ROCK1/2 signaling contributes to corticosteroid-refractory acute graft-versus-host disease

Patients with corticosteroid-refractory acute graft-versus-host disease (aGVHD) have a low one-year survival rate. Identification and validation of novel targetable kinases in patients who experience corticosteroid-refractory-aGVHD may help improve outcomes. Kinase-specific proteomics of leukocytes from patients with corticosteroid-refractory-GVHD identified rho kinase type 1 (ROCK1) as the most significantly upregulated kinase. ROCK1/2 inhibition improved survival and histological GVHD severity in mice and was synergistic with JAK1/2 inhibition, without compromising graft-versus-leukemia-effects. ROCK1/2-inhibition in macrophages or dendritic cells prior to transfer reduced GVHD severity. Mechanistically, ROCK1/2 inhibition or ROCK1 knockdown interfered with CD80, CD86, MHC-II expression and IL-6, IL-1β, iNOS and TNF production in myeloid cells. This was accompanied by impaired T cell activation by dendritic cells and inhibition of cytoskeletal rearrangements, thereby reducing macrophage and DC migration. NF-κB signaling was reduced in myeloid cells following ROCK1/2 inhibition. In conclusion, ROCK1/2 inhibition interferes with immune activation at multiple levels and reduces acute GVHD while maintaining GVL-effects, including in corticosteroid-refractory settings

Stufeneffiziente Synthese von 3,4-dioxygenierten Chinolonen ermöglicht durch Arin-Chemie

In the present thesis, the step efficient synthesis of 3,4-dioxygenated quinolinones is described. Initially, step efficient syntheses of other natural products were analyzed by using a color-coded flow chart presentation. Thus, particularly powerful strategies were identified. These included disconnection in equally sized and complex substructures, avoidance of non-strategic redox- and functional group interconversions, as well as the usage of functional group tolerant transformations capable of forging multiple bonds in a single step. By applying these principles to the natural product class of 3,4-dioxygenated quinolinones, an aryne insertion into an unsymmetric imide followed by a diastereoselective aldol reaction was recognized.The target was thus built up from two equally sized molecules whilst the aryne insertion yielded two new carbon – sigma-bonds in a single step. When performed in continuous flow, the reaction proceeded within minutes, while lower yields and longer reaction times were observed in batch. Furthermore, both aryne and imide could easily be varied so that a multitude of differently substituted 3,4-dioxygenated quinolinones were synthesized. In total, nine natural products, including (±)-peniprequinolone, (±)-aflaquinolones E and F, (±)-6-deoxyaflaquinolone E, (±)-quinolinones A and B, (±)-aniduquinolone C and yaequinolones J1 and J2, were synthesized in one to three steps

A Modular, Argon-Driven Flow Platform for Natural Product Synthesis and Late-Stage Transformations

A modular flow platform for the synthesis of natural products and their analogs was designed. To access different reaction setups with a maximum of flexibility, interchangeable 3D-printed components serve as backbone. By switching from conventional liquid- to gas-driven flow, reagent and solvent waste is minimized which translates into an advantageous sustainability and economy profile. To enable inert conditions, practical “Schlenk-in-flow” techniques for the safe handling of oxygen- and moisture sensitive reagents were developed. Adopting these techniques, reproducible transformations in natural product synthesis were achieved

Five‐Step Synthesis of Yaequinolones J1 and J2

A concise synthesis of yaequinolones J1 and J2 is reported. The route is based on the aryne insertion into the σ- C–N-bond of an unsymmetric imide followed by a diastereoselective aldol cyclization of the resulting N-acylated aminobenzophenone. The chromene motif is generated in the first step by an organocatalytic tandem Knoevenagel-electrocyclization of citral and 2-bromoresorcinol. The approach adheres to the ideality-principle, using almost exclusively strategic bond-formingreactions

Synthesis of Quinolinone Alkaloids via Aryne Insertions into Unsymmetric Imides in Flow

A general strategy for the synthesis of 3,4-dioxygenated quinolin-2-one natural products is reported. The keystep is a regioselective insertion of arynes into unsymmetric imides in flow.<br /

Refining animal welfare of wild boar (Sus scrofa) corral-style traps through behavioral and pathological investigations.

Wild boar trapping has been used as a management tool to control wild boar populations. However, it is increasingly criticized due to animal welfare concerns. While cortisol levels have been used to assess trap-related stress in wild boar, data on trap-related injuries and behavioral data are scarce. We aimed to evaluate three different corral-style traps for wild boar according to available mammal trapping standards to investigate and refine animal welfare in wild boar trapping. We examined 138 wild boars captured and killed by head shot in 27 capture events. Traps were closed by remote control only if the complete group were trapped. The behavior of the animals in the trap and during culling was recorded on video. All wild boars were examined and a pathological and radiological examination of the heads for trap- and shot-related injuries followed. Trap-related injuries occurred in 33% of the animals with superficial mild skin defects to skull fractures. One out of three traps met all the set requirements. A wire-meshed trapping system failed all. After installing an incomplete barrier in the center of the trap to slow down trapped animals, the fracture rate in one trap type was significantly reduced by 29% (p < 0.05). Our data showed that the type of trap (p = 0.007) and the number of animals trapped at once (p = 0.002) had a significant influence on the number of escape attempts. Trapping larger groups reduced the escape attempts. We emphasize the importance of an accurate pathological examination to evaluate animal welfare in traps and call for adjusting the injury categories listed in the standards and make a proposal for wild boar live trapping

Scalable Synthesis of Functionalized Ferrocenyl Azides and Amines Enabled by Flow Chemistry

A scalable access to functionalized 1,1’- and 1,2-ferrocenyl azides has been realized in flow. By halogen‒lithium exchange of ferrocenyl halides and subsequent reaction with tosyl azide, a variety of functionalized ferrocenyl azides was obtained in high yields. To allow a scalable preparation of these potentially explosive compounds, an efficient flow protocol was developed accelerating the reaction time to minutes and circumventing accumulation of potentially hazardous intermediates. Switching from homogeneous to triphasic flow amidst process was key for handling a heterogeneous reaction mixture formed after a heated reactor section. The corresponding and synthetically versatile ferrocenyl amines were then prepared by a reliable reduction process