Resolving lipid mediators maresin 1 and resolvin D2 prevent atheroprogression in mice

RATIONALE: Atheroprogression is a consequence of non-resolved inflammation and currently a comprehensive overview of the mechanisms preventing resolution is missing. However, in acute inflammation, resolution is known to be orchestrated by a switch from inflammatory to resolving lipid mediators. Therefore we hypothesized that lesional lipid mediator imbalance favors atheroprogression. OBJECTIVE: To understand the lipid mediator balance during atheroprogression and to establish an interventional strategy based on delivery of resolving lipid mediators. METHODS AND RESULTS: Aortic lipid mediator profiling of aortas from Apoe(-/-) mice fed a high fat diet for four weeks, eight weeks, or four months revealed an expansion of inflammatory lipid mediators, Leukotriene B4 (LTB4) and Prostaglandin E2 (PGE2), and a concomitant decrease of resolving lipid mediators, Resolvin D2 (RvD2) and Maresin 1 (MaR1), during advanced atherosclerosis. Functionally, aortic LTB4 and PGE2 levels correlated with traits of plaque instability while RvD2 and MaR1 levels correlated with signs of plaque stability. In a therapeutic context, repetitive RvD2 and MaR1 delivery prevented atheroprogression as characterized by halted expansion of the necrotic core and accumulation of macrophages along with increased fibrous cap thickness and smooth muscle cell numbers. Mechanistically, RvD2 and MaR1 induced a shift in macrophage profile towards a reparative phenotype which secondarily stimulated collagen synthesis in smooth muscle cells. CONCLUSIONS: We present evidence for the imbalance between inflammatory and resolving lipid mediators during atheroprogression. Delivery of RvD2 and MaR1 successfully prevented atheroprogression suggesting that resolving lipid mediators potentially represent an innovative strategy to resolve arterial inflammation

Soil-structure interaction effects in analysis of seismic fragility of bridges using an intensity-based ground motion selection procedure

The paper focuses on the effects of Soil-Structure Interaction (SSI) in seismic fragility analysis of reinforced concrete (RC) bridges, considering the vulnerability of multiple critical components of the bridge and different modelling approaches for soil-foundation and bridge-embankment interactions. A two-step procedure, based on the introduction of springs and dashpots at the pier foundations and the abutment to account for inertial and kinematic SSI effects, is incorporated into a component-based methodology for the derivation of bridge-specific fragility curves. The proposed methodology is applied for quantifying the fragility of a typical highway overpass at both the component and system level, while the effect of alternative procedures (of varying complexity) for modelling foundation and abutment boundary conditions is critically assessed. The rigorous SSI modelling method is compared with simpler methods and the results show that consideration of SSI may only slightly affect the probability of system failure, depending on the modelling assumptions made. However, soil-structure interaction may have a notable effect on component fragility, especially for the more critical damage states. This is an observation that is commonly overlooked when assessing the structural performance at the system level and can be particularly important when component fragility is an issue, e.g. when designing a retrofit scheme

Leveraging ligand affinity and properties: discovery of novel benzamide-type cereblon binders for the design of PROTACs

Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide are the most common cereblon (CRBN) recruiters in proteolysis-targeting chimera (PROTAC) design. However, these CRBN ligands induce the degradation of IMiD neosubstrates and are inherently unstable, degrading hydrolytically under moderate conditions. In this work, we simultaneously optimized physiochemical properties, stability, on-target affinity, and off-target neosubstrate modulation features to develop novel nonphthalimide CRBN binders. These efforts led to the discovery of conformationally locked benzamide-type derivatives that replicate the interactions of the natural CRBN degron, exhibit enhanced chemical stability, and display a favorable selectivity profile in terms of neosubstrate recruitment. The utility of the most potent ligands was demonstrated by their transformation into potent degraders of BRD4 and HDAC6 that outperform previously described reference PROTACs. Together with their significantly decreased neomorphic ligase activity on IKZF1/3 and SALL4, these ligands provide opportunities for the design of highly selective and potent chemically inert proximity-inducing compounds