meitinger, T., Shatunov, A., Van Eijk, K. R., de Carvalho, M., Kooyman, M., Middelkoop, B., Moisse, M., Mclaughlin, R. L., Van Es, M. A., Weber, M., Boylan, K. B., Van Blitterswijk, M., Morrison, K. E., Basak, A. N., Mora, J. S., Drory, V. E., Shaw, P. J., Turner, M. R., Talbot, K., Hardiman, O., Williams, K. L., Fifita, J. A., Nicholson, G. A., Blair, I. P., Esteban-Perez, J., Garcia-Redondo, A., Al-Chalabi, A., Al Kheifat, A., Andersen, P. M., Chio, A., Cooper-Knock, J., Dekker, A., Redondo, A. G., Gotkine, M., Hide, W., Iacoangeli, A., Kiernan, M., Landers, J. E., Mill, J., Neto, M. M., Pardina, J. M., Newhouse, S., Pinto, S., Pulit, S., Robberecht, W., Shaw, C., Sproviero, W., Tazelaar, G., Van Damme, P., van den Berg, L. H., van Vugt, J., Veldink, J. H., Zatz, M., Bauer, D. C., Twine, N. A., Rogaeva, E., Zinman, L., Brice, A., Feldman, E. L., Ludolph, A. C., Weishaupt, J. H., Trojanowski, J. Q., Stone, D. J., Tienari, P., Shaw, C. E., Traynor, B. J., Marangi G. (ORCID:0000-0002-6898-8882), Logroscino G. (ORCID:0000-0003-1301-5343), Capasso M., Mosca L. (ORCID:0000-0003-4641-0841), Fasano A., Sabatelli M. (ORCID:0000-0001-6635-4985), Zollino M. (ORCID:0000-0003-4871-9519), Conte A., Luigetti M. (ORCID:0000-0001-7539-505X), Lattante S. (ORCID:0000-0003-2891-0340), D'Alfonso S., Siciliano G., Valori M., and Landi F. (ORCID:0000-0002-3472-1389)

Abstract

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS. Using a large-scale genome-wide association study and exome sequencing, we identified KIF5A as a novel gene associated with ALS. Our data broaden the phenotype resulting from mutations in KIF5A and highlight the importance of cytoskeletal defects in the pathogenesis of ALS.

Published
2018

14. Evolved Gas Analyses of Sedimentary Rocks and Eolian Sediment in Gale Crater, Mars: Results of the Curiosity Rover's Sample Analysis at Mars (SAM) Instrument from Yellowknife Bay to the Namib Dune

Author

Sutter, B., McAdam, A. C., Mahaffy, P. R., Ming, D. W., Edgett, K. S., Rampe, E. B., Eigenbrode, J. L., Franz, H. B., Freissinet, C., Grotzinger, J. P., Steele, A., House, C. H., Archer, P. D., Malespin, C. A., Navarro-González, R., Stern, J. C., Bell, J. F., Calef, F. J., Gellert, R., Glavin, D. P., Thompson, L. M., and Yen, A. S.

Abstract

The Sample Analysis at Mars instrument evolved gas analyzer (SAM-EGA) has detected evolved water, H_2, SO_2, H_2S, NO, CO_2, CO, O_2 and HCl from two eolian sediments and nine sedimentary rocks from Gale Crater, Mars. These evolved gas detections indicate nitrates, organics, oxychlorine phase, and sulfates are widespread with phyllosilicates and carbonates occurring in select Gale Crater materials. Coevolved CO_2 (160 ± 248 - 2373 ± 820 μgC_((CO2))/g), and CO (11 ± 3 - 320 ± 130 μgC(CO)/g) suggest organic-C is present in Gale Crater materials. Five samples evolved CO_2 at temperatures consistent with carbonate (0.32± 0.05 - 0.70± 0.1 wt.% CO_3). Evolved NO amounts to 0.002 ± 0.007 - 0.06 ± 0.03 wt.% NO_3. Evolution of O_2 suggests oxychlorine phases (chlorate/perchlorate) (0.05 ± 0.025 - 1.05 ± 0.44wt. % ClO_4) are present while SO_2 evolution indicates the presence of crystalline and/or poorly crystalline Fe- and Mg-sulfate and possibly sulfide. Evolved H_2O (0.9 ± 0.3 - 2.5 ± 1.6 wt.% H_2O) is consistent with the presence of adsorbed water, hydrated salts, interlayer/structural water from phyllosilicates, and possible inclusion water in mineral/amorphous phases. Evolved H_2 and H_2S suggest reduced phases occur despite the presence of oxidized phases (nitrate, oxychlorine, sulfate, carbonate). SAM results coupled with CheMin mineralogical and APXS elemental analyses indicate that Gale Crater sedimentary rocks have experienced a complex authigenetic/diagenetic history involving fluids with varying pH, redox, and salt composition. The inferred geochemical conditions were favorable for microbial habitability and if life ever existed, there was likely sufficient organic-C to support a small microbial population.

Published
2017

15. Sorting out Compositional Trends in Sedimentary Rocks of the Bradbury Group (Aeolus Palus), Gale Crater, Mars

Author

Siebach, K. L., Baker, M. B., Grotzinger, J. P., McLennan, S. M., Gellert, R., Thompson, L. M., and Hurowitz, J. A.

Abstract

Sedimentary rocks are composed of detrital grains derived from source rocks, which are altered by chemical weathering, sorted during transport, and cemented during diagenesis. Fluvio-lacustrine sedimentary rocks of the Bradbury group, observed on the floor of Gale crater by the Curiosity rover during its first 860 Martian solar days, show trends in bulk chemistry that are consistent with sorting of mineral grains during transport. The Bradbury group rocks are uniquely suited for sedimentary provenance analysis because they appear to have experienced negligible cation loss (i.e., open-system chemical weathering) at the scale of the Alpha Particle X-ray Spectrometer bulk chemistry analyses based on low Chemical Index of Alteration values and successful modeling of >90% of the (volatile-free) targets as mixtures of primary igneous minerals. Significant compositional variability between targets is instead correlated to grain-size and textural characteristics of the rocks; the coarsest-grained targets are enriched in Al_2O_3, SiO_2, and Na_2O, whereas the finer-grained targets are enriched in mafic components. This is consistent with geochemical and mineralogical modeling of the segregation of coarse-grained plagioclase from finer-grained mafic minerals (e.g., olivine and pyroxenes), which would be expected from hydrodynamic sorting of the detritus from mechanical breakdown of subalkaline plagioclase-phyric basalts. While the presence of a distinctive K_2O-rich stratigraphic interval shows that input from at least one distinctive alkali-feldspar-rich protolith contributed to basin fill, the dominant compositional trends in the Bradbury group are consistent with sorting of detrital minerals during transport from relatively homogeneous plagioclase-phyric basalts.

Published
2017

20. Mithramycin Is a Gene-Selective Sp1 Inhibitor That Identifies a Biological Intersection between Cancer and Neurodegeneration

Author

Sleiman, S. F., primary, Langley, B. C., additional, Basso, M., additional, Berlin, J., additional, Xia, L., additional, Payappilly, J. B., additional, Kharel, M. K., additional, Guo, H., additional, Marsh, J. L., additional, Thompson, L. M., additional, Mahishi, L., additional, Ahuja, P., additional, MacLellan, W. R., additional, Geschwind, D. H., additional, Coppola, G., additional, Rohr, J., additional, and Ratan, R. R., additional

Published
2011
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27. Dispensable presequence for cellular localization and function of mitochondrial malate dehydrogenase from Saccharomyces cerevisiae

Author

Thompson, L M and McAlister-Henn, L

Abstract

The nucleotide sequence corresponding to codons for the 17-amino acid residues in the presumed targeting presequence for yeast mitochondrial malate dehydrogenase was removed by oligonucleotide-directed mutagenesis of the isolated gene (MDH1). Integrative transformation was used to insert the “leaderless” gene (mdhl−) into the MDH1 chromosomal locus of a strain containing a disrupted MDH1 gene. Expression of the mature form of malate dehydrogenase as a primary translation product was verified by demonstrating that the mature form is synthesized in mdhl−cells at the same rate as the precursor form in MDH1 cells in the presence of carbonyl cyanide m-chlorophenylhydrazone and by comparison of in vitrotranslation products of RNAs from mdhl−and MDH1 cells. Expression of mdhl−restores total cellular malate dehydrogenase activity to levels comparable to those in wild type cells and reverses the phenotype associated with strains containing MDH1 disruptions by restoring wild type rates of growth in media containing acetate as a carbon source. Immunochemical analyses and enzyme assays show comparable levels of malate dehydrogenase in the matrix fractions from mitochondria isolated from mdhl−and MDH1 cells and give no evidence for accumulation of the mature enzyme in the cytosol of mdhl−cells. These results indicate that the presequence for malate dehydrogenase is not essential for efficient mitochondrial localization or function in yeast.

Published
1989
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28. Effect of transmembrane and kinase domain mutations on fibroblast growth factor receptor 3 chimera signaling in PC12 cells. A model for the control of receptor tyrosine kinase activation.

Author

Raffioni, S, Zhu, Y Z, Bradshaw, R A, and Thompson, L M

Abstract

The effect of six point mutations causing various human skeletal dysplasias, occurring in the transmembrane (TM) and kinase domains (KD) of fibroblast growth factor receptor 3, were introduced into a chimera composed of the extracellular domain of human platelet-derived growth factor beta and the TM and intracellular domains of hFGFR3. Stable transfectants in rat PC12 cells showed distinct differences in the two classes of mutations. The cells containing TM mutants displayed normal expression and activation but higher responsiveness to lower doses of ligand. The KD mutants showed significantly altered expression patterns. Normal amounts of a lower Mr receptor (p130) reflecting incomplete glycosylation, but only greatly decreased amounts of the mature (p170) form, were observed. However, the latter material showed normal ligand-dependent activation. In contrast, the p130 form, which is regularly observed in the expression of both native and chimeric receptors, exhibits strong ligand-independent tyrosine phosphorylation, particularly with the K650E mutation. Expression of two of the KD mutants (K650M and K650E), under control of an inducible metallothionein promoter, indicated that this receptor was sufficiently autoactivated to produce at least partial differentiation and, in the case of the K650E mutation, to induce ligand-independent neurite outgrowth. A model is presented that suggests that the low Mr (p130) KD mutants can, under the right conditions, signal intracellularly, but when they are fully glycosylated and move to the cell surface they adopt a normal, inhibited conformation, in the form of ligand-independent dimers, that neutralizes the effects of the mutations. When ligands bind, these dimeric receptors are activated in a normal manner. This model suggests that unliganded dimers may be a common intermediate in receptor tyrosine kinase signaling.

Published
1998

29. Integrated proviral human immunodeficiency virus type 1 is present in CD4+ peripheral blood lymphocytes in healthy seropositive individuals

Author

Psallidopoulos, M C, Schnittman, S M, Thompson, L M, Baseler, M, Fauci, A S, Lane, H C, and Salzman, N P

Abstract

Evidence of a latent human immunodeficiency virus type 1 (HIV-1) infection in healthy, seropositive individuals who do not have viral antigens in their sera and from whom virions cannot be rescued in cocultivation experiments was examined. Proviral DNA was detected by amplification by the polymerase chain reaction procedure. In each of 10 seropositive individuals, the presence of HIV-1 proviral sequences was demonstrated in their peripheral blood mononuclear cells. By using fluorescence-activated cell sorting, we obtained highly enriched subpopulations of peripheral blood mononuclear cells and found that the CD4+ T-cell subset is the cell subset that consistently harbors the HIV-1 proviral sequences. The number of HIV-1-infected CD4+ T cells was variable among the 10 healthy individuals, ranging from 1 in 100 to 1 in 40,000. While in vitro infection of CD4+ T cells causes down regulation and eventual loss of CD4 surface molecules, this is not true in vivo where it is only the CD4+ population that harbors the virus. This disparity may reflect differences between a latent infection in vivo with the lytic response of cells infected in vitro.

Published
1989
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30. Isolation and expression of the gene encoding yeast mitochondrial malate dehydrogenase

Author

McAlister-Henn, L and Thompson, L M

Abstract

The mitochondrial tricarboxylic acid cycle enzyme malate dehydrogenase was purified from Saccharomyces cerevisiae, and an antibody to the purified enzyme was obtained in rabbits. Immunoscreening of a yeast genomic DNA library cloned into a lambda gt11 expression vector with anti-malate dehydrogenase immunoglobulin G resulted in identification of a lambda recombinant encoding an immunoreactive beta-galactosidase fusion protein. The yeast DNA portion of the coding region for the fusion protein translates into an amino acid sequence which is very similar to carboxy-terminal sequences of malate dehydrogenases from other organisms. In s. cerevisiae transformed with a multicopy plasmid carrying the complete malate dehydrogenase gene, the specific activity and immunoreactivity of the mitochondrial isozyme are increased by eightfold. Expression of both the chromosomal and plasmid-borne genes is repressed by growth on glucose. Disruption of the chromosomal malate dehydrogenase gene in haploid S. cerevisiae produces mutants unable to grow on acetate and impaired in growth on glycerol plus lactate as carbon sources.

Published
1987
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31. Conformational changes in rat liver chromatin after liver regeneration

Author

Simpkins, H, Thompson, L M, Waldeck, N, Gross, D S, and Mooney, D

Abstract

N-Pyrenemaleimide, a fluorescent probe that specifically labels histone H3 of rat liver chromatin in situ, was used to monitor the accessibility of histone H3 in chromatin isolated from rat liver at different times during degeneration. At times of maximum DNA synthesis (18–24 h after hepatectomy), the accessibility of the probe was found to be markedly (40–50%) increased. This increase is abolished, however, by treatment of the chromatin fibres with high salt (2 M-NaCl) or detergent. Tryptophan fluorescence was also enhanced at points of maximum DNA synthesis, suggesting that some non-histone tryptophan-containing protein was being synthesized. The polarization of the labelled histone H3 is not markedly altered, suggesting that fibre aggregation or dissociation does not occur. Mononucleosomes extracted from sham-operated and hepatectomized animals did not exhibit any difference in binding to the probe. Also, analysis of the chromatin protein by electrophoresis on detergent- and acid/urea/ Triton-X-100-containing polyacrylamide gels showed no detectable difference in histone H3 : 1, H3 : 2 or H3 : 3 subclasses.

Published
1981
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33. Formation of Tridymite and Evidence for a Hydrothermal History at Gale Crater, Mars

Author

Yen, A. S., Morris, R. V., Ming, D. W., Schwenzer, S. P., Sutter, B., Vaniman, D. T., Treiman, A. H., Gellert, R., Achilles, C. N., Berger, J. A., Blake, D. F., Boyd, N. I., Bristow, T. F., Chipera, S., Clark, B. C., Craig, P. I., Downs, R. T., Franz, H. B., Gabriel, T., McAdam, A. C., Morrison, S. M., O'Connell‐Cooper, C. D., Rampe, E. B., Schmidt, M. E., Thompson, L. M., VanBommel, S. J., Yen, A. S., Morris, R. V., Ming, D. W., Schwenzer, S. P., Sutter, B., Vaniman, D. T., Treiman, A. H., Gellert, R., Achilles, C. N., Berger, J. A., Blake, D. F., Boyd, N. I., Bristow, T. F., Chipera, S., Clark, B. C., Craig, P. I., Downs, R. T., Franz, H. B., Gabriel, T., McAdam, A. C., Morrison, S. M., O'Connell‐Cooper, C. D., Rampe, E. B., Schmidt, M. E., Thompson, L. M., and VanBommel, S. J.

Abstract

In August 2015, the Curiosity Mars rover discovered tridymite, a high‐temperature silica polymorph, in Gale crater. The existing model for its occurrence suggests erosion and detrital sedimentation from silicic volcanic rocks in the crater rim or central peak. The chemistry and mineralogy of the tridymite‐bearing rocks, however, are not consistent with silicic volcanic material. Using data from Curiosity, including chemical composition from the Alpha Particle X‐ray Spectrometer, mineralogy from the CheMin instrument, and evolved gas and isotopic analyses from the Sample Analysis at Mars instrument, we show that the tridymite‐bearing rocks exhibit similar chemical patterns with silica‐rich alteration halos which crosscut the stratigraphy. We infer that the tridymite formed in‐place through hydrothermal processes and show additional chemical and mineralogical results from Gale crater consistent with hydrothermal activity occurring after sediment deposition and lithification.

34. Evidence for a Diagenetic Origin of Vera Rubin Ridge, Gale Crater, Mars: Summary and Synthesis of Curiosity's Exploration Campaign

Author

Fraeman, A. A., Edgar, L. A., Rampe, E. B., Thompson, L. M., Frydenvang, J., Fedo, C. M., Catalano, J. G., Dietrich, W. E., Gabriel, T. S. J., Vasavada, A. R., Grotzinger, J. P., L'Haridon, J., Mangold, N., Sun, V. Z., House, C. H., Bryk, A. B., Hardgrove, C., Czarnecki, S., Stack, K. M., Morris, R. V., Arvidson, R. E., Banham, S. G., Bennett, K. A., Bridges, J. C., Edwards, C. S., Fischer, W. W., Fox, V. K., Gupta, S., Horgan, B. H. N., Jacob, S. R., Johnson, J. R., Johnson, S. S., Rubin, D. M., Salvatore, M. R., Schwenzer, S. P., Siebach, K. L., Stein, N. T., Turner, S., Wellington, D. F., Wiens, R. C., Williams, A. J., David, G., Wong, G. M., Fraeman, A. A., Edgar, L. A., Rampe, E. B., Thompson, L. M., Frydenvang, J., Fedo, C. M., Catalano, J. G., Dietrich, W. E., Gabriel, T. S. J., Vasavada, A. R., Grotzinger, J. P., L'Haridon, J., Mangold, N., Sun, V. Z., House, C. H., Bryk, A. B., Hardgrove, C., Czarnecki, S., Stack, K. M., Morris, R. V., Arvidson, R. E., Banham, S. G., Bennett, K. A., Bridges, J. C., Edwards, C. S., Fischer, W. W., Fox, V. K., Gupta, S., Horgan, B. H. N., Jacob, S. R., Johnson, J. R., Johnson, S. S., Rubin, D. M., Salvatore, M. R., Schwenzer, S. P., Siebach, K. L., Stein, N. T., Turner, S., Wellington, D. F., Wiens, R. C., Williams, A. J., David, G., and Wong, G. M.

Abstract

This paper provides an overview of the Curiosity rover's exploration at Vera Rubin ridge and summarizes the science results. Vera Rubin ridge (VRR) is a distinct geomorphic feature on lower Aeolis Mons (informally known as Mt. Sharp) that was identified in orbital data based on its distinct texture, topographic expression, and association with a hematite spectral signature. Curiosity conducted extensive remote sensing observations, acquired data on dozens of contact science targets, and drilled three outcrop samples from the ridge, as well as one outcrop sample immediately below the ridge. Our observations indicate that strata composing VRR were deposited in a predominantly lacustrine setting and are part of the Murray formation. The rocks within the ridge are chemically in family with underlying Murray formation strata. Red hematite is dispersed throughout much of the VRR bedrock, and this is the source of the orbital spectral detection. Gray hematite is also present in isolated, gray‐colored patches concentrated towards the upper elevations of VRR, and these gray patches also contain small, dark Fe‐rich nodules. We propose that VRR formed when diagenetic event(s) preferentially hardened rocks, which were subsequently eroded into a ridge by wind. Diagenesis also led to enhanced crystallization and/or cementation that deepened the ferric‐related spectral absorptions on the ridge, which helped make them readily distinguishable from orbit. Results add to existing evidence of protracted aqueous environments at Gale crater and give new insight into how diagenesis shaped Mars’ rock record.

35. Formation of Tridymite and Evidence for a Hydrothermal History at Gale Crater, Mars

Author

Yen, A. S., Morris, R. V., Ming, D. W., Schwenzer, S. P., Sutter, B., Vaniman, D. T., Treiman, A. H., Gellert, R., Achilles, C. N., Berger, J. A., Blake, D. F., Boyd, N. I., Bristow, T. F., Chipera, S., Clark, B. C., Craig, P. I., Downs, R. T., Franz, H. B., Gabriel, T., McAdam, A. C., Morrison, S. M., O'Connell‐Cooper, C. D., Rampe, E. B., Schmidt, M. E., Thompson, L. M., VanBommel, S. J., Yen, A. S., Morris, R. V., Ming, D. W., Schwenzer, S. P., Sutter, B., Vaniman, D. T., Treiman, A. H., Gellert, R., Achilles, C. N., Berger, J. A., Blake, D. F., Boyd, N. I., Bristow, T. F., Chipera, S., Clark, B. C., Craig, P. I., Downs, R. T., Franz, H. B., Gabriel, T., McAdam, A. C., Morrison, S. M., O'Connell‐Cooper, C. D., Rampe, E. B., Schmidt, M. E., Thompson, L. M., and VanBommel, S. J.

Abstract

In August 2015, the Curiosity Mars rover discovered tridymite, a high‐temperature silica polymorph, in Gale crater. The existing model for its occurrence suggests erosion and detrital sedimentation from silicic volcanic rocks in the crater rim or central peak. The chemistry and mineralogy of the tridymite‐bearing rocks, however, are not consistent with silicic volcanic material. Using data from Curiosity, including chemical composition from the Alpha Particle X‐ray Spectrometer, mineralogy from the CheMin instrument, and evolved gas and isotopic analyses from the Sample Analysis at Mars instrument, we show that the tridymite‐bearing rocks exhibit similar chemical patterns with silica‐rich alteration halos which crosscut the stratigraphy. We infer that the tridymite formed in‐place through hydrothermal processes and show additional chemical and mineralogical results from Gale crater consistent with hydrothermal activity occurring after sediment deposition and lithification.

36. Evidence for a Diagenetic Origin of Vera Rubin Ridge, Gale Crater, Mars: Summary and Synthesis of Curiosity's Exploration Campaign

Author

Fraeman, A. A., Edgar, L. A., Rampe, E. B., Thompson, L. M., Frydenvang, J., Fedo, C. M., Catalano, J. G., Dietrich, W. E., Gabriel, T. S. J., Vasavada, A. R., Grotzinger, J. P., L'Haridon, J., Mangold, N., Sun, V. Z., House, C. H., Bryk, A. B., Hardgrove, C., Czarnecki, S., Stack, K. M., Morris, R. V., Arvidson, R. E., Banham, S. G., Bennett, K. A., Bridges, J. C., Edwards, C. S., Fischer, W. W., Fox, V. K., Gupta, S., Horgan, B. H. N., Jacob, S. R., Johnson, J. R., Johnson, S. S., Rubin, D. M., Salvatore, M. R., Schwenzer, S. P., Siebach, K. L., Stein, N. T., Turner, S., Wellington, D. F., Wiens, R. C., Williams, A. J., David, G., Wong, G. M., Fraeman, A. A., Edgar, L. A., Rampe, E. B., Thompson, L. M., Frydenvang, J., Fedo, C. M., Catalano, J. G., Dietrich, W. E., Gabriel, T. S. J., Vasavada, A. R., Grotzinger, J. P., L'Haridon, J., Mangold, N., Sun, V. Z., House, C. H., Bryk, A. B., Hardgrove, C., Czarnecki, S., Stack, K. M., Morris, R. V., Arvidson, R. E., Banham, S. G., Bennett, K. A., Bridges, J. C., Edwards, C. S., Fischer, W. W., Fox, V. K., Gupta, S., Horgan, B. H. N., Jacob, S. R., Johnson, J. R., Johnson, S. S., Rubin, D. M., Salvatore, M. R., Schwenzer, S. P., Siebach, K. L., Stein, N. T., Turner, S., Wellington, D. F., Wiens, R. C., Williams, A. J., David, G., and Wong, G. M.

Abstract

This paper provides an overview of the Curiosity rover's exploration at Vera Rubin ridge and summarizes the science results. Vera Rubin ridge (VRR) is a distinct geomorphic feature on lower Aeolis Mons (informally known as Mt. Sharp) that was identified in orbital data based on its distinct texture, topographic expression, and association with a hematite spectral signature. Curiosity conducted extensive remote sensing observations, acquired data on dozens of contact science targets, and drilled three outcrop samples from the ridge, as well as one outcrop sample immediately below the ridge. Our observations indicate that strata composing VRR were deposited in a predominantly lacustrine setting and are part of the Murray formation. The rocks within the ridge are chemically in family with underlying Murray formation strata. Red hematite is dispersed throughout much of the VRR bedrock, and this is the source of the orbital spectral detection. Gray hematite is also present in isolated, gray‐colored patches concentrated towards the upper elevations of VRR, and these gray patches also contain small, dark Fe‐rich nodules. We propose that VRR formed when diagenetic event(s) preferentially hardened rocks, which were subsequently eroded into a ridge by wind. Diagenesis also led to enhanced crystallization and/or cementation that deepened the ferric‐related spectral absorptions on the ridge, which helped make them readily distinguishable from orbit. Results add to existing evidence of protracted aqueous environments at Gale crater and give new insight into how diagenesis shaped Mars’ rock record.

40. Commonwealth Idea and Prospect

Author

Willey, C. F., primary, Bailey, Sydney D., additional, Barker, Ernest, additional, Benda, Harry J., additional, Birch, A. H., additional, Bland, F. A., additional, Clokie, Hugh McD., additional, Collins, Charles, additional, Crisp, L. F., additional, Hodson, H. V., additional, Kilpin, Ralph, additional, Mavalankar, G. V., additional, Miller, J. D. B., additional, Namasivayam, S., additional, Nash, Walter, additional, Prasad, Rajendra, additional, Sen, Ajit Kumar, additional, Sharma, Sri Ram, additional, Silcox, C. E., additional, Thompson, L. M., additional, Wilding, N. W., additional, and Zimmern, Alfred, additional

Published
1953
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42. Die Afrikaner Bond, 1880-1900

Author

Davenport, Thomas Rodney Hope, Mandelbrote, H J, Thompson, L M, Department of Historical Studies, and Faculty of Humanities

Published
1960

43. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila.

Author

Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL, Kazantsev A, Schmidt E, Zhu YZ, Greenwald M, Kurokawa R, Housman DE, Jackson GR, Marsh JL, and Thompson LM

Subjects
Acetylation, Acetyltransferases metabolism, Animals, Animals, Genetically Modified, CREB-Binding Protein, Disease Models, Animal, Drosophila genetics, Drosophila metabolism, Drosophila Proteins genetics, Drosophila Proteins metabolism, E1A-Associated p300 Protein, Gene Expression Regulation, Glutathione Transferase metabolism, Histone Acetyltransferases, Histone Deacetylases metabolism, Histones metabolism, Huntingtin Protein, Huntington Disease enzymology, Huntington Disease metabolism, Huntington Disease prevention & control, Nerve Degeneration, Nerve Tissue Proteins chemistry, Neurodegenerative Diseases drug therapy, Neurodegenerative Diseases enzymology, Nuclear Proteins chemistry, PC12 Cells, Protein Structure, Tertiary, Rats, Repetitive Sequences, Amino Acid, Repressor Proteins genetics, Repressor Proteins metabolism, Sin3 Histone Deacetylase and Corepressor Complex, Enzyme Inhibitors metabolism, Glutamine metabolism, Histone Deacetylase Inhibitors, Nerve Tissue Proteins metabolism, Neurodegenerative Diseases metabolism, Nuclear Proteins metabolism, Peptides metabolism, Saccharomyces cerevisiae Proteins, Trans-Activators metabolism
Abstract

Proteins with expanded polyglutamine repeats cause Huntington's disease and other neurodegenerative diseases. Transcriptional dysregulation and loss of function of transcriptional co-activator proteins have been implicated in the pathogenesis of these diseases. Huntington's disease is caused by expansion of a repeated sequence of the amino acid glutamine in the abnormal protein huntingtin (Htt). Here we show that the polyglutamine-containing domain of Htt, Htt exon 1 protein (Httex1p), directly binds the acetyltransferase domains of two distinct proteins: CREB-binding protein (CBP) and p300/CBP-associated factor (P/CAF). In cell-free assays, Httex1p also inhibits the acetyltransferase activity of at least three enzymes: p300, P/CAF and CBP. Expression of Httex1p in cultured cells reduces the level of the acetylated histones H3 and H4, and this reduction can be reversed by administering inhibitors of histone deacetylase (HDAC). In vivo, HDAC inhibitors arrest ongoing progressive neuronal degeneration induced by polyglutamine repeat expansion, and they reduce lethality in two Drosophila models of polyglutamine disease. These findings raise the possibility that therapy with HDAC inhibitors may slow or prevent the progressive neurodegeneration seen in Huntington's disease and other polyglutamine-repeat diseases, even after the onset of symptoms.

Published
2001
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44. The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription.

Author

Steffan JS, Kazantsev A, Spasic-Boskovic O, Greenwald M, Zhu YZ, Gohler H, Wanker EE, Bates GP, Housman DE, and Thompson LM

Subjects
Animals, Cells, Cultured, Humans, Huntingtin Protein, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Transgenic, Cyclic AMP Response Element-Binding Protein physiology, Huntington Disease genetics, Nerve Tissue Proteins physiology, Nuclear Proteins physiology, Repressor Proteins physiology, Tumor Suppressor Protein p53 physiology
Abstract

Huntington's Disease (HD) is caused by an expansion of a polyglutamine tract within the huntingtin (htt) protein. Pathogenesis in HD appears to include the cytoplasmic cleavage of htt and release of an amino-terminal fragment capable of nuclear localization. We have investigated potential consequences to nuclear function of a pathogenic amino-terminal region of htt (httex1p) including aggregation, protein-protein interactions, and transcription. httex1p was found to coaggregate with p53 in inclusions generated in cell culture and to interact with p53 in vitro and in cell culture. Expanded httex1p represses transcription of the p53-regulated promoters, p21(WAF1/CIP1) and MDR-1. httex1p was also found to interact in vitro with CREB-binding protein (CBP) and mSin3a, and CBP to localize to neuronal intranuclear inclusions in a transgenic mouse model of HD. These results raise the possibility that expanded repeat htt causes aberrant transcriptional regulation through its interaction with cellular transcription factors which may result in neuronal dysfunction and cell death in HD.

Published
2000
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45. Bacterial counts associated with sawdust and recycled manure bedding treated with commercial conditioners.

Author

Hogan JS, Bogacz VL, Thompson LM, Romig S, Schoenberger PS, Weiss WP, and Smith KL

Subjects
Animals, Anti-Bacterial Agents, Calcium Compounds, Dust, Enterobacteriaceae isolation & purification, Female, Gram-Negative Bacteria isolation & purification, Hydrogen-Ion Concentration, Klebsiella isolation & purification, Mammary Glands, Animal microbiology, Oxides, Streptococcus isolation & purification, Wood, Cattle microbiology, Colony Count, Microbial, Housing, Animal, Manure microbiology
Abstract

Bacteria counts associated with untreated organic bedding materials were compared with those of bedding treated with either an alkaline commercial bedding conditioner, acidic commercial bedding conditioner, or hydrated lime. Bedding materials were recycled manure and kiln-dried sawdust. The effects of bedding treatments on bacteria counts differed between bedding types. Each of the bedding treatments significantly reduced bacteria in recycled manure prior to use. The alkaline conditioner and hydrated lime effectively inhibited bacteria in recycled manure for 1 d. Bedding counts and teat swabs of cows housed on recycled manure treated with the alkaline conditioner were reduced on d 2. The use of the acid conditioner in recycled manure had little effect on bacteria in bedding. Sawdust differed from recycled manure in that bacteria in untreated sawdust prior to use were minimal, and populations increased rapidly during the first 2 d after use as bedding. The acid conditioner had a bacteriostatic effect in sawdust, evident by the reduction of bacteria on d 2. The alkaline conditioner and hydrated lime did not alter bacteria counts in sawdust compared with untreated sawdust. Antibacterial activity of each conditioner deteriorated between d 2 and d 6 in both beddings. The antibacterial activities of conditioners were related to the pH of bedding materials. The use of commercial bedding conditioners initially reduced bacterial counts; however, the antibacterial effects had diminished between d 2 and 6 after use in bedding.

Published
1999
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46. Comparison of the intracellular signaling responses by three chimeric fibroblast growth factor receptors in PC12 cells.

Author

Raffioni S, Thomas D, Foehr ED, Thompson LM, and Bradshaw RA

Subjects
Animals, Cell Differentiation, Fibroblast Growth Factors metabolism, Humans, Ligands, PC12 Cells, Phosphorylation, Rats, Receptor, Platelet-Derived Growth Factor beta, Receptors, Fibroblast Growth Factor genetics, Receptors, Platelet-Derived Growth Factor genetics, Receptors, Platelet-Derived Growth Factor metabolism, Recombinant Fusion Proteins genetics, Transfection, Receptors, Fibroblast Growth Factor metabolism, Recombinant Fusion Proteins metabolism, Signal Transduction
Abstract

Stably transfected PC12 cell lines expressing similar amounts of chimeric receptors composed of the extracellular domain of the human platelet-derived growth factor (PDGF)beta receptor and the transmembrane and intracellular domains of the fibroblast growth factor receptors (FGFRs) 1, 3, and 4 undergo ligand-induced differentiation. The FGFR1 chimera (PFR1) is the most potent of the three, and PFR4 requires more frequent (every 24 hr) addition of ligand to maintain the response. Both PFR1 and -3 also show significant ligand-independent autophosphorylation but PFR4 does not. All of the chimeras activated phospholipase Cgamma, Shc, FGFR substrate (FRS)2, and the mitogen-activated protein kinases, ERK1 and 2. PFR4 was moderately weaker in stimulating these effects as well; PFR1 and -3 were comparable. None of the chimeras induced Sos association or were coprecipitated with Shc. Cotransfection of a dominant-negative Shc derivative, with tyrosine at 239, 240, and 317 replaced with phenylalanine, in the PFR-expressing cells was without effect on PDGF-induced neurite outgrowth. The same derivative substantially inhibited the response of these cells to NGF. These results indicate that FGFR1, 3, and 4 (i) are capable of signaling in a similar fashion; (ii) primarily use FRS2 and, perhaps, PLCgamma; and (iii) do not utilize Shc. The results also suggest that the principal difference between FGFR1, 3, and 4 is in the strength of the tyrosine kinase activity and that qualitative differences in signaling capacity are likely to be less important.

Published
1999
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47. A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene.

Author

Tavormina PL, Bellus GA, Webster MK, Bamshad MJ, Fraley AE, McIntosh I, Szabo J, Jiang W, Jabs EW, Wilcox WR, Wasmuth JJ, Donoghue DJ, Thompson LM, and Francomano CA

Subjects
Acanthosis Nigricans complications, Achondroplasia complications, Achondroplasia genetics, Bone and Bones diagnostic imaging, Craniosynostoses genetics, Developmental Disabilities complications, Humans, Immunoblotting, Models, Biological, Mutagenesis, Site-Directed, Mutation, Missense, Phenotype, Phosphotransferases analysis, Point Mutation, Precipitin Tests, Radiography, Receptor, Fibroblast Growth Factor, Type 3, Receptors, Fibroblast Growth Factor physiology, Thanatophoric Dysplasia complications, Thanatophoric Dysplasia diagnostic imaging, Thanatophoric Dysplasia genetics, Acanthosis Nigricans genetics, Bone and Bones abnormalities, Developmental Disabilities genetics, Protein-Tyrosine Kinases, Receptors, Fibroblast Growth Factor genetics
Abstract

We have identified a novel fibroblast growth factor receptor 3 (FGFR3) missense mutation in four unrelated individuals with skeletal dysplasia that approaches the severity observed in thanatophoric dysplasia type I (TD1). However, three of the four individuals developed extensive areas of acanthosis nigricans beginning in early childhood, suffer from severe neurological impairments, and have survived past infancy without prolonged life-support measures. The FGFR3 mutation (A1949T: Lys650Met) occurs at the nucleotide adjacent to the TD type II (TD2) mutation (A1948G: Lys650Glu) and results in a different amino acid substitution at a highly conserved codon in the kinase domain activation loop. Transient transfection studies with FGFR3 mutant constructs show that the Lys650Met mutation causes a dramatic increase in constitutive receptor kinase activity, approximately three times greater than that observed with the Lys650Glu mutation. We refer to the phenotype caused by the Lys650Met mutation as "severe achondroplasia with developmental delay and acanthosis nigricans" (SADDAN) because it differs significantly from the phenotypes of other known FGFR3 mutations.

Published
1999
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48. Friction melt distribution in a multi-ring impact basin.

Author

Spray JG and Thompson LM

Subjects
Canada, Geological Phenomena, Geology, Earth, Planet, Solar System
Abstract

It is generally accepted that multi-ring basins are the consequence of very large impacts, but the mechanism by which they form is still a matter of contention. Most of what is currently known about multi-ring basins is based on remote studies of the Moon and, to a lesser extent, Mars and Mercury. But at least two multi-ring impact basins have been recognized on Earth--the Sudbury (Canada) and Vredefort (South Africa) impact structures--providing an opportunity to study their properties directly. Here we describe the distribution of friction melt (pseudotachylyte) in the floor of the Sudbury impact basin. Although the veins and dykes of pseudotachylyte decrease in both thickness and frequency of occurrence towards the basin periphery, the greatest volumes of friction melt appear to define four rings around the central impact melt sheet. Field evidence indicates that the rings originated as zones of large displacement, which facilitated localized frictional melting of the basin floor during the modification (collapse) stage of the cratering process. By analogy, we argue that the rings of other multi-ring impact basins are also likely to be the remnants of such large-displacement fault zones.

Published
1995
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49. Contractual arrangements between residency programs and HMOs.

Author

Corrigan JM and Thompson LM

Subjects
Hospitals, Teaching, Interinstitutional Relations, Sampling Studies, United States, Contract Services statistics & numerical data, Family Practice education, Health Maintenance Organizations organization & administration, Internship and Residency organization & administration
Abstract

Background: Although one out of seven health maintenance organizations (HMOs) is directly involved in graduate medical education (GME), either as an accredited sponsoring organization or through a contractual agreement with an academic medical center or teaching hospital to serve as an ambulatory rotation site, relatively little is known about the extent to which HMOs have provider contracts with faculty or residents of GME programs. Such provider contracts are not agreements to collaborate on the education of residents, but rather contractual arrangements under which individual physicians or groups (who happen to be residents or faculty) agree to provide services to HMO enrollees in return for some form of compensation., Methods: In 1990, the Group Health Association of America conducted a survey of a sample of residency training programs in family medicine, internal medicine, and pediatrics to ascertain the extent to which (1) residents and faculty of residency training programs are participating physicians in HMOs; and (2) HMO enrollees are serving as the patient base for GME in ambulatory settings., Results: Overall, 42% of the residency program respondents indicated that they contract with HMOs to provide services to enrollees. Nearly two thirds (64%) of family practice programs have provider contracts as compared with 28% of pediatrics programs and 24% of internal medicine programs. Provider contracts with independent practice associations are by far the most common, followed by group, network, and staff model contracts, in that order., Conclusions: It is apparent that provider contractual arrangements between HMOs and primary care residency programs are quite common, especially in the area of family practice. These contractual arrangements have probably resulted in a more predictable and stable patient revenue base for residency programs. The long-term effects on provider practice styles and the financing of graduate medical education are less clear.

Published
1992

50. A recombination event that redefines the Huntington disease region.

Author

Snell RG, Thompson LM, Tagle DA, Holloway TL, Barnes G, Harley HG, Sandkuijl LA, MacDonald ME, Collins FS, and Gusella JF

Subjects
Female, Genetic Markers, Genotype, Humans, Linkage Disequilibrium, Male, Pedigree, Polymorphism, Genetic, Restriction Mapping, Chromosomes, Human, Pair 4, Huntington Disease genetics, Recombination, Genetic
Abstract

We report both a recombination event that places the Huntington disease gene proximal to the marker D4S98 and an extended linkage-disequilibrium study that uses this marker and confirms the existence of disequilibrium between it and the HD locus. We also report the cloning of other sequences in the region around D4S98, including a new polymorphic marker R10 and conserved sequences that identify a gene in the region of interest.

Published
1992

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