8 research outputs found

    The Lantern Vol. 62, No. 1, December 1994

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    • Hollow • A Little Knowledge is Dangerous • My Old Block • Life • The Natural Born Fool • Oracle • Formation of a Triangle • Marie on the Beach • The Tweed Derby • Tripping • In Vitro • The Character • Coming Home for Christmas • Unkempt • Too Much • Reimertanti-Ode • Seeds • Secrethttps://digitalcommons.ursinus.edu/lantern/1145/thumbnail.jp

    The Lantern Vol. 62, No. 2, Summer 1995

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    • In the Season of Grief • Subtleties • Crazehaze • Blacksmith • I Feel Your Weight • L\u27Amour Manque • Sense of You • Greed • Gender (Rolled) • Soliloquy of a Punter • Nightmares • God is a Frisbee • Cleansing • Flat • Chemistry of Mind • Louderback • Ritual • Rebuilding Mother • Scott Lomba • The Acting Bug • Untitled • The Seek • Gluttony • Great South Bay • Archangel • Suburban Zeus • Vespers • At Change of A-Dress • The Hierarchy of Coolness • The Apology • I Know it is Evening There • Pridehttps://digitalcommons.ursinus.edu/lantern/1146/thumbnail.jp

    The Lantern Vol. 63, No. 1, Fall 1995

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    • The Birthday Celebration • Surprise! Surprise! • Oregold • Future of Parenthood #2 • Seeds • How I Spent My Summer Vacation • Random Scenes From 1/2 Hour at Work • Life in the Coal Mines • Driveway • Midnight in the Court of Kings • The Black Quadrilateral • People I Hate to See, But Refuse to Dismiss • Metropolized • Poetry in Motion • Dream #3 • Rhythms • Mercykilling • Untitled • Lupine Lord • At the Bottom of the Cup • House of Commons • Poetry I Can\u27t Standhttps://digitalcommons.ursinus.edu/lantern/1147/thumbnail.jp

    The Lantern Vol. 63, No. 2, Spring 1996

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    • Poet, Lead Me On • St. Patrick\u27s Day • The Last Three Days • The Impressionable • Roundabout • The Bench • Carnivorous • Kyrie • Second Glance • Porch • Cruel Design • A Mime • Flaxen Crown • My Embryonic Ocean of Love • Stone Matrix • Voices from the Past • Skipping the Bullfight: Toreadors and Gaudi • Another Part of My Lacolonialism • Translucent Pane • Linguistics • Treehouse • A Disagreeable Music Piece • Vigil • A Brief History of American Poetry in Englishhttps://digitalcommons.ursinus.edu/lantern/1148/thumbnail.jp

    The Lantern Vol. 61, No. 2, Summer 1994

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    • She Was a Woman of Dignity • Retake, Scene 16 • Las Vegas Sweatshirt • Pitcher Hill • In Preparation for Wisdom (Teeth) • Moist Slacks • My Mother\u27s Purse • It Comes and Goes Everyday • The Simplicity of Marriage • The First Performance • Hunger • Pushkin\u27s Dream • Tuesday, October 19 • Poetry of Baseball • Some Things are More Important Than Others • Musician • Of What Befell Our Good Knight • Piranha • Oceans Apart • Brooklyn Cantos • Snowshower • Thankfully in Australia • Toothpaste and Tuna Fish • Living Space • Blue Monday • Afterglow • A Path to Consider • Endless Summer • Scaredy-Cathttps://digitalcommons.ursinus.edu/lantern/1144/thumbnail.jp

    Inhibiting Hippo pathway kinases releases WWC1 to promote AMPAR-dependent synaptic plasticity and long-term memory in mice

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    The localization, number, and function of postsynaptic AMPA-type glutamate receptors (AMPARs) are crucial for synaptic plasticity, a cellular correlate for learning and memory. The Hippo pathway member WWC1 is an important component of AMPAR-containing protein complexes. However, the availability of WWC1 is constrained by its interaction with the Hippo pathway kinases LATS1 and LATS2 (LATS1/2). Here, we explored the biochemical regulation of this interaction and found that it is pharmacologically targetable in vivo. In primary hippocampal neurons, phosphorylation of LATS1/2 by the upstream kinases MST1 and MST2 (MST1/2) enhanced the interaction between WWC1 and LATS1/2, which sequestered WWC1. Pharmacologically inhibiting MST1/2 in male mice and in human brain-derived organoids promoted the dissociation of WWC1 from LATS1/2, leading to an increase in WWC1 in AMPAR-containing complexes. MST1/2 inhibition enhanced synaptic transmission in mouse hippocampal brain slices and improved cognition in healthy male mice and in male mouse models of Alzheimer's disease and aging. Thus, compounds that disrupt the interaction between WWC1 and LATS1/2 might be explored for development as cognitive enhancers.</p

    Cysteine Proteases Bleomycin Hydrolase and Cathepsin Z Mediate N-terminal Proteolysis and Toxicity of Mutant Huntingtin*

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    N-terminal proteolysis of huntingtin is thought to be an important mediator of HD pathogenesis. The formation of short N-terminal fragments of huntingtin (cp-1/cp-2, cp-A/cp-B) has been demonstrated in cells and in vivo. We previously mapped the cp-2 cleavage site by mass spectrometry to position Arg167 of huntingtin. The proteolytic enzymes generating short N-terminal fragments of huntingtin remain unknown. To search for such proteases, we conducted a genome-wide screen using an RNA-silencing approach and an assay for huntingtin proteolysis based on the detection of cp-1 and cp-2 fragments by Western blotting. The primary screen was carried out in HEK293 cells, and the secondary screen was carried out in neuronal HT22 cells, transfected in both cases with a construct encoding the N-terminal 511 amino acids of mutant huntingtin. For additional validation of the hits, we employed a complementary assay for proteolysis of huntingtin involving overexpression of individual proteases with huntingtin in two cell lines. The screen identified 11 enzymes, with two major candidates to carry out the cp-2 cleavage, bleomycin hydrolase (BLMH) and cathepsin Z, which are both cysteine proteases of a papain-like structure. Knockdown of either protease reduced cp-2 cleavage, and ameliorated mutant huntingtin induced toxicity, whereas their overexpression increased the cp-2 cleavage. Both proteases partially co-localized with Htt in the cytoplasm and within or in association with early and late endosomes, with some nuclear co-localization observed for cathepsin Z. BLMH and cathepsin Z are expressed in the brain and have been associated previously with neurodegeneration. Our findings further validate the cysteine protease family, and BLMH and cathepsin Z in particular, as potential novel targets for HD therapeutics
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