1,411 research outputs found

    Most nuclear systemic autoantigens are extremely disordered proteins: implications for the etiology of systemic autoimmunity

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    Patients with systemic autoimmune diseases usually produce high levels of antibodies to self-antigens (autoantigens). The repertoire of common autoantigens is remarkably limited, yet no readily understandable shared thread links these apparently diverse proteins. Using computer prediction algorithms, we have found that most nuclear systemic autoantigens are predicted to contain long regions of extreme structural disorder. Such disordered regions would generally make poor B cell epitopes and are predicted to be under-represented as potential T cell epitopes. Consideration of the potential role of protein disorder may give novel insights into the possible role of molecular mimicry in the pathogenesis of autoimmunity. The recognition of extreme autoantigen protein disorder has led us to an explicit model of epitope spreading that explains many of the paradoxical aspects of autoimmunity – in particular, the difficulty in identifying autoantigen-specific helper T cells that might collaborate with the B cells activated in systemic autoimmunity. The model also explains the experimentally observed breakdown of major histocompatibility complex (MHC) class specificity in peptides associated with the MHC II proteins of activated autoimmune B cells, and sheds light on the selection of particular T cell epitopes in autoimmunity. Finally, the model helps to rationalize the relative rarity of clinically significant autoimmunity despite the prevalence of low specificity/low avidity autoantibodies in normal individuals

    In vivo validation of the origin of the esophageal electrocardiogram

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    Esophageal electrocardiography is a clinical and investigational technique that is useful for determining atrial conduction intervals, analyzing atrial rhythms and mapping conduction pathways. Although the left atrial origin of the esophageal electrocardiogram has long been implied, recently that origin has been questioned. In the present study, the origin of the esophageal deflection is defined by direct right and left atrial mapping studies performed with simultaneous esophageal electrograms obtained from three positions (high, mid and low). Seven patients with normal left atrial dimensions (group I) and five patients with left atrial enlargement (group II) underwent transseptal catheterization during the course of electrophysiologic study.In group I (normal left atrial dimensions), conduction time from the high right atrium to each of the three esophageal positions corresponded to conduction times to left atrial sites ranging from 1 to 3 em lateral to the left interatrial septum. The mid- and low esophageal conduction times were all significantly longer than conduction time to the left side of the septum (p < 0.05). In group II (enlarged left atrium), conduction times to each of the esophageal sites corresponded to conduction times to left atrial sites lying between the mid-left atrium and a point 1 em lateral to the left side of the septum. A significant trend toward longer conduction time to the mid-esophageal position than to the left septum was noted (p < 0.1). In both groups, conduction times measured with the esophageal catheter were significantly longer than conduction time to the right interatrial septum (p < 0.05).The esophageal electrogram corresponds to atrial deflections recorded within the left atrium distinct from the interatrial septum and right atrium. Esophageal electrocardiography is a valid technique for investigation of left atrial rhythms and interatrial conduction

    Candida Transmission and Sexual Behaviors as Risks for a Repeat Episode of Candida Vulvovaginitis

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    Objective: To assess associations between female and male factors and the risk of recurring Candida vulvovaginitis. Methods: A prospective cohort study of 148 women with Candida vulvovaginitis and 78 of their male sexual partners was conducted at two primary care practices in the Ann Arbor, Michigan, area. Results: Thirty-three of 148 women developed at least one further episode of Candida albicans vulvovaginitis within 1 year of follow-up. Cultures of Candida species from various sites of the woman (tongue, feces, vulva, and vagina) and from her partner (tongue, feces, urine, and semen) did not predict recurrences. Female factors associated with recurrence included recent masturbating with saliva (hazard ratio 2.66 [95% CI 1.17-6.06]) or cunnilingus (hazard ratio 2.94 [95% CI 1.12-7.68]) and ingestion of two or more servings of bread per day (p ≤ 0.05). Male factors associated with recurrences in the woman included history of the male masturbating with saliva in the previous month (hazard ratio 3.68 [95% CI 1.24-10.87]) and lower age at first intercourse (hazard ratio 0.83 [95% CI 0.71-0.96]). Conclusions: Sexual behaviors, rather than the presence of Candida species at various body locations of the male partner, are associated with recurrences of C. albicans vulvovaginitis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63382/1/154099903322643901.pd

    The Ursinus Weekly, May 26, 1958

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    MSGA plans tentative 1958 customs program • Junior advisory committee named • Big-little sister committee asks for applicants • Many U.C. seniors accepted at post-grad schools • Last Y commission meetings are held to plan for next Fall semester • R.G. Dunlop to speak at June 9th graduation • Ursinus\u27 Rowe gets scholarship • Editorial: Customs • Letters to the editor • Are fraternities? • Cindermen whip Mules, Dutchmen; Take three meets • Netmen finish season; Defeat Elizabethtown, 6-3 • Bears win 10th game; Lose final tilt by 8-1 • Girls\u27 tennis team beats Penn; Finish undefeated • Beta Sigma Lambda beats Sigma Rho Lambda in 9th • New Library accessionshttps://digitalcommons.ursinus.edu/weekly/1409/thumbnail.jp

    Parameter estimation on gravitational waves from neutron-star binaries with spinning components

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    Inspiraling binary neutron stars are expected to be one of the most significant sources of gravitational-wave signals for the new generation of advanced ground-based detectors. We investigate how well we could hope to measure properties of these binaries using the Advanced LIGO detectors, which began operation in September 2015. We study an astrophysically motivated population of sources (binary components with masses 1.2 M1.2~\mathrm{M}_\odot--1.6 M1.6~\mathrm{M}_\odot and spins of less than 0.050.05) using the full LIGO analysis pipeline. While this simulated population covers the observed range of potential binary neutron-star sources, we do not exclude the possibility of sources with parameters outside these ranges; given the existing uncertainty in distributions of mass and spin, it is critical that analyses account for the full range of possible mass and spin configurations. We find that conservative prior assumptions on neutron-star mass and spin lead to average fractional uncertainties in component masses of 16%\sim 16\%, with little constraint on spins (the median 90%90\% upper limit on the spin of the more massive component is 0.7\sim 0.7). Stronger prior constraints on neutron-star spins can further constrain mass estimates, but only marginally. However, we find that the sky position and luminosity distance for these sources are not influenced by the inclusion of spin; therefore, if LIGO detects a low-spin population of BNS sources, less computationally expensive results calculated neglecting spin will be sufficient for guiding electromagnetic follow-up.Comment: 10 pages, 9 figure

    The First Two Years of Electromagnetic Follow-Up with Advanced LIGO and Virgo

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    We anticipate the first direct detections of gravitational waves (GWs) with Advanced LIGO and Virgo later this decade. Though this groundbreaking technical achievement will be its own reward, a still greater prize could be observations of compact binary mergers in both gravitational and electromagnetic channels simultaneously. During Advanced LIGO and Virgo's first two years of operation, 2015 through 2016, we expect the global GW detector array to improve in sensitivity and livetime and expand from two to three detectors. We model the detection rate and the sky localization accuracy for binary neutron star (BNS) mergers across this transition. We have analyzed a large, astrophysically motivated source population using real-time detection and sky localization codes and higher-latency parameter estimation codes that have been expressly built for operation in the Advanced LIGO/Virgo era. We show that for most BNS events the rapid sky localization, available about a minute after a detection, is as accurate as the full parameter estimation. We demonstrate that Advanced Virgo will play an important role in sky localization, even though it is anticipated to come online with only one-third as much sensitivity as the Advanced LIGO detectors. We find that the median 90% confidence region shrinks from ~500 square degrees in 2015 to ~200 square degrees in 2016. A few distinct scenarios for the first LIGO/Virgo detections emerge from our simulations.Comment: 17 pages, 11 figures, 5 tables. For accompanying data, see http://www.ligo.org/scientists/first2year

    Potent and Broad Inhibition of HIV-1 by a Peptide from the gp41 Heptad Repeat-2 Domain Conjugated to the CXCR4 Amino Terminus.

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    HIV-1 entry can be inhibited by soluble peptides from the gp41 heptad repeat-2 (HR2) domain that interfere with formation of the 6-helix bundle during fusion. Inhibition has also been seen when these peptides are conjugated to anchoring molecules and over-expressed on the cell surface. We hypothesized that potent anti-HIV activity could be achieved if a 34 amino acid peptide from HR2 (C34) were brought to the site of virus-cell interactions by conjugation to the amino termini of HIV-1 coreceptors CCR5 or CXCR4. C34-conjugated coreceptors were expressed on the surface of T cell lines and primary CD4 T cells, retained the ability to mediate chemotaxis in response to cognate chemokines, and were highly resistant to HIV-1 utilization for entry. Notably, C34-conjugated CCR5 and CXCR4 each exhibited potent and broad inhibition of HIV-1 isolates from diverse clades irrespective of tropism (i.e., each could inhibit R5, X4 and dual-tropic isolates). This inhibition was highly specific and dependent on positioning of the peptide, as HIV-1 infection was poorly inhibited when C34 was conjugated to the amino terminus of CD4. C34-conjugated coreceptors could also inhibit HIV-1 isolates that were resistant to the soluble HR2 peptide inhibitor, enfuvirtide. When introduced into primary cells, CD4 T cells expressing C34-conjugated coreceptors exhibited physiologic responses to T cell activation while inhibiting diverse HIV-1 isolates, and cells containing C34-conjugated CXCR4 expanded during HIV-1 infection in vitro and in a humanized mouse model. Notably, the C34-conjugated peptide exerted greater HIV-1 inhibition when conjugated to CXCR4 than to CCR5. Thus, antiviral effects of HR2 peptides can be specifically directed to the site of viral entry where they provide potent and broad inhibition of HIV-1. This approach to engineer HIV-1 resistance in functional CD4 T cells may provide a novel cell-based therapeutic for controlling HIV infection in humans

    The Future Role of Strategic Landpower

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    Recent Russian aggression in Ukraine has reenergized military strategists and senior leaders to evaluate the role of strategic Landpower. American leadership in the European theater has mobilized allies and partners to reconsider force postures for responding to possible aggression against NATO members. Although Russian revisionist activity remains a threat in Europe, the challenges in the Pacific for strategic Landpower must also be considered. At the same time, the homeland, the Arctic, climate change, and the results of new and emerging technology also challenge the application of strategic Landpower. This publication serves as part of an enduring effort to evaluate strategic Landpower’s role, authorities, and resources for accomplishing the national strategic goals the Joint Force may face in the next conflict. This study considers multinational partners, allies, and senior leaders that can contribute to overcoming these enduring challenges. The insights derived from this study, which can be applied to both the European and Indo-Pacific theaters, should help leaders to consider these challenges, which may last a generation. Deterrence demands credible strategic response options integrated across warfighting functions. This valuable edition will continue the dialogue about addressing these issues as well as other emerging ones.https://press.armywarcollege.edu/monographs/1959/thumbnail.jp
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