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The triazole antifungals posaconazole and itraconazole can cause pseudohyperaldosteronism with hypertension and hypokalemia, edema, and gynecomastia by inhibiting steroid synthesis and metabolism. Mechanisms underlying pseudohyperaldosteronism include inhibition of adrenal 11β-hydroxylase cytochrome-P450 (CYP) 11B1 and 17α-hydroxylase (CYP17A1) as well as peripherally expressed 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). To enhance specificity for fungal CYP51, tetrazoles have been developed. This study employed H295R adrenocortical cells and enzyme activity assays to assess the potential risk of oteseconazole and two other tetrazoles, VT-1598 and quilseconazole, to inhibit adrenal steroidogenesis or 11β-HSD2. Steroidomic footprint analyses of H295R cell supernatants using untargeted liquid-chromatography-high-resolution mass-spectrometry (LC-HRMS) indicated overall patterns common to oteseconazole, quilseconazole and itraconazole, as well as similarities between VT-1598 and isavuconazole. Additionally, more specific features of the steroid signatures were observed. Targeted quantification of nine adrenal steroids in supernatants from treated H295R cells revealed an overall inhibition of adrenal steroidogenesis by the three tetrazoles, itraconazole and isavuconazole, providing an explanation for their similar steroidomic pattern. Applying recombinant enzymes indicated that this effect is not due to direct inhibition of steroidogenic enzymes because no or only weak inhibition could be observed. Moreover, oteseconazole and the two other tetrazoles did not inhibit 11β-HSD2, suggesting that they do not pose a risk of pseudohyperaldosteronism. Furthermore, oteseconazole did not alter steroid concentrations in a recent clinical study. Nevertheless, follow-up studies should assess the mechanism underlying the observed overall steroidogenesis inhibition by tetrazoles, itraconazole and isavuconazole, and whether concentrations achievable in a subgroup of susceptible patients might cause adrenal insufficiency and hyperplasia.

Azole antifungals, designed to inhibit fungal CYP51, have a liability to inhibit human CYP enzymes. Whilst drug-metabolizing CYPs are covered in preclinical safety assessment, those metabolizing endogenous bioactive molecules are usually not. Posaconazole and itraconazole were recently found to cause pseudohyperaldosteronism with hypokalemia and hypertension by inhibiting CYP11B1-dependent adrenal cortisol biosynthesis. Because this was overlooked in preclinical safety assessment, the present study tested whether applying adrenal carcinoma H295R cells could have predicted this liability and whether other systemic triazole antifungals interfere with adrenal steroidogenesis. Forskolin-stimulated H295R cells were exposed to systemic triazole antifungals that are currently used, and key adrenal steroids were quantified by UHPLC-MS/MS. To support the findings from the H295R model, activity assays for steroidogenic enzymes were performed. The analysis of the steroid profiles and product/substrate ratios predicted the CYP11B1 and CYP11B2 inhibition by posaconazole and itraconazole. Comparison of their steroid profiles allowed distinguishing their effects and suggested inhibition of adrenal androgen synthesis by posaconazole but not itraconazole, which was confirmed by CYP17A1 17,20-lyase activity measurements. In line with clinical observations, there was no evidence from these experiments for an inhibition of either CYP11B1/2 or CYP17A1 by voriconazole, fluconazole or isavuconazole. However, itraconazole and isavuconazole exerted an overall inhibition of steroidogenesis by a mechanism warranting further investigations. In conclusion, analyses of steroid profiles from the H295R assay and product/substrate ratios provide important information on the interference of a chemical with adrenal steroidogenesis and the underlying mechanism. This approach facilitates prioritization of further investigations, including enzyme expression and activity studies.

Objective: We want to better understand what incentives firms to pursue innovations. For this purpose, we set up a new intertemporal principal-agent model. We then proceed to empirically assess the determinants of innovation activities unfolded by German firms between 2006 and 2019 and to also look at the causal factors – related to innovation activities – for the occurrence of patent registration in Germany. Research Design & Methods: In the theoretical part, we make use of intertemporal optimization tools based on the principal-agent model (PAM). In the empirical part, we apply the so-called DuPont decomposition and non-linear regression techniques. Findings: It seems that investment activities in conjunction with product innovations are the major determinants of innovation intensity. The latter (and other innovation related variables) in turn, is (are) responsible for the dynamics of patent registration in Germany. Implications & Recommendations: Our results highlight the importance of smart reward systems in R&D departments in order to incentivize innovative activities. Our findings also point at the significance of a patent regulation friendly to the innovator. Contribution & Value Added: Our findings deliver a new foundation of innovation activities based on an intertemporal principal agent approach which is confirmed by the empirical facts in the case of Germany.

La Gran Recesión ha enfatizado la necesidad de diferentes políticas económicas y reformas estructurales para impulsar el crecimiento económico y la contratación de las economías avanzadas y emergentes. Partimos del concepto teórico relativamente novedoso: la brecha de producción modificada (MOG), basada tanto en la curva de Phillips como en la de Beveridge, que revela la relación explícitamente positiva entre la tasa de vacantes de empleo y la tasa de inflación. Empíricamente se estima la relación mediante el desarrollo de tres modelos de datos de panel diferentes: de efectos fijos (FE), de efectos aleatorios (RE) y un sistema GMM (Método generalizado de momentos). Los resultados muestran que una pérdida de la eficiencia en el ajuste en el mercado laboral combinada con un aumento de la demanda en los mercados de bienes y servicios elevará la inflación. Se evidencia la relevancia empírica de la brecha de producción modificada para España durante la Gran Recesión y cómo afecta la implementación del plan de estímulo económico liderado por el gobierno español para impulsar la economía en este período.

There are numerous new technologies whose implementation in food industry is hampered by the fact that people hesitate to invest in expensive systems which they cannot be sure will work or at least are questionable in terms of a given product. Until recently, preservation by HHP, high hydrostatic pressure, was such a technology, and still is today in some branches of the food industry. Investigations were conducted to answer the question of whether the literature, the laboratory, and the industrial (or at least pilot plant) measurements and results agree with one another. We compared the literature data with two HHP systems which were significantly different in terms of treatment capacity, but their efficiency in killing microbes was studied under the same treatment parameters. Our results show that in nearly all cases only minimal differences exist between the data in the literature and the measurements taken on the two appliances.

Terrestrial microcosms (TMCs) are frequently used for testing the durability of wood and wood-based materials, as well as the protective effectiveness of wood preservatives. In contrary to experiments in soil ecology sciences, the experimental setup is usually rather simple. However, for service life prediction of wood exposed in ground, it is of imminent interest to better understand the different parameters defining the boundary conditions in TMCs. This study focused, therefore, on soil−wood−moisture interactions. Terrestrial microcosms were prepared from the same compost substrate with varying water holding capacities (WHCs) and soil moisture contents (MCsoil). Wood specimens were exposed to 48 TMCs with varying WHCs and MCsoil. The wood moisture content (MCwood) was studied as well as its distribution within the specimens. For this purpose, the compost substrate was mixed with sand and peat and its WHC was determined using two methods in comparison, i.e., the “droplet counting method” and the “cylinder sand bath method” in which the latter turned out advantageous over the other. The MCwood increased generally with rising MCsoil, but WHC was often negatively correlated with MCwood. The distance to water saturation Ssoil from which MCwood increased most intensively was found to be wood-species specific and might, therefore, require further consideration in soil-bed durability-testing and service life modelling of wood in soil contact.

The triazole antifungals posaconazole and itraconazole can cause pseudohyperaldosteronism with hypertension and hypokalemia, edema, and gynecomastia by inhibiting steroid synthesis and metabolism. Mechanisms underlying pseudohyperaldosteronism include inhibition of adrenal 11β-hydroxylase cytochrome-P450 (CYP) 11B1 and 17α-hydroxylase (CYP17A1) as well as peripherally expressed 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). To enhance specificity for fungal CYP51, tetrazoles have been developed. This study employed H295R adrenocortical cells and enzyme activity assays to assess the potential risk of oteseconazole and two other tetrazoles, VT-1598 and quilseconazole, to inhibit adrenal steroidogenesis or 11β-HSD2. Steroidomic footprint analyses of H295R cell supernatants using untargeted liquid-chromatography-high-resolution mass-spectrometry (LC-HRMS) indicated overall patterns common to oteseconazole, quilseconazole and itraconazole, as well as similarities between VT-1598 and isavuconazole. Additionally, more specific features of the steroid signatures were observed. Targeted quantification of nine adrenal steroids in supernatants from treated H295R cells revealed an overall inhibition of adrenal steroidogenesis by the three tetrazoles, itraconazole and isavuconazole, providing an explanation for their similar steroidomic pattern. Applying recombinant enzymes indicated that this effect is not due to direct inhibition of steroidogenic enzymes because no or only weak inhibition could be observed. Moreover, oteseconazole and the two other tetrazoles did not inhibit 11β-HSD2, suggesting that they do not pose a risk of pseudohyperaldosteronism. Furthermore, oteseconazole did not alter steroid concentrations in a recent clinical study. Nevertheless, follow-up studies should assess the mechanism underlying the observed overall steroidogenesis inhibition by tetrazoles, itraconazole and isavuconazole, and whether concentrations achievable in a subgroup of susceptible patients might cause adrenal insufficiency and hyperplasia. [ABSTRACT FROM AUTHOR]

Looking at both the Gini coefficients ex-ante as well as at the Gini coefficients ex-post reveals that the distribution of personal incomes has become more unequal in the USA in the periods between 1947 and 2020. This paper investigates the possible underlying concepts of income distribution targets and argues, based on empirical findings, that neither clear electoral/partisan cycles nor station-arity (equilibrium) in the figures of income distribution of the USA can be detected. Instead, one observes an unbroken cyclical upward trend in inequality, which contributes significantly to the fission in the US society and economy. Surprisingly, as measured by the results produced by US presidents on the national level since 1947, the Republican Party and the Democratic Party have made similar contributions to lowering the inequality. [ABSTRACT FROM AUTHOR]