Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells.

Immunoparalysis is a compensatory and persistent anti-inflammatory response to trauma, sepsis or another serious insult, which increases the risk of opportunistic infections, morbidity and mortality. Here, we show that in cultured primary human monocytes, interleukin-4 (IL4) inhibits acute inflammation, while simultaneously inducing a long-lasting innate immune memory named trained immunity. To take advantage of this paradoxical IL4 feature in vivo, we developed a fusion protein of apolipoprotein A1 (apoA1) and IL4, which integrates into a lipid nanoparticle. In mice and non-human primates, an intravenously injected apoA1-IL4-embedding nanoparticle targets myeloid-cell-rich haematopoietic organs, in particular, the spleen and bone marrow. We subsequently demonstrate that IL4 nanotherapy resolved immunoparalysis in mice with lipopolysaccharide-induced hyperinflammation, as well as in ex vivo human sepsis models and in experimental endotoxemia. Our findings support the translational development of nanoparticle formulations of apoA1-IL4 for the treatment of patients with sepsis at risk of immunoparalysis-induced complications.We thank M. Jaeger (Radboudumc) for kindly providing flourescein isothiocyanate-labelled Candida albicans. D. Williams (East Tennessee State University) provided the β-glucan we used in our initial experiments. H. Lemmers (Radboudumc) kindly prepared the purified lipopolysaccharide used for stimulation of primary human monocytes and macrophages. Part of the figures were prepared using (among other software) Biorender.com. B.N. is supported by a National Health and Medical Research Council (Australia) Investigator Grant (APP1173314). This work was supported by National Institutes of Health grants R01 HL144072, R01 CA220234 and P01 HL131478, as well as a Vici grant from the Dutch Research Council NWO and an ERC Advanced Grant (all to W.J.M.M.). M.G.N. was supported by a Spinoza grant from Dutch Research Council NWO and an ERC Advanced Grant (#833247).S

Fatty acid desaturation and lipoxygenase pathways support trained immunity

Infections and vaccines can induce enhanced long-term responses in innate immune cells, establishing an innate immunological memory termed trained immunity. Here, we show that monocytes with a trained immunity phenotype, due to exposure to the Bacillus Calmette-Guerin (BCG) vaccine, are characterized by an increased biosynthesis of different lipid mediators (LM) derived from long-chain polyunsaturated fatty acids (PUFA). Pharmacological and genetic approaches show that long-chain PUFA synthesis and lipoxygenase-derived LM are essential for the BCG-induced trained immunity responses of human monocytes. Furthermore, products of 12-lipoxygenase activity increase in monocytes of healthy individuals after BCG vaccination. Grasping the underscoring lipid metabolic pathways contributes to our understanding of trained immunity and may help to identify therapeutic tools and targets for the modulation of innate immune responses.Cellular functional states are supported by metabolic pathways, including lipid metabolism. Here, authors examine the contribution of differential biosynthesis of lipid mediators to innate immune memory (or trained immunity), in human monocytes following Bacillus Calmette-Guerin (BCG) vaccination.Proteomic

Design and Synthesis of Type-IV Inhibitors of BRAF Kinase That Block Dimerization and Overcome Paradoxical MEK/ERK Activation

Despite the clinical success of BRAF inhibitors like vemurafenib in treating metastatic melanoma, resistance has emerged through "paradoxical MEK/ERK signaling" where transactivation of one protomer occurs as a result of drug inhibition of the other partner in the activated dimer. The importance of the dimerization interface in the signaling potential of wild-type BRAF in cells expressing oncogenic Ras has recently been demonstrated and proposed as a site of therapeutic intervention in targeting cancers resistant to adenosine triphosphate competitive drugs. The proof of concept for a structure-guided approach targeting the dimerization interface is described through the design and synthesis of macrocyclic peptides that bind with high affinity to BRAF and that block paradoxical signaling in malignant melanoma cells occurring through this drug target. The lead compounds identified are type-IV kinase inhibitors and represent an ideal framework for conversion into next-generation BRAF inhibitors through macrocyclic drug discovery. © 2019 American Chemical Society

A DEVELOPMENT METHODOLOGY FOR PARAMETRIC SYNTHESIS TOOLS

ABSTRACT Software to support the solution generation phase of the engineering design process has been developed in academia for decades. Computational synthesis software enables generation of solutions on both conceptual and embodiment level. This paper focuses on the class of parametric design, such as documented in mechanical engineering handbooks. Examples include machine elements such as bearings, springs, fasteners, transmissions, etc. A parametric synthesis tool automates the engineering design process from functional requirements to quantified solutions, for a single machine element. Since the amount of machine elements is vast and software development time should be low, a generic methodology is helpful to speed up this process. This paper discusses such a methodology to develop synthesis tools for the class of parametric designs. It includes an analysis-oriented approach to formalize the design process' parameters in terms of embodiment, performance and scenario. Mathematical constraint solving techniques are used to generate candidate solutions. Graphical presentation and exploration of the solution space is done with interactive plots. A standardized layout for the graphical user interface is suggested to allow uniform and intuitive use. A demonstrator is developed using the described methodology and several challenges are discussed for improved constraint solving techniques, more advanced visualization and handling problems with higher complexity. Although small in size, parametric design processes are time consuming due to their reoccurring nature. Developing synthesis tools for these designs will allow engineers to save time and improve design quality. INTRODUCTION The industrial product design process is experiencing an increasing amount of pressure to cut cost and reduce time to market [1], [2], while product complexity increases. Both from an engineer's and manager's point of view, uncertainties and risks in the engineering design process are being reduced where possible Software support to increase the efficiency of the design process has been developed for decades. Ullman [4] describes an ideal support system for the mechanical engineering design process: it should allow the designer to work from functional requirements to a feasible product. The system should provide insight in the relationship between the set of requirements and the eventual product. This should be an automated process, guided by the preferences of the engineer, leading him/her towards the best possible design. Support systems that provide multiple possible solutions give an overview of alternatives and allow the engineer to select the best solution, rather than find one acceptable design. Academia have recognized the need for support systems to generate (alternative) solutions. Decades of research have proven successful in exploring different types of support in different phases of the design process using a number of approaches and techniques. For example, computational synthesis offers support for design processes ranging from engineering design problems to shape driven (architectural) design

Toward adequate control of internal interfaces utilizing nitrile-based electrolytes

Methods to control internal interfaces in lithium ion batteries often require sophisticated procedures to deposit coating layers or introduceinterphases, which are typically difficult to apply. This particularly holds for protection from parasitic reactions at the current collector,which reflects an internal interface for the electrode composite material and the electrolyte. In this work, electrolyte formulationsbased on aliphatic cyclic nitriles, cyclopentane-1-carbonitrile and cyclohexane-1-carbonitrile, are introduced that allow for successful suppressionof aluminum dissolution and control of internal interfaces under application-relevant conditions. Such nitrile-based electrolytesshow higher intrinsic oxidative and thermal stabilities as well as similar capacity retentions in lithium nickel–manganese–cobalt oxideLiNi3/5Mn1/5Co1/5O2 (NMC622)||graphite based full cells compared to the state-of-the-art organic carbonate-based electrolytes, even whenbis(trifluoro-methane)sulfonimide lithium salt is utilized. Moreover, the importance of relative permittivity, degree of ion dissociation, andviscosity of the applied electrolyte formulations for the protection of current collector interfaces is emphasized