Translocation of heme oxygenase-1 contributes to imatinib resistance in chronic myelogenous leukemia

Heme oxygenase-1 (HO-1) degrades heme to bilirubin. In addition, it is upregulated in malignant disease and has been described as an important factor for cancer prognosis and therapy. Under physiological conditions HO-1 is anchored to the endoplasmic reticulum (ER). Under stress conditions HO-1 can be cleaved and subsequently translocates to the cytosol and nucleus. In this study we systematically investigated the influence of HO-1’s catabolic activity and subcellular localization on resistance against the tyrosine kinase inhibitor imatinib in leukemia cells by confocal laser scanning microscopy, hemoglobin synthesis experiments and cell viability assays. We created two types of monoclonal K562 cell lines stably transfected with GFP-tagged HO-1: cell lines expressing ER anchored HO-1 or anchorless HO-1. Since translocation of HO-1 disrupts the association with cytochrome P450 reductase, heme degrading activity was higher for ER anchored versus anchorless HO-1. Cell viability tests with increasing concentrations of imatinib showed IC50-values for all six cell lines with ER localized HO-1 that were similar to control cells. However, out of the seven cell lines with anchorless HO-1, two showed a statistically significant increase in the imatinib IC50 (19.76 μM and 12.35 μM versus 2.35 – 7.57 μM of sensitive cell lines) corresponding to plasma concentrations outside the therapeutic range. We conclude that the presence of translocated HO-1 in the cytosol and nucleus supports imatinib resistance while it is not sufficient to cause imatinib resistance in every cell line. In contrast, an increase in ER anchored HO-1 with high heme degrading activity does not contribute to imatinib resistance

Diagnostic tests in canine andrology - What do they really tell us about fertility?

Dog breeders often require breeding soundness evaluations which include andrological examinations of the genital organs, hormone measurements, and semen analyses. During the past decades, a considerable number of research results have been published, allowing diagnoses of specific andrological conditions and fertility assessment. For specific examinations, however, no standard procedures have been defined and for some parameters different reference ranges have been published. Therefore, examination results from different facilities are difficult to compare and profound conclusions regarding health and fertility of a male dog are not always possible. Conventional semen examination, however, is still useful in identifying deviations or no deviations from normality, especially if confounding factors are taken into account and if the exam is repeated in case of inconclusive findings. A standardization of examination procedures and reference ranges would help to harmonize the exchange of examination results and interpretation of the findings

Simulation-based roadmap for the integration of poly-silicon on oxide contacts into screen-printed crystalline silicon solar cells

We present a simulation-based study for identifying promising cell structures, which integrate poly-Si on oxide junctions into industrial crystalline silicon solar cells. The simulations use best-case measured input parameters to determine efficiency potentials. We also discuss the main challenges of industrially processing these structures. We find that structures based on p-type wafers in which the phosphorus diffusion is replaced by an n-type poly-Si on oxide junction (POLO) in combination with the conventional screen-printed and fired Al contacts show a high efficiency potential. The efficiency gains in comparsion to the 23.7% efficiency simulated for the PERC reference case are 1.0% for the POLO BJ (back junction) structure and 1.8% for the POLO IBC (interdigitated back contact) structure. The POLO BJ and the POLO IBC cells can be processed with lean process flows, which are built on major steps of the PERC process such as the screen-printed Al contacts and the Al2O3/SiN passivation. Cell concepts with contacts using poly-Si for both polarities (POLO 2-concepts) show an even higher efficiency gain potential of 1.3% for a POLO 2 BJ cell and 2.2% for a POLO 2 IBC cell in comparison to PERC. For these structures further research on poly-Si structuring and screen-printing on p-type poly-Si is necessary. © 2021, The Author(s)

The ABC transporter MsbA adopts the wide inward-open conformation in E. coli cells

Membrane proteins are currently investigated after detergent extraction from native cellular membranes and reconstitution into artificial liposomes or nanodiscs, thereby removing them from their physiological environment. However, to truly understand the biophysical properties of membrane proteins in a physiological environment, they must be investigated within living cells. Here, we used a spin-labeled nanobody to interrogate the conformational cycle of the ABC transporter MsbA by double electron-electron resonance. Unexpectedly, the wide inward-open conformation of MsbA, commonly considered a nonphysiological state, was found to be prominently populated in Escherichia coli cells. Molecular dynamics simulations revealed that extensive lateral portal opening is essential to provide access of its large natural substrate core lipid A to the binding cavity. Our work paves the way to investigate the conformational landscape of membrane proteins in cells

For none, one, or two polarities—How do POLO junctions fit best into industrial Si solar cells?

We present a systematic study on the benefit of the implementation of poly-Si on oxide (POLO) or related junctions into p-type industrial Si solar cells as compared with the benchmark of Passivated Emitter and Rear Cell (PERC). We assess three aspects: (a) the simulated efficiency potential of representative structures with POLO junctions for none (=PERC+), one, and for two polarities; (b) possible lean process flows for their fabrication; and (c) experimental results on major building blocks. Synergistic efficiency gain analysis reveals that the exclusive suppression of the contact recombination for one polarity by POLO only yields moderate efficiency improvements between 0.23%abs and 0.41%abs as compared with PERC+ because of the remaining recombination paths. This problem is solved in a structure that includes POLO junctions for both polarities (POLO2), for whose realization we propose a lean process flow, and for which we experimentally demonstrate the most important building blocks. However, two experimental challenges—alignment tolerances and screen-print metallization of p+ poly-Si—are unsolved so far and reduced the efficiency of the “real” POLO2 cell as compared with an idealized scenario. As an intermediate step, we therefore work on a POLO IBC cell with POLO junctions for one polarity. It avoids the abovementioned challenges of the POLO2 structure, can be realized within a lean process flow, and has an efficiency benefit of 1.59%abs as compared with PERC—because not only contact recombination is suppressed but also the entire phosphorus emitter is replaced by an n+ POLO junction

Fermentative production of isobutene

Isobutene (2-methylpropene) is one of those chemicals for which bio-based production might replace the petrochemical production in the future. Currently, more than 10 million metric tons of isobutene are produced on a yearly basis. Even though bio-based production might also be achieved through chemocatalytic or thermochemical methods, this review focuses on fermentative routes from sugars. Although biological isobutene formation is known since the 1970s, extensive metabolic engineering is required to achieve economically viable yields and productivities. Two recent metabolic engineering developments may enable anaerobic production close to the theoretical stoichiometry of 1isobutene + 2CO2 + 2H2O per mol of glucose. One relies on the conversion of 3-hydroxyisovalerate to isobutene as a side activity of mevalonate diphosphate decarboxylase and the other on isobutanol dehydration as a side activity of engineered oleate hydratase. The latter resembles the fermentative production of isobutanol followed by isobutanol recovery and chemocatalytic dehydration. The advantage of a completely biological route is that not isobutanol, but instead gaseous isobutene is recovered from the fermenter together with CO2. The low aqueous solubility of isobutene might also minimize product toxicity to the microorganisms. Although developments are at their infancy, the potential of a large scale fermentative isobutene production process is assessed. The production costs estimate is 0.9 € kg−1, which is reasonably competitive. About 70% of the production costs will be due to the costs of lignocellulose hydrolysate, which seems to be a preferred feedstock

Situating language register across the ages, languages, modalities, and cultural aspects: Evidence from complementary methods

In the present review paper by members of the collaborative research center “Register: Language Users' Knowledge of Situational-Functional Variation” (CRC 1412), we assess the pervasiveness of register phenomena across different time periods, languages, modalities, and cultures. We define “register” as recurring variation in language use depending on the function of language and on the social situation. Informed by rich data, we aim to better understand and model the knowledge involved in situation- and function-based use of language register. In order to achieve this goal, we are using complementary methods and measures. In the review, we start by clarifying the concept of “register”, by reviewing the state of the art, and by setting out our methods and modeling goals. Against this background, we discuss three key challenges, two at the methodological level and one at the theoretical level: (1) To better uncover registers in text and spoken corpora, we propose changes to established analytical approaches. (2) To tease apart between-subject variability from the linguistic variability at issue (intra-individual situation-based register variability), we use within-subject designs and the modeling of individuals' social, language, and educational background. (3) We highlight a gap in cognitive modeling, viz. modeling the mental representations of register (processing), and present our first attempts at filling this gap. We argue that the targeted use of multiple complementary methods and measures supports investigating the pervasiveness of register phenomena and yields comprehensive insights into the cross-methodological robustness of register-related language variability. These comprehensive insights in turn provide a solid foundation for associated cognitive modeling.Peer Reviewe