Neptune on tiptoes: dynamical histories that preserve the cold classical Kuiper belt

The current dynamical structure of the Kuiper belt was shaped by the orbital evolution of the giant planets, especially Neptune, during the era following planet formation, when the giant planets may have undergone planet-planet scattering and/or planetesimal-driven migration. Numerical simulations of this process, while reproducing many properties of the belt, fail to generate the high inclinations and eccentricities observed for some objects while maintaining the observed dynamically "cold" population. We present the first of a three-part parameter study of how different dynamical histories of Neptune sculpt the planetesimal disk. Here we identify which dynamical histories allow an in situ planetesimal disk to remain dynamically cold, becoming today's cold Kuiper belt population. We find that if Neptune undergoes a period of elevated eccentricity and/or inclination, it secularly excites the eccentricities and inclinations of the planetesimal disk. We demonstrate that there are several well-defined regimes for this secular excitation, depending on the relative timescales of Neptune's migration, the damping of Neptune's orbital inclination and/or eccentricity, and the secular evolution of the planetesimals. We model this secular excitation analytically in each regime, allowing for a thorough exploration of parameter space. Neptune's eccentricity and inclination can remain high for a limited amount of time without disrupting the cold classical belt. In the regime of slow damping and slow migration, if Neptune is located (for example) at 20 AU, then its eccentricity must stay below 0.18 and its inclination below 6{\deg}.Comment: Accepted to ApJ. Update: Fixed typos in text and Appendix equations. Published as ApJ, 746, 17

For Y am sorwe, and sorwe ys Y” : melancholy, despair, and pathology in Middle English literature

Thesis (Ph. D.)--University of Rochester. Dept. of English, 2008This dissertation argues that modern concepts of melancholia and depression first take shape in the extraordinary efflorescence of highly personalized vernacular writing that occurs in the late Middle Ages, much of which features characters in the throes of paralyzing sadness, longing, and loss. This cultural heritage begins in the confessional booth. The central claim of my thesis is that confessional practices mandated for all Christians in the Middle Ages directly affected the literary representation of despairing and depressed subjects. Because of the universal injunction, following the Fourth Lateran Council (1215), to examine and re-examine one’s conscience in confession, continental Europe saw a plethora of penitential handbooks encouraging practices that induced the reflexive turning that initiates subjective consciousness. This turning, I argue, resulted in the discovery of the psyche as fundamentally flawed. Jacque Lacan’s mirror in this sense corresponds to the medieval speculum hominis, in that late medieval subjects define themselves through recognition of and investment in a broken and divided self. My dissertation examines the developing relationship between this concept of the conscience and the definition and performance of sadness as a cultural idea. I closely examine four texts spanning the fourteenth and fifteenth centuries: Geoffrey Chaucer’s Book of the Duchess, the anonymous Pearl, William Langland’s Piers Plowman, and The Book of Margery Kempe. My project explores those questions of subject formation, class and gender identity, and power relationships that inform the development of a despairing identity. In addition to describing and explaining how medieval despairing subjects write themselves, get written, and get read in fourteenth and fifteenth century England, I convey the powerful appeal of these subjects for their original medieval audiences and for twenty-first century readers, a large part of which lies in the remarkably rich ways that these writings respond to diagnostic methods of literary interrogation such as psychoanalysis and clinical psychology

Prospective clinical and radiographic evaluation of an allogeneic bone matrix containing stem cells (Trinity Evolution® Viable Cellular Bone Matrix) in patients undergoing two-level anterior cervical discectomy and fusion

Abstract Background Trinity Evolution® (TE), a viable cellular bone allograft, previously demonstrated high fusion rates and no safety-related concerns after single-level anterior cervical discectomy and fusion (ACDF) procedures. This prospective multicenter clinical study was performed to assess the radiographic and clinical outcomes of TE in subjects undergoing two-level ACDF procedures. Methods In a prospective, multicenter study, 40 subjects that presented with symptomatic cervical degeneration at two adjacent vertebral levels underwent instrumented ACDF using TE autograft substitute in a polyetherethereketone (PEEK) cage. At 12 months, radiographic fusion status was evaluated by dynamic motion plain radiographs and thin cut CT with multiplanar reconstruction by a panel that was blinded to clinical outcome. Fusion success was defined by angular motion (≤4°) and the presence of bridging bone across the adjacent vertebral endplates. Clinical pain and function assessments included the Neck Disability Index (NDI), neck and arm pain as evaluated by visual analog scales (VAS), and SF-36 at both 6 and 12 months. Results At both 6 and 12 months, all clinical outcome scores (SF-36, NDI, and VAS pain) improved significantly (p < 0.05) compared to baseline values. There were no adverse events or infections that were attributed to the graft material, no subjects that required revisions, and no significant decreases to mean neurological evaluations at any time as compared to baseline. At 12 months, the per subject and per level fusion rate was 89.4 and 93.4%, respectively. Subgroup analysis of subjects with risk factors for pseudoarthrosis (current or former smokers, diabetic, or obese/extremely obese) compared to those without risk factors demonstrated no significant differences in fusion rates. Conclusions Patients undergoing two-level ACDF with TE in combination with a PEEK interbody spacer and supplemental anterior fixation had a high rate of fusion success without any serious adverse events related to the graft material. Trial registration Trinity Evolution in Anterior Cervical Disectomy and Fusion (ACDF) NCT0095193

The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site

The Phe43 cavity of HIV-1 envelope glycoproteins (Env) is an attractive druggable target. New promising compounds, including small CD4 mimetics (CD4mc), were shown to insert deeply into this cavity. Here, we identify a new network of residues that helps to shape this highly conserved CD4 binding pocket and characterize the structural determinants responsible for Env sensitivity to small CD4 mimetics.The HIV-1 envelope glycoproteins (Env) undergo conformational changes upon interaction of the gp120 exterior glycoprotein with the CD4 receptor. The gp120 inner domain topological layers facilitate the transition of Env to the CD4-bound conformation. CD4 engages gp120 by introducing its phenylalanine 43 (Phe43) in a cavity (“the Phe43 cavity”) located at the interface between the inner and outer gp120 domains. Small CD4-mimetic compounds (CD4mc) can bind within the Phe43 cavity and trigger conformational changes similar to those induced by CD4. Crystal structures of CD4mc in complex with a modified CRF01_AE gp120 core revealed the importance of these gp120 inner domain layers in stabilizing the Phe43 cavity and shaping the CD4 binding site. Our studies reveal a complex interplay between the gp120 inner domain and the Phe43 cavity and generate useful information for the development of more-potent CD4mc

CHIP phosphorylation by protein kinase G enhances protein quality control and attenuates cardiac ischemic injury

Carboxyl terminus of Hsc70-interacting protein (CHIP) is proteostasis regulator. Here the authors show that CHIP-mediated protein turnover is enhanced by PKG-mediated phosphorylation, which results in attenuated cardiac ischemic proteotoxicity