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Nancy E. Martinez Dr. Tobias J. Zimmermann Christian Goosmann Dr. Tobias Alexander Prof. Dr. Christian Hedberg Dr. Slava Ziegler Prof. Dr. Arturo Zychlinsky Prof. Dr. Dr. Herbert Waldmann 《Chembiochem : a European journal of chemical biology》2017,18(10):888-893
Neutrophils are short‐lived leukocytes that migrate to sites of infection as part of the acute immune response, where they phagocytose, degranulate, and form neutrophil extracellular traps (NETs). During NET formation, the nuclear lobules of neutrophils disappear and the chromatin expands and, accessorized with neutrophilic granule proteins, is expelled. NETs can be pathogenic in, for example, sepsis, cancer, and autoimmune and cardiovascular diseases. Therefore, the identification of inhibitors of NET formation is of great interest. Screening of a focused library of natural‐product‐inspired compounds by using a previously validated phenotypic NET assay identified a group of tetrahydroisoquinolines as new NET formation inhibitors. This compound class opens up new avenues for the study of cellular death through NET formation (NETosis) at different stages, and might inspire new medicinal chemistry programs aimed at NET‐dependent diseases. 相似文献
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As digitization supports customers in gaining increased market transparency (Desai Hastings Law Journal, 65(6), 1469–1482, 2014), migrating from one organization to another (“customer migration”) is becoming easier and more attractive. Thus, taking measures to regain customers who terminated their relationship (“customer recovery”) has become increasingly important for organizations. With the growing importance of customer recovery in present times, organizations face even more challenges pertaining to risk of making wrong investment decisions. Organizations can either mistakenly invest in customer relations that are “alive” or irretrievably “dead.” Furthermore, it has the risk of not investing in inactive customer relations that have a chance to be revived (“dying”). Consequently, it is necessary for organizations to consider the probability that a customer relation is “alive,” “dying,” or “dead” when deciding on customer recovery. Based on these probabilities, an economically reasonable decision has to be made on whether to invest in the recovery of an individual customer relationship. Accordingly, based on a comprehensive discussion of related work, we propose a formal decision model on whether to invest in customer relation recovery. To demonstrate the decision model’s applicability, an illustrative case with sample calculation is presented and expert interviews are conducted. 相似文献
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Enantioselective Organocatalytic Synthesis of a Secoyohimbane‐Inspired Compound Collection with Neuritogenic Activity
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Tim Förster Dr. Sara López‐Tosco Dr. Slava Ziegler Dr. Andrey P. Antonchick Prof. Dr. Herbert Waldmann 《Chembiochem : a European journal of chemical biology》2017,18(12):1098-1108
Natural products provide evolutionary validated core structures to inspire the synthesis of new compound collections endowed with neurite growth‐promoting activity. Rhynchophylline is the major component of Uncaria species, and has been used to treat neurological diseases in Chinese traditional medicine. Based on the structure of this spirocyclic secoyohimbane alkaloid, we developed a highly enantioselective and efficient organocatalyzed synthesis method to provide a tetracyclic secoyohimbane scaffold incorporating a quaternary and three tertiary stereogenic centers, in a one‐pot multistep reaction sequence. A compound collection of derived secoyohimbanes was synthesized and expanded by decorating the periphery of the basic scaffold with additional substituents to increase the diversity. Evaluation of the different subcollections of secoyohimbanes for modulation of neurite outgrowth in the SH‐SY5Y human cell line led to the discovery of new compounds that promote neurite outgrowth. 相似文献
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C. Waldmann R. Eggers A. Pietsch 《European Journal of Lipid Science and Technology》1994,96(3):100-106
Investigations on the Bleaching Process of Edible Oils using High-Pressure Technology The four process steps de-gumming, neutralization, bleaching and deodorization of the refining of vegetable oils, gained by extraction or mechanical fluid-solid separation, are necessary to attain a product of food quality. During the bleaching an oiled adsorbent accumulates which has to be disposed after use. The investigations about de-oiling and recycling of the adsorbents and oil-recovery led to two alternatives to teh conventional bleaching process. The adsorption from the supercritical fluid phase enables the integration of the bleaching into the cycle process of high-pressure-extraction of oil seeds. Our investigations show that oils can be bleached in an adsorbent bed even with a short time of direct contact without oiling the adsorbent. Furthermore the adsorption in the fluid phase with inert gas pressure up to 10 MPa is a possible pressure-bleaching for traditionally gained oils. Especially at supercritical conditions of the CO2 used, the pressure bleaching shows an accelerated kinetic behaviour and a a reduction of the necessary dosage of bleaching clay. 相似文献
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Small Molecules Inspired by the Natural Product Withanolides as Potent Inhibitors of Wnt Signaling
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Dr. Michael Sheremet Dr. Shobhna Kapoor Dr. Peter Schröder Dr. Kamal Kumar Dr. Slava Ziegler Prof. Dr. Dr. Herbert Waldmann 《Chembiochem : a European journal of chemical biology》2017,18(18):1797-1806
Wnt signaling is a fundamental pathway that drives embryonic development and is essential for stem cell maintenance and tissue homeostasis. Dysregulation of Wnt signaling is linked to various diseases, and a constitutively active Wnt pathway drives tumorigenesis. Thus, disruption of the Wnt response is deemed a promising strategy for cancer drug discovery. However, only few clinical drug candidates that target Wnt signaling are available so far, and new small‐molecule modulators of Wnt‐related processes are in high demand. Here we describe the synthesis of small molecules inspired by withanolide natural products by using a pregnenolone‐derived β‐lactone as the key intermediate that was transformed into a δ‐lactone appended to the D‐ring of the steroidal scaffold. This natural‐product‐inspired compound library contained potent inhibitors of Wnt signaling that act upstream of the destruction complex to stabilize Axin in a tankyrase‐independent manner. 相似文献
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Markus Waltering Volker Bungard Danile Waldmann Stefan Maas Arno Zürbes 《Beton- und Stahlbetonbau》2009,104(10):628-641
Risse in Stahlbeton‐ und Spannbetontragwerken führen zu einem Steifigkeitsverlust, der die statischen und dynamischen Eigenschaften der jeweiligen Struktur beeinflusst. Eine klassische Methode zur Bestimmung statischer Kennwerte sind Probebelastungen, bei denen gemessene Verformungen mit rechnerischen Werten abgeglichen werden und somit einen Rückschluss auf die Tragfähigkeit der Struktur ermöglichen. Bei Bauwerken wie Brücken können derartige Tests sehr kosten‐, zeit‐ und materialaufwändig sein und erfordern häufig eine längerfristige Sperrung. Des Weiteren müssen die gemessenen Verformungen vor Ort durch erfahrene Ingenieure überwacht werden, um gegebenenfalls bei Überschreiten kritischer Werte den Test abzubrechen. Auch die dynamischen Eigenschaften von Strukturen werden maßgeblich durch die Steifigkeit beeinflusst und können in vielen Fällen schnell und mit wenig Aufwand bestimmt werden. Im Rahmen dieses Aufsatzes werden die Ergebnisse statischer und dynamischer Untersuchungen zur Zustandsbewertung, durchgeführt an Stahlbeton‐ und Spannbetonbauteilen im Labor und an einer schrittweise geschädigten Spannbetonbrücke, hinsichtlich ihrer Sensibilität auf Schäden und Handhabbarkeit in der praktischen Anwendung gegenübergestellt. Comparison of Static and Dynamic Methods to Assess the State of Reinforced and Prestressed Concrete Structures Cracks in reinforced and prestressed concrete structures lead to a reduction in stiffness and therefore to an influence on the static and dynamic properties. A conventional method to assess the static characteristics are static load tests which enable to correlate measured deformations with calculated values and to draw conclusions about the loading capacity. In case of bridges, these tests can be very cost‐intensive and time‐consuming and often require a closure of the bridge. Furthermore the measured deformations have to be examined in situ, in order to abort the test if the deformations exceed critical values. As well, the dynamic properties are affected by changes in stiffness and in many cases they can be quickly determined without large effort. Within this article the results of static and dynamic tests with laboratory reinforced and prestressed concrete structures and tests on a gradually damaged prestressed concrete bridge are presented. The results are compared with regard to the sensitivity of the different methods to damage. 相似文献