Functions of p120ctn in development and disease

p120 catenin (p120ctn), a component of the cadherin-catenin complex, was the first member to be identified in a most interesting subfamily of the Armadillo family. Several p120ctn isoforms are generated by alternative splicing. These isoforms fulfill pleiotropic functions according to their subcellular localization: modulating the turnover rate of membrane-bound cadherins, regulating the activation of small Rho GTPases in the cytoplasm, and modulating nuclear transcription. Over the last two decades, knowledge of p120ctn has grown remarkably, and this has been achieved in part by using different animal models. At least in frog and mammals, p120ctn is essential for normal development and homeostasis. Here we will discuss the effects of different p120ctn isoforms on cadherin turnover and on signaling in the cytoplasm and the nucleus. We will also elaborate on the structure and function of other members of the p120ctn subfamily: ARVCF, p0071 and delta-catenin. Finally, we will overview the respective roles of p120ctn family members in pathological processes, and particularly in cancer as p120ctn is frequently downregulated or mislocalized in various human tumors

Functions of p120ctn isoforms in cell-cell adhesion and intracellular signaling

The functions of many organs depend on the generation of an epithelium. The transition from a set of loosely connected nonpolarized cells to organized sheets of closely associated polarized epithelial cells requires the assembly of specialized cell junctions. In vertebrates, three major types of junctions are responsible for epithelial integrity: adherens junctions, tight junctions, and desmosomes. p120 catenin (p120ctn) is an Armadillo family member and a component of the cadherin-catenin complex in the adherens junction. It fulfils pleiotropic functions according to its subcellular localization: modulating the turnover rate of membrane-bound cadherins, regulating the activation of small RhoGTPases in the cytoplasm, and modulating nuclear transcription. Over the last two decades, knowledge of p120ctn obtained from in vitro experiments has been confirmed and extended by using different animal models. It has become clear that p120ctn is essential for normal development and homeostasis, at least in frog and mammals. p120ctn is a Src substrate that can be phosphorylated at different tyrosine, serine and threonine residues and can dock various kinases and phosphatases. Thereby, p120ctn regulates the phosphorylation status and the junctional stability of the cadherin-catenin complex. Multiple p120ctn isoforms are generated by alternative splicing, which allows the translation to be initiated from four start codons and enables the inclusion of four alternatively used exons. We will discuss the effects of different p120ctn isoforms on cadherin turnover and intracellular signaling, in particular RhoGTPase activity and phosphorylation events

Development of a stereovision-based technique to measure the spread patterns of granular fertilizer spreaders

Centrifugal fertilizer spreaders are by far the most commonly used granular fertilizer spreader type in Europe. Their spread pattern however is error-prone, potentially leading to an undesired distribution of particles in the field and losses out of the field, which is often caused by poor calibration of the spreader for the specific fertilizer used. Due to the large environmental impact of fertilizer use, it is important to optimize the spreading process and minimize these errors. Spreader calibrations can be performed by using collection trays to determine the (field) spread pattern, but this is very time-consuming and expensive for the farmer and hence not common practice. Therefore, we developed an innovative multi-camera system to predict the spread pattern in a fast and accurate way, independent of the spreader configuration. Using high-speed stereovision, ejection parameters of particles leaving the spreader vanes were determined relative to a coordinate system associated with the spreader. The landing positions and subsequent spread patterns were determined using a ballistic model incorporating the effect of tractor motion and wind. Experiments were conducted with a commercial spreader and showed a high repeatability. The results were transformed to one spatial dimension to enable comparison with transverse spread patterns determined in the field and showed similar results

Neural defects caused by total and Wnt1-Cre mediated ablation of p120ctn in mice

Background p120 catenin (p120ctn) is an important component in the cadherin-catenin cell adhesion complex because it stabilizes cadherin-mediated intercellular junctions. Outside these junctions, p120ctn is actively involved in the regulation of small GTPases of the Rho family, in actomyosin dynamics and in transcription regulation. We and others reported that loss of p120ctn in mouse embryos results in an embryonic lethal phenotype, but the exact developmental role of p120ctn during brain formation has not been reported. Results We combined floxed p120ctn mice with Del-Cre or Wnt1-Cre mice to deplete p120ctn from either all cells or specific brain and neural crest cells. Complete loss of p120ctn in mid-gestation embryos resulted in an aberrant morphology, including growth retardation, failure to switch from lordotic to fetal posture, and defective neural tube formation and neurogenesis. By expressing a wild-type p120ctn from the ROSA26 locus in p120ctn-null mouse embryonic stem cells, we could partially rescue neurogenesis. To further investigate the developmental role of p120ctn in neural tube formation, we generated conditional p120ctn(fl/fl);Wnt1Cre knockout mice. p120ctn deletion in Wnt1-expressing cells resulted in neural tube closure defects (NTDs) and craniofacial abnormalities. These defects could not be correlated with misregulation of brain marker genes or cell proliferation. In contrast, we found that p120ctn is required for proper expression of the cell adhesion components N-cadherin, E-cadherin and beta-catenin, and of actin-binding proteins cortactin and Shroom3 at the apical side of neural folds. This region is of critical importance for closure of neural folds. Surprisingly, the lateral side of mutant neural folds showed loss of p120ctn, but not of N-cadherin, beta-catenin or cortactin. Conclusions These results indicate that p120ctn is required for neurogenesis and neurulation. Elimination of p120ctn in cells expressing Wnt1 affects neural tube closure by hampering correct formation of specific adhesion and actomyosin complexes at the apical side of neural folds. Collectively, our results demonstrate the crucial role of p120ctn during brain morphogenesis

Disintegration of sedimentary rocks used as building material: evaluation and quantification in 4D

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Teaching an old dog new tricks : activity-on-target interferon to treat T-cell acute lymphoblastic leukemia

Background Type 1 interferon (IFN) has a long history in the treatment of cancer, including hematological malignancies. The anti-cancer effects induced by IFN result from a combination of 1) direct cancer cell growth inhibition by cell cycle arrest, apoptosis, or differentiation and 2) the activation of the immune system involving antigen presentation by Clec9A+ dendritic cells and priming of cytotoxic CD8+ T-cells. However, IFN therapy experienced variable and unpredictable success in the clinic. Its clinical application is severely impeded by a complex pattern of adverse side-effects, due to the multifaceted activity pattern of IFN. Therefore, safe exploitation of the anti-cancer potential of IFN requires strategies to direct their activity to selected target cells, avoiding systemic toxicity. Aims Safe exploitation of the anti-cancer potential of IFN requires strategies to direct their activity to selected target cells, avoiding systemic toxicity. Methods To improve the therapeutic index of IFN, we have developed AcTaferons (Activity-on-Target Interferon), optimized (mutant) immunocytokines. Mutated IFNa2Q124R, with a strongly reduced affinity for its receptor complex, was fused to single domain antibodies targeting cell-specific domains, which selectively restores the AcTaferon (AFN) activity in a cell-type specific manner. As such, CD8-AFN and Clec9A-AFN were generated which selectively target either CD8+ T(-ALL) cells or Clec9A+ dendritic cells. Results Using CD8- and CD8+ mouse T-ALL cell lines, we evaluated the direct and indirect anti-leukemic effects of our novel AFNs, in vitro and in vivo upon transplantation in immunocompromised and immunocompetent syngeneic hosts. A significant reduction in the leukemic burden was observed. These anti-cancer effects of AFN were similar as observed for the wildtype IFN, but in a cell-type specific manner and with drastically reduced adverse side-effects. Monotherapy was even sufficient to completely cure a proportion of leukemic mice, which highlights the strong anti-leukemic power of these optimized immunocytokines. Strinkingly only the direct effect CD8-AFN on in vivo CD8+ T-ALL was synergistic with asparaginase treatment. No synergism was observed between asparaginase and the indirect immune-mediated Clec9A-AFN anti-leukemic effect. Conclusion In conclusion, we have developed novel optimized immunocytokines as an off-the-shelve targeted immunotherapy for T-ALL

Novel strategy for rapid functional in vivo validation of oncogenic drivers in haematological malignancies

In cancer research, it remains challenging to functionally validate putative novel oncogenic drivers and to establish relevant preclinical models for evaluation of novel therapeutic strategies. Here, we describe an optimized and efficient pipeline for the generation of novel conditional overexpression mouse models in which putative oncogenes, along with an eGFP/Luciferase dual reporter, are expressed from the endogenous ROSA26 (R26) promoter. The efficiency of this approach was demonstrated by the generation and validation of novel R26 knock-in (KI) mice that allow conditional overexpression of Jarid2, Runx2, MN1 and a dominant negative allele of ETV6. As proof of concept, we confirm that MN1 overexpression in the hematopoietic lineage is sufficient to drive myeloid leukemia. In addition, we show that T-cell specific activation of MN1 in combination with loss of Pten increases tumour penetrance and stimulates the formation of Lyl1(+) murine T-cell lymphoblastic leukemias or lymphomas (T-ALL/T-LBL). Finally, we demonstrate that these luciferase-positive murine AML and T-ALL/T-LBL cells are transplantable into immunocompromised mice allowing preclinical evaluation of novel antileukemic drugs in vivo

Irradiation-dependent topology optimization of metallization grid patterns and variation of contact layer thickness used for latitude-based yield gain of thin-film solar modules

We show that the concept of topology optimization for metallization grid patterns of thin-film solar devices can be applied to monolithically integrated solar cells. Different irradiation intensities favor different topological grid designs as well as a different thickness of the transparent conductive oxide (TCO) layer. For standard laboratory efficiency determination, an irradiation power of 1000W/m$^{2}$ is generally applied. However, this power rarely occurs for real-world solar modules operating at mid-latitude locations. Therefore, contact layer thicknesses and also lateral grid patterns should be optimized for lower irradiation intensities. This results in material production savings for the grid and TCO layer of up to 50 % and simultaneously a significant gain in yield of over 1% for regions with a low annual mean irradiation

Host and environmental predictors of exhaled breath temperature in the elderly

BACKGROUND: Exhaled breath temperature has been suggested as a new method to detect and monitor pathological processes in the respiratory system. The putative mechanism of this approach is based upon changes in the blood flow. So far potential factors that influence breath temperature have not been studied in the general population. METHODS: The exhaled breath temperature was measured in 151 healthy non-smoking elderly (aged: 60–80 years) at room temperature with the X-halo device with an accuracy of 0.03°C. We related exhaled breath temperature by use of regression models with potential predictors including: host factors (sex, age) and environmental factors (BMI, physical activity, and traffic indicators). RESULTS: Exhaled breath temperature was lower in women than in men and was inversely associated with age, physical activity. BMI and daily average ambient temperature were positively associated with exhaled breath temperature. Independent of the aforementioned covariates, exhaled breath temperature was significantly associated with several traffic indicators. Residential proximity to major road was inversely associated with exhaled breath temperature: doubling the distance to the nearest major intense road was observed a decrease of 0.17°C (95% CI: -0.33 to -0.01; p = 0.036). CONCLUSIONS: Exhaled breath temperature has been suggested as a noninvasive method for the evaluation of airway inflammation. We provide evidence that several factors known to be involved in proinflammatory conditions including BMI, physical activity and residential proximity to traffic affect exhaled breath temperature. In addition, we identified potential confounders that should be taken into account in clinical and epidemiological studies on exhaled breath temperature including sex, age, and ambient temperature