590 research outputs found
(10) The Papers of Robert H. Goddard, Volume II: 1925-1937 [1932-1934: Interlude at Clark University]
No full textMeticulously curated and edited by Esther C. Goddard and G. Edward Pendray, The Papers of Robert H. Goddard is a 1700-page 3 volume set published in 1970. The set presents a careful and exhaustive chronological presentation of Robert Goddard’s life through diary snippets, notebook entries, correspondence, publications, speeches, patent outlines, school papers, press, reports and more.This section covers a brief period in Robert Goddard\u27s life, from mid 1932 to mid 1934, between his two grant funded periods (1930-1932, 1934-1942) for rocket research in Roswell, New Mexico. During this time, he continued to teach at Clark University and conduct research funded by the Smithsonian Institution and the Daniel and Florence Guggenheim Foundation.
This section contains correspondence by, to, and about Robert H. Goddard from the following people and entities: Charles Greeley Abbot, John C. Merriam, Wallace W. Atwood, Legation of Switzerland, Werner Brügel, Claude A. Swanson, Henry L. Roosevelt, Edwin Fitch Northrup, Fred S. Tobey, Harry F. Guggenheim, Admiral William Harrison Standley, H. Gordon Garbedian, Florence Schloss Guggenheim, Charles Lindbergh.
Disclaimer: The images in these scans have been rendered somewhat distorted after the fact. We apologize for this error. Thankfully, most of the photographs used in these papers are part of the The Goddard Rocket Researches: A Photographic Record and can be seen individually in high-quality scans.https://commons.clarku.edu/papersgoddard/1009/thumbnail.jp
Ocular therapeutics eye on new discoveries/ Edit.: Thomas Yorio; Abbot F. Clark; Martin B. Wax
No full textxiii, 520 hal.: ill, tab.; 26 cm
(05) The Papers of Robert H. Goddard, Volume I: 1898-1924 [1915-1920: Experimentation with Solid Propellants]
No full textMeticulously curated and edited by Esther C. Goddard and G. Edward Pendray, The Papers of Robert H. Goddard is a 1700-page 3 volume set published in 1970. The set presents a careful and exhaustive chronological presentation of Robert Goddard’s life through diary snippets, notebook entries, correspondence, publications, speeches, patent outlines, school papers, press, reports and more.
This section covers Robert Goddard\u27s life from 1915 through 1920. During this time, he became an Assistant Professor in Physics at Clark University, demonstrated that reaction takes place in a vacuum, hence a rocket could function in airless space, received his first Smithsonian grant for rocket work, conducted research for the U.S. Signal Corps and Army Ordinance, demonstrated solid-propellant military rockets, published A Method of Reaching Extreme Altitudes , and began his twenty-plus year tenure as Professor of Physics at Clark University.
This section contains the following published articles by Goddard (there are also unpublished works on subjects such as atomic disintegration): Approximate Solution of a General Case of Rocket Action , Physical Review (1919) A Method of Reaching Extreme Altitudes , Smithsonian Miscellaneous Collections (1919) On High-altitude Research , Science (1920) The Rocket Method , Journal of the Worcester Polytechnic Institute (1920) The Possibilities of the Rocket in Weather Forecasting , Proceedings of the National Academy of Sciences (1920)
This section contains correspondence by, to, and about Robert H. Goddard from the following people and entities: William T. Foster, Edmund C. Sanford, Edward Charles Pickering, Charles Greeley Abbot, Charles Doolittle Walcott, Edgar Buckingham, Hudson Maxim, Richard Rathbun, George I. Rockwood, Samuel Wesley Stratton, Rear Admiral Ralph Earle, Major General George O. Squier, Colonel Edward Marsh Shinkle, Robert Simpson Woodard, Nahum D. Goddard, George E. Hale, Hugh M. Dorsey, General Clark C. Williams, Hudson Maxim, General George W. Burr, Walter S. Adams, Major W.A. Borden, Clarence N. Hickman, Lieutenant Colonel Herbert O’Leary, Charles F. Marvin, Gordon S. Fulcher, Bronx Exposition Inc, A. Russell Bond (Scientific American Monthly), Karl Taylor Compton, Henry N. Crowther, Rear Admiral Ralph Earle, Robert Esnault-Peleterie, Lieutenant Colonel Amos A. Fries, Macmillian & Co., Ltd., Lieutenant Commander Olaf M. Hustveldt, William de C. Ravenel, F.P. Fergusson.
Disclaimer: The images in these scans have been rendered somewhat distorted after the fact. We apologize for this error. Thankfully, most of the photographs used in these papers are part of the The Goddard Rocket Researches: A Photographic Record and can be seen individually in high-quality scans.https://commons.clarku.edu/papersgoddard/1004/thumbnail.jp
(09) The Papers of Robert H. Goddard, Volume II: 1925-1937 [1930-1932: The First New Mexico Adventure]
No full textMeticulously curated and edited by Esther C. Goddard and G. Edward Pendray, The Papers of Robert H. Goddard is a 1700-page 3 volume set published in 1970. The set presents a careful and exhaustive chronological presentation of Robert Goddard’s life through diary snippets, notebook entries, correspondence, publications, speeches, patent outlines, school papers, press, reports and more. This section covers Robert Goddard\u27s life from mid 1930 to mid 1932 when Goddard received his first Guggenheim grant (this one from Daniel) which would bring Robert and Esther to Roswell, New Mexico for two years of rocket research. They would soon relocate to Roswell for a much longer stretch of time, 1934-1942, under grants from the Daniel and Florence Guggenheim Foundation. In April of 1932, Goddard achieved the first flight of a rocket with gyroscopic stabilization.
This section contains correspondence by, to, and about Robert H. Goddard from the following people and entities: Charles Greeley Abbot, John C. Merriam, Franz Oskar Leo Elder von Hoefft, Wallace W. Atwood, David Lasser, Ivy Lee, Carl L. Bausch, W.F. Clark, L.T.E. Thompson, George Crompton, Lawrence Mansur, Walter S. Adams, Ernest O. Lawrence, John A. Fleming, Nils Thure Ljungquist, Florence Schloss Guggenheim, Major Kenneth B. Harmon, Frederick G. Keyes, George K. Burgess, Willis Ford Insurance Agency, G. Edward Pendray, R.E Turpin, Robert A. Millikan, Charles Franklin Brooks, Russell B. Hastings, H. Gordon Garbedian, H.G. Wells, Rudyard Kipling, Percy M. Roope, E.G. Minton, Charles F. Brooks, Lieutenant Colonel W.A. Capron.
Disclaimer: The images in these scans have been rendered somewhat distorted after the fact. We apologize for this error. Thankfully, most of the photographs used in these papers are part of the The Goddard Rocket Researches: A Photographic Record and can be seen individually in high-quality scans.https://commons.clarku.edu/papersgoddard/1008/thumbnail.jp
Glucororticoid Receptor Alternative Splicing: Key Players and Role in TM and Glaucoma
No full textElevated intraocular pressure (IOP) is the primary risk factor in glaucoma, a leading cause of irreversible blindness. Various morphological and biochemical changes in the trabecular meshwork (TM) appear to be responsible for blocking aqueous humor outflow, thereby elevating IOP. Glucocorticoids (GCs) are known to induce ocular hypertension and other biochemical changes associated with glaucoma. Interestingly, there are differences in steroid responsiveness among the population, with 40% people known as responders who significantly elevate IOP upon GC treatment and others being classified as nonresponders. The steroid-responders are at higher risk of developing primary open angle glaucoma (POAG) as compared to the steroid nonresponders. At the same time, almost all POAG patients are moderate to high steroid responders. GC responsiveness is regulated by the relative ratios of the GC activated transcription factor GC receptor alpha (GRα) and the alternatively spliced dominant negative regulator isoform of this receptor (GRβ). Glaucomatous TM cell strains have a higher GRα/GRβ ratio compared to normal TM cells making them more sensitive to GCs. Regulation of the GRα/GRβ splicing is not very well documented. The role of splicing factors that regulate spliceosome assembly seems to be one of the key factors regulating the process of alternative splicing. We have shown that the relative levels of the different serine-arginine (SR) proteins (SRps) in the TM regulate the differential expression of the two alternatively spliced isoforms of GR, GRα and GRβ and that expression of these SR proteins regulates GC responsiveness in TM cells.
In addition, we evaluated a special class of compounds (thailanstatins or TSTs) and found them to modulate this splicing process to enhance GRβ levels in TM cells. These splicing modulators increased GRβ/GRα in TM, decreased GC response and provide potential glaucoma therapeutic agents
Identifying Unique Therapeutic Targets To Rescue Retinal Ganglion Cells From Degeneration After Optic Nerve Crush
No full textCentral nervous system (CNS) trauma and neurodegenerative disorders trigger a cascade of cellular and molecular events resulting in neuronal apoptosis and regenerative failure. The pathogenic mechanisms and gene expression changes associated with these detrimental events can be effectively studied using a rodent optic nerve crush (ONC) model. The purpose of this study was to use a mouse ONC model to: (a) evaluate changes in retina and ON gene expression, (b) identify neurodegenerative pathogenic pathways, (c) discover potential new therapeutic targets, and (d) evaluate the neuroprotective and axogenic properties of one selected therapeutic target on axotomized RGCs in vitro and the optic nerve crush (ONC) mouse model in vivo. Meta-analysis of altered gene expression (≥1.5 changes and ≤1.5 changes, p [less than] 0.05 demonstrated 29 up- and 20 downregulated retinal gene clusters and 82 up- and 42 down-regulated optic nerve clusters. Regulated gene clusters included regenerative change, synaptic plasticity, axonogenesis, neuron projection, and neuron differentiation related genes. Expression of selected genes (Vsnl1, Syt1, Synpr and Nrn1) from retinal and ON neuronal clusters was qualitatively and quantitatively examined for their relation to axonal neurodegeneration by immunohistochemistry and qRT-PCR. Axotomized RGCs treated with recombinant hNrn1 (selected target) significantly increased survival of RGCs by 29% (n=8, p [less than] 0.01) and neurite outgrowth of cultured neurons by 261% compared to controls in cultured neurons (n=5-7, p [less than] 0.05). RGC transduction with AAV2-CAG-hNRN1 prior to ONC promoted RGC survival (42%, n=5-8, p [less than] 0.05) and significantly preserved ERG RGC function by 41% until 28 dpc (n=6, p [less than] 0.05) compared to the control AAV2-CAG-GFP transduction group. These ONC induced neuronal loss and regenerative failure associated clusters can be extrapolated to changes occurring in other forms of CNS trauma or in clinical neurodegenerative pathological settings. In conclusion, this study identified potential therapeutic targets to address two key mechanisms of CNS trauma and neurodegeneration: neuronal loss and regenerative failure and presented Nrn1 as a potential therapeutic target for CNS neurodegenerative diseases
TGF Beta 2 and Gremlin Signaling Pathways Regulate Extracellular Matrix Changes in TM Cells: Implications for Glaucoma
No full textPurpose: Glaucoma is a leading cause of blindness worldwide. The leading risk factor is elevated intraocular pressure (IOP) due to fibrotic changes in the trabecular meshwork (TM) tissue. The profibrotic cytokine TGFβ2 is elevated in the aqueous humor and TM of glaucomatous eyes. TGFβ2-mediated extracellular matrix (ECM) deposition in the TM appears to be responsible for increased IOP in ex vivo and in vivo models. Bone morphogenetic proteins (BMPs) inhibit TGFβ regulation of ECM, and elevated levels of the BMP antagonist gremlin in the glaucomatous TM restores the fibrotic response of TGFβ2. Lysyl oxidase (LOX) is a collagen and elastin polymer crosslinking enzyme, and recent genome wide association studies showed that SNPs in LOXL1, a LOX family member, significantly increased the risk of developing exfoliation glaucoma. The overall aim of my work is to delineate the signaling pathways involved in TGFβ2 and gremlin alteration of the TM ECM and to evaluate the potential role of the LOX family of cross-linking enzymes in this TM ECM remodeling.
Methods: Human TM cells were cultured in the presence or absence of recombinant human TGFβ (0.1-10 ng/ml) or mouse gremlin (100-5000 ng/ml) for 1-72 hours, and total RNA or protein lysates and conditioned medium were harvested from the cells. Effects of gremlin treatment on ECM gene and protein expression were assayed by qRT-PCR and western immunoblotting, respectively. TGFβ2- and gremlin-treated TM cells were also examined for Smad2/3, p38, and JNK activation using western immunoblotting. Cells were treated with ii Smad3 inhibitor SIS3 (5 uM), TGFβ receptor inhibitors LY364947 and SB431542 (5 uM), JNK inhibitor SP600125 (10 uM), and AP-1 inhibitor SR11342 (5 uM) with or without TGFβ2/gremlin, to examine the involvement of the TGFβ/Smad signaling pathway.
Results: TGFβ2 and gremlin induced expression of each other in TM cells. TGFβ2 activated both Smad and non-Smad pathways and strongly induced mRNA and protein expression of all 5 LOX genes. Using a novel LOX activity assay, we observed greater ECM crosslinking in TGFβ- treated cells. Gremlin elevated ECM gene and protein expression via the Smad signaling pathway.
Conclusions: The TGFβ induction of LOXs and gremlin-induction of ECM proteins highlight the complex interplay of Smad and the non-Smad signaling in regulating the TGFβ response. TGFβ2 and gremlin are profibrotic in a feed forward loop. The TGFβ response in TM cells involves evasion of BMP inhibition by gremlin induction and also ECM crosslinking through the LOX enzymes
MIEN1 Drives Breast Cancer Invasion by Regulating Cytoskeletal-Focal Adhesions Dynamics
No full textIn the recent years, Migration and Invasion Enhancer 1(MIEN1) has emerged as a potential biomarker and a plausible target in breast cancer. Located in the 17q12-21 region of the human chromosome, next to the Her-2/neu loci, MIEN1 presents a robust expression in breast carcinomas; however is completely absent or low in the normal tissues. MIEN1 is post-translationally modified by geranyl-geranyl transferase-I (GgtaseI), which adds isoprenyl group to the carboxyl-terminal of the protein. Prenylated MIEN1 then associates with the inner leaflet of the plasma membrane and acts as an adaptor protein triggering downstream signaling through the Akt/NF-kB axis to regulate the expression of key proteases and angiogenic factors like MMP-9, uPA and VEGF. In migrating cells, MIEN1 enhances filopodium formation at the leading edge. Aside from its prenylation and redox-active motifs, MIEN1 also contains a canonical ITAM, reported to be associated with epithelial-to-mesenchymal transition. Although the role MIEN1 in cell migration and invasion is well known, the underlying molecular mechanisms remain elusive.
Here, we show that MIEN1 interacts with Annexin A2, a cytoskeletal protein and a regulator of the plasminogen/plasmin system in breast cancer cells to increase migration and invasion. We confirmed that MIEN1 regulates actin dynamics by associating with cytoskeletal effectors in the lamellum. We also show that MIEN1 expression redirects breast tumor cell migration toward a collective migration. Our studies validate MIEN1-ITAM and CAAX as key motifs to MIEN1-induced functions.
In conclusion, our findings confirm the role of MIEN1 in the remodeling of the actin cytoskeleton during motility. Furthermore it attests to previous findings suggesting that motility patterns depend on various environmental factors along with regulatory genes involved. Our study demonstrates an interesting example from cell biology where adaptor proteins regulate various signaling pathways and control cellular processes through protein-protein interactions
The Flip-Flop of AMPA Receptors in Retinal Ganglion Cell Survival
No full textElevated glutamate produces a cascade of events inducing neuronal death (known as “excitotoxicity”) in which the AMPA receptor (AMPAR), one of the ionotropic glutamate receptors (iGluRs), is hypothesized to play a role in neurodegenerative diseases such as glaucoma. Overstimulation of iGluRs increases intracellular calcium, leading to cellular dysfunction, and eventually apoptotic death of neurons. The activation of AMPARs has been well demonstrated to induce cell death in vivo; however, the mechanism of AMPAR mediated excitotoxicity is not fully understood. We hypothesized that AMPAR desensitization is the determinant of excitotoxicity in retinal ganglion cells (RGCs) in vitro. In this study, we evaluated AMPARs’ dual role in RGCs in mediating both neuroprotection and excitotoxicity following AMPAR stimulation.
Overstimulation of AMPARs (100μM s-AMPA) in purified RGCs was not able to induce the apoptotic pathway or produce RGC death. s-AMPA (desensitizing agonist) was able to increase RGC survival and increase the phosphorylation of cAMP response element-binding protein through the influx of Ca2+. However, RGC survival decreased when RGC cultures were stimulated with kainic acid (non-desensitizing AMPAR agonist) or when co-treated with s-AMPA and cyclothiazide (inhibits desensitization). Following an ischemic-like insult, AMPAR’s alternative spliced flip (decrease desensitization) and flop (increase desensitization) isoforms in purified RGCs were characterized, for the first time, to determine if the flip and flop isoforms play role in RGC excitotoxicity. A decrease in the mRNA expression of GLUA2 and 3 flop isoforms was observed.
In conclusion, we found a dual role for AMPARs in RGCs, where these receptors can mediate both cell survival and cell death. Additionally, for the first time, the decrease in AMPAR desensitization was associated with AMPAR-mediated excitotoxicity, through the changes in the post-transcriptional modifications (alternative splicing and RNA editing of the R/G site) of the AMPAR. This new mechanism of RGC death through AMPAR desensitization gives us a better insight into the pathogenesis and new targets to combat diseases, such as glaucoma, in which neurodegeneration is a hallmark
The life and works of Osbert of Clare
No full textOsbert of Clare was an English monastic writer, whose works extended from
the mid-1120s to the mid-1150s. His Latin hagiography reflects a deep admiration for
Anglo-Saxon saints and spirituality, while his letters provide a personal perspective
on his turbulent career. As prior of Westminster Abbey, Osbert of Clare worked to
strengthen the rights and prestige of his monastery. His production of forged or
altered charters makes him one of England's most prolific medieval forgers. At times
his passion for reform put him at odds with his abbots, and he was sent into exile
under both Abbot Herbert (1121-c.1136) and Abbot Gervase (1138-c.1157). Also
Osbert, as one of the first proponents of the Immaculate Conception of Mary, wrote
about the feast, worked to legitimize its celebration, and provided us with the only
significant narration of its introduction to England.
This thesis is divided into two sections. The first section is principally
historical and the second is principally literary. In the first section, I provide an
overview of Osbert of Clare's career and examine in greater detail two of his most
significant undertaking: his promotion of Westminster Abbey and his attempted
canonization of Edward the Confessor. In the second section, I give a philological
study of Osbert Latin style and examine themes that nm throughout his writings, such
as virginity, exile and kingship. Osbert's promotion of the feast of the Immaculate
Conception is included in the second section of the thesis because of its ties to the
themes of virginity and femininity within his writings. There are also two appendices:
the first is a survey of the extant manuscripts of Osbert's writings, and the second is
an edition of Osbert's unpublished Life of St Ethelbert from Gotha,
Forschungsbibliothek MS Memb. i. 8l
- …
