Programming the magnitude and persistence of antibody responses with innate immunity

Many successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence indicates that they activate dendritic cells via Toll-like receptors (TLRs). For example, the yellow fever vaccine YF-17D, one of the most successful empiric vaccines ever developed, activates dendritic cells via multiple TLRs to stimulate proinflammatory cytokines. Triggering specific combinations of TLRs in dendritic cells can induce synergistic production of cytokines, which results in enhanced T-cell responses, but its impact on antibody responses remain unknown. Learning the critical parameters of innate immunity that program such antibody responses remains a major challenge in vaccinology. Here we demonstrate that immunization of mice with synthetic nanoparticles containing antigens plus ligands that signal through TLR4 and TLR7 induces synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with nanoparticles containing antigens plus a single TLR ligand. Consistent with this there was enhanced persistence of germinal centres and of plasma-cell responses, which persisted in the lymph nodes for >1.5 years. Surprisingly, there was no enhancement of the early short-lived plasma-cell response relative to that observed with single TLR ligands. Molecular profiling of activated B cells, isolated 7 days after immunization, indicated that there was early programming towards B-cell memory. Antibody responses were dependent on direct triggering of both TLRs on B cells and dendritic cells, as well as on T-cell help. Immunization protected completely against lethal avian and swine influenza virus strains in mice, and induced robust immunity against pandemic H1N1 influenza in rhesus macaques.     

The insulin-degrading enzyme is an allosteric modulator of the 20S proteasome and a potential competitor of the 19S

The interaction of insulin-degrading enzyme (IDE) with the main intracellular proteasome assemblies (i.e, 30S, 26S and 20S) was analyzed by enzymatic activity, mass spectrometry and native gel electrophoresis. IDE was mainly detected in association with assemblies with at least one free 20S end and biochemical investigations suggest that IDE competes with the 19S in vitro. IDE directly binds the 20S and affects its proteolytic activities in a bimodal fashion, very similar in human and yeast 20S, inhibiting at (IDE)?≤?30 nM and activating at (IDE)?≥?30 nM. Only an activating effect is observed in a yeast mutant locked in the “open” conformation (i.e., the α-3ΔN 20S), envisaging a possible role of IDE as modulator of the 20S “open”–”closed” allosteric equilibrium. Protein–protein docking in silico proposes that the interaction between IDE and the 20S could involve the C-term helix of the 20S α-3 subunit which regulates the gate opening of the 20S.     

An evolutionary design methodology

The purpose of this paper is to elaborate on a design methodology for the resolution of problem situations concerning complex organizations with opposing and conflicting substructures and facing dramatic environmental fluctuations necessitating major changes in the basic characteristics of the organization. To this end the organization is itself taken as a design methodology system which demonstrates one instance of the application of the paradigm of dissipative structures to social systems. The proposed methodology, precisely because it is applicable in an evolutionary system, is called an evolutionary design methodology. The primary goal of this method is to oversee the emergence of the legitimation authority for the truth arising from linguistic games, or narration, developed during the application of the method. This question of legitimation is directly connected with critical thought, because it forces out the philosophical position of the problem solver. It reveals his beliefs about social order and social change. Therefore it is assumed that the perspective of this paper fits within critical systems thinking.     

Emancipation and truth in critical systems methodologies

This paper deals with the need for stakeholders to participate actively in organizations, so that systems methodologies can be applied in a critical fashion with the objective of arousing the emancipatory interest. It discusses the meaning of emancipation in the labor movement tradition and the emergence of the apathy of working people toward it. Critical Systems Thinking is obliged to face this apathy in its attempt to motivate the emancipatory interest.     

Parasites of the Lessepsian invasive fish Lagocephalus sceleratus (Gmelin 1789) in the eastern Mediterranean Sea

Lagocephalus sceleratus, is a Lessepsian invasive fish species introduced into the Mediterranean Sea through the Suez Canal. This study investigated it as host of parasites. Out of 41 individuals caught from northern and southern locations of the eastern Aegean Sea, nine were found to host parasites. Gnathia sp. praniza larva, an ectoparasite, was associated with severe damage of the primary and secondary structures of the gills and it was found in one specimen (prevalence 2.4%). Regarding endoparasites, Anisakis type I third-stage larvae were found in two specimens (prevalence 4.9%). In addition, adult nematodes of Hysterothylacium aduncum were found in another six specimens (prevalence 14.6%). Lagocephalus sceleratus is a new host for some indigenous parasites, with low host specificity, in the Mediterranean Sea, providing an additional niche for the success and increase of local populations of these parasites and, to our knowledge, this is the first record of L. sceleratus parasites in this area. Whether these parasites can control the invasion success of L. sceleratus needs to be further investigated. However, the low mean intensity of infection found in this study does not support such control.