Increased Immunoreactivity to Two Overlapping Peptides of Myelin Proteolipid Protein in Multiple Sclerosis

We tested the proliferative responses of peripheral blood mononuclear cells from 61 patients with multiple sclerosis, 56 healthy control subjects and 52 patients with other neurological diseases to seven synthetic peptides of myelin proteolipid protein (PLP) and 19 synthetic peptides of myelin basic protein (MBP). Increased proliferative responses to two overlapping PLP peptides, PLP184-199 and PLP190-209, were found significantly more frequently in blood from patients with relapsing-remitting or secondary progressive multiple sclerosis (52.3%), but not from those with primary progressive multiple sclerosis (18.2%), than in that from healthy control subjects (8.9%) and patients with other neurological diseases (20.8%). Reactivity to these PLP peptides was most frequently seen in blood from patients with multiple sclerosis of 6-15 years duration and with moderate to severe disability (Kurtzke's Expanded Disability Status Scale > 4.0); the blood from 15 of 19 patients in this group reacted to one or both of the peptides. Both peptides could be recognized by short-term T-cell lines specific for whole PLP, and lines specific for one or other of the two overlapping peptides were able to recognize whole PLP, indicating that these peptides can be processed naturally from the intact molecule. This region of PLP is encephalitogenic in a number of strains of mice. Samples from multiple sclerosis patients did not react more frequently to any of the MBP peptides than those from healthy control subjects. The proportions of patients with other neurological diseases whose blood responded to the MBP peptides that most frequently elicited responses in blood from multiple sclerosis patients were significantly lower than the proportions of multiple sclerosis patients and healthy control subjects whose blood responded to these peptides

Roles for common MLL/COMPASS subunits and the 19S proteasome in regulating CIITA pIV and MHC class II gene expression and promoter methylation

<p>Abstract</p> <p>Background</p> <p>Studies indicate that the 19S proteasome contributes to chromatin reorganization, independent of the role the proteasome plays in protein degradation. We have previously shown that components of the 19S proteasome are crucial for regulating inducible histone activation events in mammalian cells. The 19S ATPase Sug1 binds to histone-remodeling enzymes, and in the absence of Sug1, a subset of activating epigenetic modifications including histone H3 acetylation, H3 lysine 4 trimethylation and H3 arginine 17 dimethylation are inhibited at cytokine-inducible major histocompatibilty complex (MHC)-II and class II transactivator (CIITA) promoters, implicating Sug1 in events required to initiate mammalian transcription.</p> <p>Results</p> <p>Our previous studies indicate that H3 lysine 4 trimethylation at cytokine-inducible MHC-II and CIITA promoters is dependent on proteolytic-independent functions of 19S ATPases. In this report, we show that multiple common subunits of the mixed lineage leukemia (MLL)/complex of proteins associated with Set I (COMPASS) complexes bind to the inducible MHC-II and CIITA promoters; that overexpressing a single common MLL/COMPASS subunit significantly enhances promoter activity and MHC-II <it>HLA-DRA </it>expression; and that these common subunits are important for H3 lysine 4 trimethylation at MHC-II and CIITA promoters. In addition, we show that H3 lysine 27 trimethylation, which is inversely correlated with H3 lysine 4 trimethylation, is significantly elevated in the presence of diminished 19S ATPase Sug1.</p> <p>Conclusion</p> <p>Taken together, these experiments suggest that the 19S proteasome plays a crucial role in the initial reorganization of events enabling the relaxation of the repressive chromatin structure surrounding inducible promoters.</p

Nonproteolytic Roles of 19S ATPases in Transcription of CIITApIV Genes

Accumulating evidence shows the 26S proteasome is involved in the regulation of gene expression. We and others have demonstrated that proteasome components bind to sites of gene transcription, regulate covalent modifications to histones, and are involved in the assembly of activator complexes in mammalian cells. The mechanisms by which the proteasome influences transcription remain unclear, although prior observations suggest both proteolytic and non-proteolytic activities. Here, we define novel, non-proteolytic, roles for each of the three 19S heterodimers, represented by the 19S ATPases Sug1, S7, and S6a, in mammalian gene expression using the inflammatory gene CIITApIV. These 19S ATPases are recruited to induced CIITApIV promoters and also associate with CIITA coding regions. Additionally, these ATPases interact with elongation factor PTEFb complex members CDK9 and Hexim-1 and with Ser5 phosphorylated RNA Pol II. Both the generation of transcripts from CIITApIV and efficient recruitment of RNA Pol II to CIITApIV are negatively impacted by siRNA mediated knockdown of these 19S ATPases. Together, these results define novel roles for 19S ATPases in mammalian gene expression and indicate roles for these ATPases in promoting transcription processes

A Multi-Wavelength Mass Analysis of RCS2 J232727.6-020437, a ~3x1015^{15}M⊙_{\odot} Galaxy Cluster at z=0.7

We present an initial study of the mass and evolutionary state of a massive and distant cluster, RCS2 J232727.6-020437. This cluster, at z=0.6986, is the richest cluster discovered in the RCS2 project. The mass measurements presented in this paper are derived from all possible mass proxies: X-ray measurements, weak-lensing shear, strong lensing, Sunyaev Zel'dovich effect decrement, the velocity distribution of cluster member galaxies, and galaxy richness. While each of these observables probe the mass of the cluster at a different radius, they all indicate that RCS2 J232727.6-020437 is among the most massive clusters at this redshift, with an estimated mass of M_200 ~3 x10^15 h^-1 Msun. In this paper, we demonstrate that the various observables are all reasonably consistent with each other to within their uncertainties. RCS2 J232727.6-020437 appears to be well relaxed -- with circular and concentric X-ray isophotes, with a cool core, and no indication of significant substructure in extensive galaxy velocity data.Comment: 19 pages, 15 figures, submitted to ApJ on March 5, 2015; in press. Manuscript revised following the referee revie

BMQ

BMQ: Boston Medical Quarterly was published from 1950-1966 by the Boston University School of Medicine and the Massachusetts Memorial Hospitals

The negatively charged nitrogen-vacancy centre in diamond: the electronic solution

The negatively charged nitrogen-vacancy centre is a unique defect in diamond that possesses properties highly suited to many applications, including quantum information processing, quantum metrology, and biolabelling. Although the unique properties of the centre have been extensively documented and utilised, a detailed understanding of the physics of the centre has not yet been achieved. Indeed there persists a number of points of contention regarding the electronic structure of the centre, such as the ordering of the dark intermediate singlet states. Without a sound model of the centre's electronic structure, the understanding of the system's unique dynamical properties can not effectively progress. In this work, the molecular model of the defect centre is fully developed to provide a self consistent model of the complete electronic structure of the centre. The application of the model to describe the effects of electric, magnetic and strain interactions, as well as the variation of the centre's fine structure with temperature, provides an invaluable tool to those studying the centre and a means to design future empirical and ab initio studies of this important defect.Comment: 24 pages, 6 figures, 10 table

String-like Clusters and Cooperative Motion in a Model Glass-Forming Liquid

A large-scale molecular dynamics simulation is performed on a glass-forming Lennard-Jones mixture to determine the nature of dynamical heterogeneities which arise in this model fragile liquid. We observe that the most mobile particles exhibit a cooperative motion in the form of string-like paths (``strings'') whose mean length and radius of gyration increase as the liquid is cooled. The length distribution of the strings is found to be similar to that expected for the equilibrium polymerization of linear polymer chains.Comment: 6 pages of RevTex, 6 postscript figures, uses epsf.st

Implicit theories and offender representativeness in judgments about sexual crime

Implicit theories structure the way people understand and respond to various human actions. Typically, people believe attributes are either fixed (entitists) or malleable (incrementalists). The present study aimed to examine: (a) whether attitudes towards sexual offenders differ depending upon one’s implicit theory about human nature and sexual offenders, and (b) whether implicit theories are associated with judgments made about different types of child abuser. A sample of 252 community participants was recruited. Their attitudes, implicit theories, and political orientation were assessed via self-report. One of three vignettes describing an incidence of child sexual abuse was then presented. The cases were identical except the perpetrator was either an adult male, an adult female, or a male juvenile. Participants then made judgments about the offender's deserved sentence and moral character. Entitists (across both domains) held more negative attitudes than incrementalists, although the magnitude of the difference was greatest when examining implicit theories about sexual offenders. Compared to those with an incremental theory of sexual offenders, entity theorists judged sexual offending to be more: (a) indicative of the perpetrator’s moral character, and (b) deserving of punishment. However, scores were greater towards the adult male relative to the adult female and juvenile. The findings suggest that implicit theories about sexual offenders are domain-specific. They also indicate that judgments made by those with an entity theory (about sexual offenders) are affected by whether a case is representative of a stereotypical sexual offender. Implications of the findings are discussed, along with limitations and future research

Increased circulating T cell reactivity to GM3 and GQ1b gangliosides in primary progressive multiple sclerosis

We have previously shown that patients with primary progressive multiple sclerosis (MS) have significantly elevated plasma levels of antibody to GM3 ganglioside compared to patients with relapsing-remitting MS, healthy subjects and patients with other neurological diseases. Anti-GM3 antibody levels were elevated also in patients with secondary progressive MS but to a lesser extent than in primary progressive MS. As gangliosides are particularly enriched in the axonal membrane, these findings suggested that antiganglioside immune responses might contribute to the axonal damage in progressive forms of MS. The present study was performed to determine whether peripheral blood T cell responses to GM3 are also increased in progressive MS. Blood was collected from 98 untreated patients with MS (40 with relapsing-remitting, 27 with secondary progressive and 31 with primary progressive MS), 50 healthy subjects and 24 patients with other disorders of the CNS, and reactivity to GM1, GM3, GD1a, GD1b, GD3, GT1b, GQ1b and sulphatide was assessed by 6-day T cell proliferation assays. Increased T cell reactivity to GM3 and GQ1b occurred significantly more often in patients with primary progressive MS than in healthy subjects and patients with other CNS diseases. These findings suggest that ganglioside-specific T cells may contribute to the axonal damage in primary progressive MS. (C) 2002 Elsevier Science Ltd. All rights reserved

Influence of the shot-peening intensity on the structure and near-surface mechanical properties of Ti40Zr10Cu38Pd12 bulk metallic glass

This article may be downloaded for personal use only. Any other use requires prior permission of the author and the American Institute of Physics.Shot-peening (SP) changes the near-surface structure and mechanical properties of a Ti40Zr10 Cu 38Pd12 bulk metallic glass. Near the surface, the hardness, Young's modulus, and elastic strain limit are all reduced. Measurements of the heat of relaxation show that an exceptionally high stored energy of cold work can be induced, implying a large increase in free volume. At the highest SP intensity there is partial nanocrystallization enabled by the increased free volume and not by the increase in temperature