MAgPIE 4 – a modular open-source framework for modeling global land systems

The open-source modeling framework MAgPIE (Model of Agricultural Production and its Impact on the Environment) combines economic and biophysical approaches to simulate spatially explicit global scenarios of land use within the 21st century and the respective interactions with the environment. Besides various other projects, it was used to simulate marker scenarios of the Shared Socioeconomic Pathways (SSPs) and contributed substantially to multiple IPCC assessments. However, with growing scope and detail, the non-linear model has become increasingly complex, computationally intensive and non-transparent, requiring structured approaches to improve the development and evaluation of the model. Here, we provide an overview on version 4 of MAgPIE and how it addresses these issues of increasing complexity using new technical features: modular structure with exchangeable module implementations, flexible spatial resolution, in-code documentation, automatized code checking, model/output evaluation and open accessibility. Application examples provide insights into model evaluation, modular flexibility and region-specific analysis approaches. While this paper is focused on the general framework as such, the publication is accompanied by a detailed model documentation describing contents and equations, and by model evaluation documents giving insights into model performance for a broad range of variables. With the open-source release of the MAgPIE 4 framework, we hope to contribute to more transparent, reproducible and collaborative research in the field. Due to its modularity and spatial flexibility, it should provide a basis for a broad range of land-related research with economic or biophysical, global or regional focus

A New CYP2E1 Inhibitor, 12-Imidazolyl-1-dodecanol, Represents a Potential Treatment for Hepatocellular Carcinoma

Cytochrome P450 2E1 (CYP2E1) is a key target protein in the development of alcoholic and nonalcoholic fatty liver disease (FLD). The pathophysiological correlate is the massive production of reactive oxygen species. The role of CYP2E1 in the development of hepatocellular carcinoma (HCC), the final complication of FLD, remains controversial. Specifically, CYP2E1 has not yet been defined as a molecular target for HCC therapy. In addition, a CYP2E1-specific drug has not been developed. We have already shown that our newly developed CYP2E1 inhibitor 12-imidazolyl-1-dodecanol (I-ol) was therapeutically effective against alcoholic and nonalcoholic steatohepatitis. In this study, we investigated the effect of I-ol on HCC tumorigenesis and whether I-ol could serve as a possible treatment option for terminal-stage FLD. I-ol exerted a very highly significant antitumour effect against hepatocellular HepG2 cells. Cell viability was reduced in a dose-dependent manner, with only the highest doses causing a cytotoxic effect associated with caspase 3/7 activation. Comparable results were obtained for the model colorectal adenocarcinoma cell line, DLD-1, whose tumorigenesis is also associated with CYP2E1. Transcriptome analyses showed a clear effect of I-ol on apoptosis and cell-cycle regulation, with the increased expression of p27Kip1 being particularly noticeable. These observations were confirmed at the protein level for HepG2 and DLD-1 cells grafted on a chorioallantoic membrane. Cell-cycle analysis showed a complete loss of proliferating cells with a simultaneous increase in S-phase arrest beginning at a threshold dose of 30 μM. I-ol also reduced xenograft tumour growth in nude mice. This antitumour effect was not associated with tumour cachexia. I-ol was not toxic to healthy tissues or organs. This study demonstrates for the first time the therapeutic effect of the specific CYP2E1 inhibitor I-ol on the tumorigenesis of HCC. Our findings imply that I-ol can potentially be applied therapeutically on patients at the final stage of FLD. © 2021 Torsten Diesinger et al

Temporal binding past the Libet clock: testing design factors for an auditory timer

Voluntary actions and causally linked sensory stimuli are perceived to be shifted towards each other in time. This so-called temporal binding is commonly assessed in paradigms using the Libet Clock. In such experiments, participants have to estimate the timing of actions performed or ensuing sensory stimuli (usually tones) by means of a rotating clock hand presented on a screen. The aforementioned task setup is however ill-suited for many conceivable setups, especially when they involve visual effects. To address this shortcoming, the line of research presented here establishes an alternative measure for temporal binding by using a sequence of timed sounds. This method uses an auditory timer, a sequence of letters presented during task execution, which serve as anchors for temporal judgments. In four experiments, we manipulated four design factors of this auditory timer, namely interval length, interval filling, sequence predictability, and sequence length, to determine the most effective and economic method for measuring temporal binding with an auditory timer

A New CYP2E1 Inhibitor, 12-Imidazolyl-1-dodecanol, Represents a Potential Treatment for Hepatocellular Carcinoma

Cytochrome P450 2E1 (CYP2E1) is a key target protein in the development of alcoholic and nonalcoholic fatty liver disease (FLD). The pathophysiological correlate is the massive production of reactive oxygen species. The role of CYP2E1 in the development of hepatocellular carcinoma (HCC), the final complication of FLD, remains controversial. Specifically, CYP2E1 has not yet been defined as a molecular target for HCC therapy. In addition, a CYP2E1-specific drug has not been developed. We have already shown that our newly developed CYP2E1 inhibitor 12-imidazolyl-1-dodecanol (I-ol) was therapeutically effective against alcoholic and nonalcoholic steatohepatitis. In this study, we investigated the effect of I-ol on HCC tumorigenesis and whether I-ol could serve as a possible treatment option for terminal-stage FLD. I-ol exerted a very highly significant antitumour effect against hepatocellular HepG2 cells. Cell viability was reduced in a dose-dependent manner, with only the highest doses causing a cytotoxic effect associated with caspase 3/7 activation. Comparable results were obtained for the model colorectal adenocarcinoma cell line, DLD-1, whose tumorigenesis is also associated with CYP2E1. Transcriptome analyses showed a clear effect of I-ol on apoptosis and cell-cycle regulation, with the increased expression of p27Kip1 being particularly noticeable. These observations were confirmed at the protein level for HepG2 and DLD-1 cells grafted on a chorioallantoic membrane. Cell-cycle analysis showed a complete loss of proliferating cells with a simultaneous increase in S-phase arrest beginning at a threshold dose of 30 μM. I-ol also reduced xenograft tumour growth in nude mice. This antitumour effect was not associated with tumour cachexia. I-ol was not toxic to healthy tissues or organs. This study demonstrates for the first time the therapeutic effect of the specific CYP2E1 inhibitor I-ol on the tumorigenesis of HCC. Our findings imply that I-ol can potentially be applied therapeutically on patients at the final stage of FLD