Autoreactive Preplasma Cells Break Tolerance in the Absence of Regulation by Dendritic Cells and Macrophages

The ability to induce antibody responses to pathogens while maintaining the quiescence of autoreactive cells is an important aspect of immune tolerance. During activation of Toll-like receptor-4 (TLR4), dendritic cells (DCs) and macrophages (MFs) repress autoantibody production through their secretion of IL-6 and soluble CD40L (sCD40L). These soluble mediators selectively repress B cells chronically exposed to antigen, but not naïve cells, suggesting a means to maintain tolerance during TLR4 stimulation, yet allow immunity. In this study, we identify TNFα as a third repressive factor, which together with IL-6 and CD40L, account for nearly all the repression conferred by DCs and MFs. Like IL-6 and sCD40L, TNFα did not alter B cell proliferation or survival. Rather, it reduced the number of antibody secreting cells. To address whether the soluble mediators secreted by DCs and MFs functioned in vivo, we generated mice lacking IL-6, CD40L and TNFα. Compared to wildtype mice, these mice showed prolonged anti-nuclear antibody responses following TLR4 stimulation. Further, adoptive transfer of autoreactive B cells into chimeric IL-6-/- × CD40L-/- × TNFα-/- mice showed that pre-plasma cells secreted autoantibodies independent of germinal center formation or extrafollicular foci. These data indicate that in the absence of genetic predisposition to autoimmunity, loss of endogenous IL-6, CD40L, and TNFα promotes autoantibody secretion during TLR4 stimulation

Green Globe 21 Kaikoura community benchmarking pilot study

This document reports on a pilot study that assesses the processes involved in the GREEN GLOBE 21 Benchmarking of the Kaikoura District, New Zealand. This study represents the third of three pilot studies that examine the processes associated with the GREEN GLOBE 21 Community Benchmarking procedure. This study also serves to contextualise the GREEN GLOBE 21 Community Standard for the New Zealand setting. One of the four objectives of the New Zealand Tourism strategy is to ‘secure and conserve a long-term future’. A key recommendation under this objective is to continue to implement Green Globe or similar systems of environmental certification (NZTS, 2001). GREEN GLOBE is a global benchmarking, certification and improvement system for sustainable travel and tourism and is based on the Agenda 21 principles for Sustainable Development

Characterization of the C3H6O+. ion from 2-methoxyethanol. Mixture analysis by dissociation and neutralization—reionization

The C3H6O+. ion formed upon the dissociative ionization of 2-methoxyethanol is identified by a combination of several tandem mass spectrometry methods, including metastable ion (MI) characteristics, collisionally activated dissociation (CAD), and neutralization—reionization mass spectrometry (NRMS). The experimental data conclusively show that 2-methoxyethanol molecular ion, namely, HOCH2CH2OCH3+., loses H2O to yield mainly the distonic radical ion ·CH2CH2OCH2+ along with a smaller amount of ionized methyl vinyl ether, namely, CH2=CHOCH3+.. Ring-closed products, such as the oxetane or the propylene oxide ion are not observed. The proportion of ·CH2CH2OCH2+ increases with decreasing internal energy of the 2-methoxyethanol ion, which indicates a lower critical energy for the pathway leading to this product than for the competitive generation of CH2=CHOCH3+.. The present study also uses MI, CAD, and NRMS data to assess the structure of the distonic ion+ (CH3)CHOCH2 · (ring-opened ionized propylene oxide) and evaluate its isomerization proclivity toward the methyl vinyl ether ion

The Third Role of Australian Universities in Human Capital Formation

The roles of universities have evolved over the last twenty years. Universities were once regarded as focusing on two key roles -- teaching and research -- which were exogenous to, and independent from, specific economic and social development imperatives. Today, it is increasingly recognised that universities perform important roles as enablers, even leaders, of regional economic and social development and in regional innovation systems; which has been captured in the notion of a third role for universities. This paper explores the nature of the third role of universities in the Australian setting as it applies to human capital formation. The roles of universities in this regard is categorised as being either generative or developmental in nature, based on the triple helix model of university, industry, government relations and the emerging literature on university engagement. This categorisation is explored using three case studies of non core-metropolitan universities. The study explores the nature of the roles performed by the universities in human capital formation and considers possible explanations of variation in the roles performed

The sodium ion affinities of cytosine and its methylated derivatives.

International audienceThe sodium ion affinities of cytosine (Cyt), 5-methylcytosine (5MeCyt) and 1-methylcytosine (1MeCyt) have been determined by experimental and quantum chemical methods. Na(+)-bound heterodimers were produced carrying one cytosine or methylated cytosine ligand (designated as C) and one peptide or amino acid reference base (designated as Pep); the Pep molecules included the peptides GlyLeu, GlyPhe, SerGly, and PheGly, and the amino acid His. The dissociation kinetics of these C--Na(+)--Pep ions were determined by collisionally activated dissociation (CAD) and converted to relative and absolute Na(+) affinities via kinetic method approaches. Relative Na(+) affinities increase in the order (kJ/mol): GlyLeu (0) < Cyt (3) < GlyPhe (4) < SerGly (6) < 5MeCyt (8) < PheGly (11) < 1MeCyt (13) < His (17). Anchoring the relative values of the nucleobases to the absolute affinities of the reference bases leads to absolute Na(+) affinities of 214 +/- 8, 219 +/- 8, and 224 +/- 8 kJ/mol for Cyt, 5MeCyt, and 1MeCyt, respectively. Ab initio calculations were used to confirm these results. The computed affinities of Cyt (213 kJ/mol) and 1MeCyt (217 kJ/mol) are in very good agreement with the experiments. These values unambiguously correspond to Na(+) complexes with the keto form of cytosine and its methyl derivatives. Ab initio calculations on tautomerization mechanisms in the gas versus condensed phase are used to discuss why the sodiated keto isomers were formed in the present electrospray ionization (ESI) experiments, but the enol isomers in previous fast atom bombardment (FAB) experiments

Characterization of linear and branched polyacrylates by tandem mass spectrometry

The unimolecular degradation of alkali-metal cationized polyacrylates with the repeat unit CH(2)CH(COOR) and a variety of ester pendants has been examined by tandem mass spectrometry. The fragmentation patterns resulting from collisionally activated dissociation depend sensitively on the size of the ester alkyl substituent (R). With small alkyl groups, as in poly(methyl acrylate), lithiated or sodiated oligomers (M) decompose via free-radical chemistry, initiated by random homolytic C-C bond cleavages along the polymer chain. The radical ions formed this way dissociate further by backbiting rearrangements and beta scissions to yield a distribution of terminal fragments with one of the original end groups and internal fragments with 2-3 repeat units. If the ester alkyl group bears three or more carbon atoms, cleavages within the ester moieties become the predominant decomposition channel. This distinct reactivity is observed if R = t-butyl, n-butyl, or the mesogenic group (CH(2))(11)-O-C(6)H(4)-C(6)H(4)-CN. The [M+alkali metal](+) ions of the latter polyacrylates dissociate largely by charge-remote 1,5-H rearrangements that convert COOR to COOH groups by expulsion of 1-alkenes. The acid groups may displace an alcohol unit from a neighboring ester pendant to form a cyclic anhydride, unless hindered by steric effects. Using atom transfer radical polymerization, hyperbranched polyacrylates were prepared carrying ester groups both within and between the branches. Unique alkenes and alcohols are cleaved from ester groups at the branching points, enabling determination of the branching architecture