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Can consumption-based mechanisms generate positive and time-varying real term premia as we see in the data? I show that only models with time-varying risk aversion or models with high consumption risk can independently produce these patterns. The latter explanation has not been analysed before with respect to real term premia, and it relies on a small group of investors exposed to high consumption risk. Additionally, it can give rise to a “consumption-based arbitrageur” story of term premia. In relation to preferences, I consider models with both time-separable and recursive utility functions. Specifically for recursive utility, I introduce a novel perturbation solution method in terms of the intertemporal elasticity of substitution. This approach has not been used before in such models, it is easy to implement, and it allows a wide range of values for the parameter of intertemporal elasticity of substitution.
We propose a model with mean-variance foreign investors who exhibit a convex disutility associated to brown bond holdings. The model predicts that bond green premia should be smaller in economies with a closer financial account and highly volatile exchange rates. This happens because foreign intermediaries invest relatively less in such economies, and this lowers the marginal disutility of investing in polluting activities. We find strong empirical evidence in favor of this hypothesis using a global bond market dataset. Exchange rate volatility and financial account openness are thus able to explain the higher financing costs of green projects in emerging markets relative to advanced economies, especially when green bonds are denominated in local currency: a disadvantage that we can call the "green sin" of emerging economies.
The European bison was saved from the brink of extinction due to considerable conservation efforts since the early 20th century. The current global population of > 9,500 individuals is the result of successful ex situ breeding based on a stock of only 12 founders, resulting in an extremely low level of genetic variability. Due to the low allelic diversity, traditional molecular tools, such as microsatellites, fail to provide sufficient resolution for accurate genetic assessments in European bison, let alone from non-invasive samples. Here, we present a SNP panel for accurate high-resolution genotyping of European bison, which is suitable for a wide variety of sample types. The panel accommodates 96 markers allowing for individual and parental assignment, sex determination, breeding line discrimination, and cross-species detection. Two applications were shown to be utilisable in further Bos species with potential conservation significance. The new SNP panel will allow to tackle crucial tasks in European bison conservation, including the genetic monitoring of reintroduced populations, and a molecular assessment of pedigree data documented in the world’s first studbook of a threatened species.
ISOE-Newsletter Nr. 4/2023
(2023)
„Ein verregneter Sommer bringt uns das verlorene Grundwasser nicht zurück“ +++ Klimawandel und Gleichstellungspolitik – Session mit ISOE-Forscher bei der LABOR.A 2023 +++ Zukunft aus dem Reallabor? Was die Forschungsmethode für die Nachhaltigkeitsforschung bringt und wie das geplante „Reallabor-Gesetz“ zu bewerten ist +++ ISOE-Wissenschaftler*innen stellen sozial-ökologische Forschungsarbeiten beim „DKG’23“ vor +++ Wie steht es um die kommunale Klimaanpassung in Deutschland? +++ „Das Experiment hat uns überrascht“ – wie nachhaltiges Pendeln durch einen Reallabor-Versuch gelingen kann +++ Wie Chemikalieneinsatz und der Verlust der Artenvielfalt zusammenhängen +++ Das ISOE in den Medien +++ Aktuelle Beiträge im ISOE-Blog +++ Termine +++ Publikationen
ISOE-Newsletter Nr. 2/2023
(2023)
Flurina Schneider in den Klimabeirat der Hessischen Landesregierung berufen +++ Reallaborprojekt „transform-R“ für kommunalen Klimaschutz und interkommunale Zusammenarbeit gestartet +++ Verlust der Insektenvielfalt in Naturschutzgebieten – wie Handlungsbereitschaft für Insektenschutz entstehen kann +++ Soziale Ökologie und Transdisziplinarität in der Lehre +++ So lassen sich Herausforderungen transdisziplinärer Forschung angehen +++ Insektenvielfalt in der Stadt: Frankfurter Forschungsprojekt ruft Bürger*innen zum Mitmachen auf +++ Rückblick auf das Forschungsjahr 2022 +++ Gesellschaft für transdisziplinäre und partizipative Forschung gegründet +++ Bundesministerin Paus beruft ISOE-Forscher in Kommission für Gleichstellungsbericht +++ Interessenkonflikte um den Wald der Zukunft +++ Aktuelle Beiträge im ISOE-Blog +++ Aus dem ISOE +++ Termine +++ Publikationen
ISOE-Newsletter Nr. 5/2023
(2023)
Bundesweite Befragung zur Klimaanpassung in Deutschland erfolgreich abgeschlossen +++ Wasserknappheit – eine unterschätzte Gefahr? +++ Lehrveranstaltungen des ISOE zur Sozialen Ökologie +++ Wie eine Trendwende beim Biodiversitätsschutz gelingen kann +++ Transferprogramm „GeisTreich“ für zukunftsfähigen Weinbau gestartet +++ Sonderausstellung „Stadtinsekten – Frankfurts kleine Helfer“ +++ Reallabore-Gesetz: Experimentierräume nachhaltig und partizipativ gestalten +++ Aktuelle Beiträge im ISOE-Blog +++ Aus dem ISOE +++ Das ISOE in den Medien +++ Termine +++ Publikationen
ISOE-Newsletter Nr. 3/2023
(2023)
Alternativen zum privaten Auto – wie ein Umstieg gelingt +++ Insect Embassy – eine diplomatische Vertretung für Insekten in der Stadt +++ Dokuabend Rhein-Main: Frankfurt – eine Stadt für Insekten? +++ Wie die Grundwasserqualität geschützt werden kann +++ tdAcademy startet in die zweite Forschungsphase +++ Mit RNAi gegen gefährliche Stechmücken – neue technologische Entwicklung aus Hessen kann vor der Verbreitung tropischer Krankheiten schützen +++ Gründungsfeier in Berlin der Fachgesellschaft für transdisziplinäre und partizipative Forschung +++ „Das ist für mich so Pendelfreizeit“ – Interviewstudie im Forschungsprojekt PendelLabor erschienen +++ Das ISOE in den Medien +++ Aktuelle Beiträge im ISOE-Blog +++ Termine +++ Publikationen
This thesis comprises the usage of two commonly known hinge-binding moieties in drug discovery. First, the quinazoline scaffold of gefitinib (5) was utilized in a macrocyclization strategy to introduce selectivity. In general, the quinazoline hinge-binding moiety is a commonly used scaffold which can be found in 14% of approved kinase inhibitors. The most familiar applications are EGFR inhibitors such as gefitinib (5), erlotinib (6), afatinib, or dacomitinib for the treatment of NSCLC. But other kinases like CDK2, CDK4, or p38 are reported targets as well.
The N-phenylquinazolin-4-amine moiety of gefitinib (5) was conserved however, the residues at the aromatic ring in the linker were modified, the residue targeting the solvent-exposed region was varied, and the linker at the C6 position of the quinazoline was adjusted to enable the macrocyclization. An overview of the structural modifications is shown in Figure 35A.
Kinome-wide screening of gefitinib (5) revealed several off-targets besides EGFR (Figure 35B), making it an excellent starting point for a macrocyclization strategy. Introducing a linker to the N phenylquinazoline-4-amine scaffold and retaining the residues on the aromatic ring as well as the methoxy group targeting the solvent-exposed region improved the selectivity profile and the efficacy towards EGFR WT and its mutants. Truncation of the linker moiety led to the mutant selective macrocycle 26f with an excellent kinome-wide selectivity profile (Figure 35B). An inhibitor that is effective on EGFR mutations while ineffective on the EGFR WT could represent an enhancement of patient treatment, as it potentially causes less side effects. Further studies could determine the effect of the most promising macrocycles in lung cancer cell lines. Additionally, the pharmacokinetic properties could be optimized, e.g. by introducing solubilizing groups, targeting the solvent-exposed region.
The second scaffold comprises the 3-aminopyrazole-based hinge-binding moiety. It is a privileged scaffold in medicinal chemistry for the development of kinase inhibitors. Previous publications report the anti-proliferative and anti-cancer potential of pyrazole-based molecules. They play a crucial role in the treatment of various diseases and cancer types like inflammation disorders, lymphoma, or breast cancer. This scaffold can be found e.g. in the aurora kinase inhibitor tozasertib or in the promiscuous kinase inhibitor 23, published by Statsuk et. al. Rescreening compound 23 in a comprehensive kinase panel against 468 human protein kinases confirmed the unselective behavior with a selectivity score of S35 = 0.56 (Figure 36B), making it a great starting point for further optimizations. The N-(1H-pyrazol-3-yl)pyrimidin-4-amine scaffold was conserved however, the residues targeting the solvent-exposed region were varied and different linkers were attached.
The introduction of different residues at the pyrazole dramatically influenced the selectivity profile of the desired kinases. Ester moieties caused to a favorable combination of selectivity and potency towards the kinase of interest CDK16. The removal of additional residues at the pyrimidine, targeting the solvent-exposed region, increased the efficiency towards CDK16. Further optimization led to the highly potent and selective CDK16 inhibitor 98d (IC50 = 33 nM). NanoBRETTM screening against the complete CDK family revealed a preferred inhibition of the PCTAIRE and PFTAIRE subfamily with cellular IC50 values of 20 nM – 120 nM and 50 nM – 180 nM, respectively. A FUCCI cell cycle assay and viability assessment of 98d confirmed previously published results, reporting a G2/M cell cycle arrest followed by apoptosis and accumulation of p27 through knockout of CDK16 in SCC cells. Consequently, further studies could evaluate the anti-tumor activity of 98d in SCC and NSCLC or elucidate the effect of 98d in AMPK-related macroautophagy. 98d represents a novel tool compound to investigate the understudied kinases of the PCTAIRE family and enable to enlighten the biological role of those kinases.
Macrocyclization of the N-(1H-pyrazol-3-yl)pyrimidin-4-amine core resulted in the selective BMPR2 inhibitor 110a. It showed a good binding affinity towards BMPR2 with a KD value of 205 nM as well as a good potency with an IC50 value of 506 nM. A comprehensive selectivity screen against 468 kinases revealed an excellent selectivity profile with S35 = 0.01. As no BMPR2 inhibitors have been published so far, 110a represents a novel compound that may provide further insights into the canonical BMP pathway, noncanonical signaling, or its impact on BMPR2-associated diseases like PAH.
The introduction of additional residues targeting the solvent-exposed region shifted the selectivity towards the MST kinases. The exchange from the pyrimidine to a quinazoline moiety resulted in the highly potent and selective macrocyclic MST3 inhibitor 113c. NanoBRETTM measurements demonstrated the preferred inhibition of MST3 with IC50 values of 210 nM and 30 nM for intact and lysed cells, respectively. A weaker activity could be seen for MST4 with 1.8 µM and 510 nM, while MST1 and MST2 were not affected. To date, no selective MST3 inhibitors have been published, making 113c a valuable tool compound for further functional studies. As MST3 is influencing the cell cycle progression, 113c could be tested in a further cell cycle assay to elucidate the inhibitory effect of 113c on MST3 and consequently on the cell cycle. Furthermore, the anti-tumor activity of 113c in breast cancer could be determined, as Madsen et. al. reported a high MST3 and MST4 activity triggered by FAM40B mutations.
My aim in this paper is to make the debates about epistemic injustice fruitful for an analysis of trust in the knowledge of others. Epistemic trust is understood here in a broad sense: not only as trust in scientific knowledge or expert knowledge, but also as trust in implicit, positioned and experience-based knowledge. Using insights from discussions of epistemic injustice, I argue for three interrelated theses:
1. Questions of epistemic trust and trustworthiness cannot be answered with reference to individual virtue alone; rather, they have a structural component.
2. The rationality of epistemic trust must be analyzed against the background of social structures and social relations of domination.
3. Epistemic trust is (also) a political phenomenon and epistemically just relations depend on political transformation processes that promote equality.