MIF homologues from a filarial nematode parasite synergize with IL-4 to induce alternative activation of host macrophages

Macrophage migration inhibitory factor (MIF) is a highly conserved cytokine considered to exert wide-ranging, proinflammatory effects on the immune system. Recently, members of this gene family have been discovered in a number of invertebrate species, including parasitic helminths. However, chronic helminth infections are typically associated with a Th2-dominated, counter-inflammatory phenotype, in which alternatively activated macrophages (AAMs) are prominent. To resolve this apparent paradox, we have analyzed the activity of two helminth MIF homologues from the filarial nematode Brugia malayi, in comparison with the canonical MIF from the mouse. We report that murine MIF (mMIF) and Brugia MIF proteins induce broadly similar effects on bone marrow-derived mouse macrophages, eliciting a measured release of proinflammatory cytokines. In parallel, MIF was found to induce up-regulation of IL-4R on macrophages, which when treated in vitro with MIF in combination with IL-4, expressed markers of alternative activation [arginase, resistin-like molecule α (RELM-α) or found in inflammatory zone 1, Ym-1, murine macrophage mannose receptor] and differentiated into functional AAMs with in vitro-suppressive ability. Consistent with this finding, repeated in vivo administration of Brugia MIF induced expression of alternative macrophage activation markers. As mMIF did not induce RELM-α or Ym-1 in vivo, alternative activation may require components of the adaptive immune response to Brugia MIF, such as the production of IL-4. Hence, MIF may accentuate macrophage activation according to the polarity of the environment, thus promoting AAM differentiation in the presence of IL-4-inducing parasitic helminths

Hybrid system for concentrating solar power and energy from waste integration

This paper focuses on the energy analysis and plant design of a hybrid system based on CSP (Concentrating Solar to Power) and EfW (Energy from Waste) for improving its energy efficiency and the reduction of LCOE (Levelized Cost of Electricity). Based on the energy analysis of the plant, the incorporation of CSP was modeled to achieve increasing of annual solar fraction, assuming annual RDF (refuse derived fuel) availability, and maximizing annual energy production. The arrangement was chosen and the best configuration of the cycle was determined according optima design. The efficiency was quantified and the LCOE was selected as economic index. The energy analysis was carried out along an annual profile formed by 4 scenarios: EfW (Energy from Waste) plant processing raw domestic waste, CSP plant without storage, CSP with 7h TES (Thermal Energy Storage) and the hybrid system where CSP and EfW is integrated. According to the preliminary results, from standard CSP and CSP with 7h TES scenarios, the hybrid concept increases efficiency by 11% and 1%, as well as and the capacity factor by 580% and 109%, respectively. The LCOE reduce from 193,22 US$/MWh and 160,52 US$/MWh to 28,20 US$/MWh respectively. If compared with standard EfW, the efficiency increase 42$/MWh)

Systemic dysfunction and plasticity of the immune macroenvironment in cancer models

Understanding of the factors governing immune responses in cancer remains incomplete, limiting patient benefit. In this study, we used mass cytometry to define the systemic immune landscape in response to tumor development across five tissues in eight mouse tumor models. Systemic immunity was dramatically altered across models and time, with consistent findings in the peripheral blood of patients with breast cancer. Changes in peripheral tissues differed from those in the tumor microenvironment. Mice with tumor-experienced immune systems mounted dampened responses to orthogonal challenges, including reduced T cell activation during viral or bacterial infection. Antigen-presenting cells (APCs) mounted weaker responses in this context, whereas promoting APC activation rescued T cell activity. Systemic immune changes were reversed with surgical tumor resection, and many were prevented by interleukin-1 or granulocyte colony-stimulating factor blockade, revealing remarkable plasticity in the systemic immune state. These results demonstrate that tumor development dynamically reshapes the composition and function of the immune macroenvironment

A new class of isothiocyanate-based irreversible inhibitors of macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) is a homotrimeric multifunctional proinflammatory cytokine that has been implicated in the pathogenesis of several inflammatory and autoimmune diseases. Current therapeutic strategies for targeting MIF focus on developing inhibitors of its tautomerase activity or modulating its biological activities using anti-MIF neutralizing antibodies. Herein we report a new class of isothiocyanate (ITC)-based irreversible inhibitors of MIF. Modification by benzyl isothiocyanate (BITC) and related analogues occurred at the N-terminal catalytic proline residue without any effect on the oligomerization state of MIF. Different alkyl and arylalkyl ITCs modified MIF with nearly the same efficiency as BITC. To elucidate the mechanism of action, we performed detailed biochemical, biophysical, and structural studies to determine the effect of BITC and its analogues on the conformational state, quaternary structure, catalytic activity, receptor binding, and biological activity of MIF. Light scattering, analytical ultracentrifugation, and NMR studies on unmodified and ITC-modified MIF demonstrated that modification of Pro1 alters the tertiary, but not the secondary or quaternary, structure of the trimer without affecting its thermodynamic stability. BITC induced drastic effects on the tertiary structure of MIF, in particular residues that cluster around Pro1 and constitute the tautomerase active site. These changes in tertiary structure and the loss of catalytic activity translated into a reduction in MIF receptor binding activity, MIF-mediated glucocorticoid overriding, and MIF-induced Akt phosphorylation. Together, these findings highlight the role of tertiary structure in modulating the biochemical and biological activities of MIF and present new opportunities for modulating MIF biological activities in vivo

A new class of isothiocyanate-based irreversible inhibitors of macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) is a homotrimeric multifunctional proinflammatory cytokine that has been implicated in the pathogenesis of several inflammatory and autoimmune diseases. Current therapeutic strategies for targeting MIF focus on developing inhibitors of its tautomerase activity or modulating its biological activities using anti-MIF neutralizing antibodies. Herein we report a new class of isothiocyanate (ITC)-based irreversible inhibitors of MIF. Modification by benzyl isothiocyanate (BITC) and related analogues occurred at the N-terminal catalytic proline residue without any effect on the oligomerization state of MIF. Different alkyl and arylalkyl ITCs modified MIF with nearly the same efficiency as BITC. To elucidate the mechanism of action, we performed detailed biochemical, biophysical, and structural studies to determine the effect of BITC and its analogues on the conformational state, quaternary structure, catalytic activity, receptor binding, and biological activity of MIF. Light scattering, analytical ultracentrifugation, and NMR studies on unmodified and ITC-modified MIF demonstrated that modification of Pro1 alters the tertiary, but not the secondary or quaternary, structure of the trimer without affecting its thermodynamic stability. BITC induced drastic effects on the tertiary structure of MIF, in particular residues that cluster around Pro1 and constitute the tautomerase active site. These changes in tertiary structure and the loss of catalytic activity translated into a reduction in MIF receptor binding activity, MIF-mediated glucocorticoid overriding, and MIF-induced Akt phosphorylation. Together, these findings highlight the role of tertiary structure in modulating the biochemical and biological activities of MIF and present new opportunities for modulating MIF biological activities in vivo