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See detailUsing Regularization to Infer Cell Line Specificity in Logical Network Models of Signaling Pathways.
De Landtsheer, Sébastien; Lucarelli, Philippe UL; Sauter, Thomas UL

in Frontiers in physiology (2018), 9

Understanding the functional properties of cells of different origins is a long-standing challenge of personalized medicine. Especially in cancer, the high heterogeneity observed in patients slows down ... [more ▼]

Understanding the functional properties of cells of different origins is a long-standing challenge of personalized medicine. Especially in cancer, the high heterogeneity observed in patients slows down the development of effective cures. The molecular differences between cell types or between healthy and diseased cellular states are usually determined by the wiring of regulatory networks. Understanding these molecular and cellular differences at the systems level would improve patient stratification and facilitate the design of rational intervention strategies. Models of cellular regulatory networks frequently make weak assumptions about the distribution of model parameters across cell types or patients. These assumptions are usually expressed in the form of regularization of the objective function of the optimization problem. We propose a new method of regularization for network models of signaling pathways based on the local density of the inferred parameter values within the parameter space. Our method reduces the complexity of models by creating groups of cell line-specific parameters which can then be optimized together. We demonstrate the use of our method by recovering the correct topology and inferring accurate values of the parameters of a small synthetic model. To show the value of our method in a realistic setting, we re-analyze a recently published phosphoproteomic dataset from a panel of 14 colon cancer cell lines. We conclude that our method efficiently reduces model complexity and helps recovering context-specific regulatory information. [less ▲]

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See detailAnalysis of carbohydrate degradation during fermentation by an adapted Anthron-method
Greger, Manfred UL; Schlienz, Markus UL; Benito Martin, Patricia Cristina UL

in Landtechnik (2018)

To measure the degradation of carbohydrates during fermentation the photometrical Anthron method has been adapted. The method has been verified in mesophilic batch tests with the model substrates glucose ... [more ▼]

To measure the degradation of carbohydrates during fermentation the photometrical Anthron method has been adapted. The method has been verified in mesophilic batch tests with the model substrates glucose (water-soluble), corn-starch and cellulose (both insoluble in water). First, the content of soluble carbohydrates was measured. For determination of carbo-hydrates in soluble phase, the samples were filtered (syringe PTFE-filter with mesh size 0.45 μm) to separate the solution from all types of particles, particulate carbohydrates included. The soluble phase reacted with the Anthron solution for 8 minutes at 100 °C. Afterwards, the coloration reaction was stopped by a quick (5 min) cooling step in ice water to ensure repeatability of the method considering a larger number of samples to be measured. Afterwards samples had been equilibrated at room temperature for at least 30 minutes. Before measurement, the sample had to be diluted to reduce on the one hand the intensity of the background and on the other hand to obtain the measuring range (l = 625 nm) of soluble carbohydrates of 10 to 100 mg/l. The total carbohydrate content, which consists of the soluble and particulate fraction, was determined by an additional pre-hydrolysis step (50 % sulfuric acid at 100 °C during 8 minutes) before the Anthron reaction was started. To measure insoluble carbohydrates, e.g. starch and cellulose, they had to pass an additional pre-hydrolysis step, which is performed before filtration and the subsequent Anthron reaction. This additional step (in the following called “indirect method”) is necessary to measure the part of insoluble respectively polymeric carbohydrates of a sample. The amount of particulate carbohydrates is further be calculated by the difference between total and soluble carbohydrates. [less ▲]

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See detailTesting Autonomous Cars for Feature Interaction Failures using Many-Objective Search
Ben Abdessalem (helali), Raja UL; Panichella, Annibale; Nejati, Shiva UL et al

in Proceedings of the 33rd IEEE/ACM International Conference on Automated Software Engineering (ASE 2018) (2018)

Complex systems such as autonomous cars are typically built as a composition of features that are independent units of functionality. Features tend to interact and impact one another’s behavior in unknown ... [more ▼]

Complex systems such as autonomous cars are typically built as a composition of features that are independent units of functionality. Features tend to interact and impact one another’s behavior in unknown ways. A challenge is to detect and manage feature interactions, in particular, those that violate system requirements, hence leading to failures. In this paper, we propose a technique to detect feature interaction failures by casting our approach into a search-based test generation problem. We define a set of hybrid test objectives (distance functions) that combine traditional coverage-based heuristics with new heuristics specifically aimed at revealing feature interaction failures. We develop a new search-based test generation algorithm, called FITEST, that is guided by our hybrid test objectives. FITEST extends recently proposed many-objective evolutionary algorithms to reduce the time required to compute fitness values. We evaluate our approach using two versions of an industrial self-driving system. Our results show that our hybrid test objectives are able to identify more than twice as many feature interaction failures as two baseline test objectives used in the software testing literature (i.e., coverage-based and failure-based test objectives). Further, the feedback from domain experts indicates that the detected feature interaction failures represent real faults in their systems that were not previously identified based on analysis of the system features and their requirements. [less ▲]

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See detailLe droit commun et l'avenir du droit luxembourgeois
Kinsch, Patrick UL

in Actes de la Section des sciences morales et politiques (2018), XXI

Le droit commun est un ensemble de règles ordinaires, censées être équilibrées, qui évite le spectaculaire, l’exorbitant, les privilèges. En droit privé, c’est (pour faire bref et un peu inexact) le droit ... [more ▼]

Le droit commun est un ensemble de règles ordinaires, censées être équilibrées, qui évite le spectaculaire, l’exorbitant, les privilèges. En droit privé, c’est (pour faire bref et un peu inexact) le droit du Code civil ; au-delà du droit civil, il existe du droit commun dans toutes les branches du droit, même en droit fiscal. Ne sous-estimons pas le droit commun ; il est précieux. Mais a-t-il un véritable avenir au Luxembourg ? Il a quelques alliés, il est vrai : le contrôle de la constitutionnalité des lois, et le contrôle des clauses abusives dans les contrats. Deux puissants facteurs jouent cependant contre lui : 1° le manque, paradoxal mais réel, de ressources qui permettraient de faire évoluer le droit commun, en particulier sur le plan législatif ; 2° le souhait de le remplacer par du droit dérogatoire (et compétitif dans le marché international des normes), qui n’a aucune des caractéristiques, rappelées ci-dessus, du droit commun. [less ▲]

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See detailLoss of inter-cellular cooperation by complete epithelial-mesenchymal transition supports favorable outcomes in basal breast cancer patients
Grosse-Wilde, Anne; Kuestner, Rolf E.; Skelton, Stephanie M. et al

in Oncotarget (2018), 9(28), 20018

According to the sequential metastasis model, aggressive mesenchymal (M) metastasis-initiating cells (MICs) are generated by an epithelial-mesenchymal transition (EMT) which eventually is reversed by a ... [more ▼]

According to the sequential metastasis model, aggressive mesenchymal (M) metastasis-initiating cells (MICs) are generated by an epithelial-mesenchymal transition (EMT) which eventually is reversed by a mesenchymal-epithelial transition (MET) and outgrowth of life-threatening epithelial (E) macrometastases. Paradoxically, in breast cancer M signatures are linked with more favorable outcomes than E signatures, and M cells are often dispensable for metastasis in mouse models. Here we present evidence at the cellular and patient level for the cooperation metastasis model, according to which E cells are MICs, while M cells merely support E cell persistence through cooperation. We tracked the fates of co-cultured E and M clones and of fluorescent CDH1-promoter-driven cell lines reporting the E state derived from basal breast cancer HMLER cells. Cells were placed in suspension state and allowed to reattach and select an EMT cell fate. Flow cytometry, single cell and bulk gene expression analyses revealed that only pre-existing E cells generated E cells, mixed E/M populations, or stem-like hybrid E/M cells after suspension and that complete EMT manifest in M clones and CDH1-negative reporter cells resulted in loss of cell plasticity, suggesting full transdifferentiation. Mechanistically, E-M coculture experiments supported the persistence of pre-existing E cells where M cells inhibited EMT of E cells in a mutual cooperation via direct cell-cell contact. Consistently, M signatures were associated with more favorable patient outcomes compared to E signatures in breast cancer, specifically in basal breast cancer patients. These findings suggest a potential benefit of complete EMT for basal breast cancer patients. [less ▲]

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See detailData-driven dynamical model indicates that the heat shock response in Chlamydomonas reinhardtii is tailored to handle natural temperature variation
Magni, Stefano UL; Succurro, Antonella; Skupin, Alexander UL et al

in Journal of The Royal Society Interface (2018), 15(142), 20170965

Global warming exposes plants to severe heat stress, with consequent crop yield reduction. Organisms exposed to high temperature stresses typically protect themselves with a heat shock response (HSR ... [more ▼]

Global warming exposes plants to severe heat stress, with consequent crop yield reduction. Organisms exposed to high temperature stresses typically protect themselves with a heat shock response (HSR), where accumulation of unfolded proteins initiates the synthesis of heat shock proteins through the heat shock transcription factor HSF1. While the molecular mechanisms are qualitatively well characterized, our quantitative understanding of the under- lying dynamics is still very limited. Here, we study the dynamics of HSR in the photosynthetic model organism Chlamydomonas reinhardtii with a data-driven mathematical model of HSR. We based our dynamical model mostly on mass action kinetics, with a few nonlinear terms. The model was parametrized and validated by several independent datasets obtained from the literature. We demonstrate that HSR quantitatively and significantly differs if an increase in temperature of the same magnitude occurs abruptly, as often applied under laboratory conditions, or gradually, which would rather be expected under natural conditions. In contrast to rapid temperature increases, under gradual changes only negligible amounts of misfolded proteins accumulate, indicating that the HSR of C. reinhardtii efficiently avoids the accumulation of misfolded proteins under conditions most likely to prevail in nature. The mathematical model we developed is a flexible tool to simulate the HSR to different conditions and complements the current experimental approaches. [less ▲]

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See detailCaSiAn: a Calcium Signaling Analyzer tool
Moein, Mahsa UL; Grzyb, Kamil UL; Gonçalves Martins, Teresa et al

in Bioinformatics (2018), 1

Ca2þ is a central second messenger in eukaryotic cells that regulates many cellular proc- esses. Recently, we have indicated that typical Ca2þ signals are not purely oscillatory as widely assumed, but ... [more ▼]

Ca2þ is a central second messenger in eukaryotic cells that regulates many cellular proc- esses. Recently, we have indicated that typical Ca2þ signals are not purely oscillatory as widely assumed, but exhibit stochastic spiking with cell type and pathway specific characteristics. Here, we present the Calcium Signaling Analyzer (CaSiAn), an open source software tool that allows for quantifying these signal characteristics including individual spike properties and time course statis- tics in a semi-automated manner. CaSiAn provides an intuitive graphical user interface allowing experimentalists to easily process a large amount of Ca2þ signals, interactively tune peak detection, revise statistical measures and access the quantified signal properties as excel or text files. [less ▲]

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See detailLuxembourg and the EU: How to Integrate in the Face of Diversity
Högenauer, Anna-Lena UL

in Kaeding, Michael; Pollack, Johannes; Schmidt, Paul (Eds.) The Future of Europe: Views from the Capitals (2018)

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See detailActivity of translation regulator eukaryotic elongation factor-2 kinase is increased in Parkinson disease brain and its inhibition reduces alpha synuclein toxicity
Jan, Asad; Jansonius, Brandon; Delaidelli, Alberto et al

in Acta Neuropathologica Communications (2018)

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See detailTongji-Grace02s and Tongji-Grace02k: high-precision static GRACE-only global Earth's gravity field models derived by refined data processing strategies
Qiujie, Chen; Yunzhong, Shen; Francis, Olivier UL et al

in Journal of Geophysical Research: Solid Earth (2018), 0(ja),

Abstract In order to derive high-precision static GRACE-only gravity field solutions, the following strategies were implemented in this study: (1) a refined accelerometer calibration model that treats ... [more ▼]

Abstract In order to derive high-precision static GRACE-only gravity field solutions, the following strategies were implemented in this study: (1) a refined accelerometer calibration model that treats monthly accelerometer scales as a 3-order polynomial and daily accelerometer biases as a 5-order polynomial was developed to calibrate accelerometer measurements; (2) the errors of the acceleration and attitude data were estimated together with the geopotential coefficients and accelerometer parameters on the basis of the weighted least-squares adjustments; (3) a nearly complete observation series of GRACE mission was used to decrease the condition number of normal equation; and (4) the GRACE data collected in lower orbit altitude were also included to decrease the condition number. Our results show that: (1) the refined accelerometer calibration model with much less parameters performs as well as previous methods (i.e. solving daily scales and hourly biases or estimating biases along with bias rates every two hours). However, it provides a system of more stable normal equation and less high-frequency noise in gravity field solutions; (2) high-frequency noise in the gravity field solution is reduced by modelling the errors of the acceleration and attitude data; (3) the geopotential coefficients at all degrees is greatly enhanced by using longer GRACE time series (especially the data by the end of 2010); and (4) due to lower orbit altitude, the GRACE data collected since 2014 lead to a significant improvement of the gravity field solution as the satellites are more sensitive to higher-frequency signal. Using the refined strategies, an unconstrained static solution (named Tongji-Grace02s) up to degree and order 180 was derived. For further suppressing the high-frequency noise, a regularization strategy based on the Kaula rule is applied to the degrees and orders beyond 80, leading to a regularized model Tongji-Grace02k. To validate the quality of the derived models, both Tongji-Grace02s and Tongji-Grace02k were compared to the latest GRACE-only models (i.e. GGM05S, ITU\_GRACE16, ITSG-Grace2014s and ITSG-Grace2014k) and validated using independent data (i.e. GNSS/Levelling data and DTU13 oceanic gravity data). Compared to other models, much less spatial noise in terms of global gravity anomalies with respect to the state-of-the-art model EIGEN6C4 and far higher accuracy at high degrees are achieved by Tongji-Grace02s. The same conclusions can be drawn for Tongji-Grace02k when the same analyses were applied to the regularized solutions ITSG-Grace2014k and Tongji-Grace02k. Validations with independent data confirm that Tongji-Grace02s has the least noise among the unconstrained GRACE-only models and Tongji-Grace02k is the one with the best accuracy among the regularized GRACE-only solutions. For the tests up to degree and order 180 using GNSS/Levelling data, the improvements of Tongji-Grace02s with respect to ITSG-Grace2014s reach 13\% over the Canada and 23\% in the Mexico. Even better, no less than 58\% of improvement is achieved by both Tongji-Grace02s relative to ITSG-Grace2014s and Tongji-Grace02k with respect to ITSG-Grace2014k in the validation based on DTU13 data. [less ▲]

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See detailCross-border vocational education and training as a process of cross-border learning. The example of the Saarland-Lorraine border region
Funk, Ines; Nienaber, Birte UL; Dörrenbächer, H. Peter

Scientific Conference (2018)

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See detailDevelopment of a Data-Driven Approach based on Kalman filtering for CFD Reactor Analysis
Introini, Carolina; Cammi, Antonio; Lorenzi, Stefano et al

in PHYSOR 2018 (2018)

In the last several years, computer-based simulation has become an important analysis and design tool in many engineering fields. The common practice involves the use of low-fidelity models, which in most ... [more ▼]

In the last several years, computer-based simulation has become an important analysis and design tool in many engineering fields. The common practice involves the use of low-fidelity models, which in most cases are able to provide fairly accurate results while maintaining a low computational cost. However, for complex systems such as nuclear reactors, more detailed models are required for the in-depth analysis of the problem at hand, due for example to the complex geometries of the physical domain. Nevertheless, such models are affected by potentially critical uncertainties and inaccuracies. In this context, the use of data assimilation methods such as the Kalman filter to integrate local experimental data witihin the numerical model looks very promising as a high-fidelity analysis tool. In this work, the focus is the application of such methods to the problem of fluid-dynamics analysis of the reactor. Indeed, in terms of nuclear reactor investigation, a detailed characterization of the coolant behaviour within the reactor core is of manda- tory importance in order to understand, among others, the operating conditions of the system, and the potential occurrence of accident scenarios. In this context, the use of data assimilation methods allows the extraction of information of the thermo-dynamics state of the system in a benchmarked transitory in order to increase the fidelity of the com- putational model. Conversely to the current application of control-oriented black-box in the nuclear energy community, in this work the integration of the data-driven paradigm into the numerical formulation of the CFD problem is proposed. In particular, the al- gorithm outlined embeds the Kalman filter into a segregated predictor-corrector formu- lation, commonly adopted for CFD analysis. Due to the construction of the developed method, one of the main challenges achieved is the preservation of mass-conservation for the thermo-dynamics state during each time instant. As a preliminary verification, the proposed methodology is validated on a benchmark of the lid-driven cavity. The obtained results highlight the efficiency of the proposed method with respect to the state-of-art low fidelity approach. [less ▲]

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See detailLa rhétorique communicationnelle en droit judiciaire européen
Menetrey, Séverine UL

in La concurrence des juges en Europe (2018)

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See detailA Reduced Order Kalman Filter for Computational Fluid-Dynamics Applications
Introini, Carolina; Cammi, Antonio; Lorenzi, Stefano et al

Poster (2018)

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See detailOn the phase space structure of IP3 induced Ca2+ signalling and concepts for predictive modeling
Falcke, Martin; Moein, Mahsa UL; Tilunaite et al

in Chaos: An Interdisciplinary Journal of Nonlinear Science (2018), 28(4), 045115

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See detailLa nature juridique de l’enrôlement
Menetrey, Séverine UL

in Pasicrisie Luxembourgeoise : Recueil Trimestriel de la Jurisprudence Luxembourgeoise (2018)

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See detailTHE PARKINSON’S DISEASE ASSOCIATED PINK1-PARKIN PATHWAY IN PATHOLOGY AND DEVELOPMENT
Jarazo, Javier UL

Doctoral thesis (2018)

Parkinson’s disease (PD) has an aetiology not completely understood. One of the hypothesis in the field is that many neurodegenerative diseases are influenced by developmental disorders. The underlying ... [more ▼]

Parkinson’s disease (PD) has an aetiology not completely understood. One of the hypothesis in the field is that many neurodegenerative diseases are influenced by developmental disorders. The underlying concept is that already during brain development some processes are deregulated producing a higher degree of susceptibility for neurodegeneration during aging. Two hereditary early onset forms of PD are caused by recessive mutations in PTEN-induced putative kinase 1 (PINK1) and Parkin genes that regulate mitochondrial function and morphology, quarantining damaged mitochondria before their degradation as well as triggering the process of mitophagy. Our hypothesis is that alterations of the Pink1-Parkin pathway have an impact in mitochondrial physiology tempering the differentiation ability of neuroepithelial stem cells into dopaminergic neurons. For evaluating this hypothesis we reprogramed patients’ fibroblasts carrying PINK1 mutations, as well as from healthy individuals, to human induced pluripotent stem cells. We developed a streamlined technique of gene editing (FACE) by using the CRISPR/Cas9 system combined with a composite of fluorescent proteins in the donor template for biallelic gene targeting. Isogenic controls were generated using this technique that allowed us to analyze the contribution of corrected patients’ mutations in the cellular defects observed. Human iPSCs were differentiated into a neuroepithelial stem cell state (NESC) from where the cells were further differentiated into neurons. We established different algorithms for pattern recognition and applied them for image analysis of different features such as mitochondrial morphology, proliferation capacity, apoptosis and differentiation. Patient’s derived cells presented an impaired differentiation efficiency into dopaminergic neurons as well as an imbalanced cell renewal that can be linked to the mitochondrial differences. Using 3D cultures, such as microfluidics and organoids, we were able to recapitulate this differentiation impairment in a system that mimics better the context of an in vivo environment. We evaluated the energetic capabilities of the NESCs and the firing activity of differentiated neurons, which also showed a dysregulation in patient cells. We introduced a new system for large-scale analysis of the autophagy and mitophagy pathways by the combination of stably integrated Rosella constructs in different patients’ lines and an image analysis script for classification of the different subcellular structures involved in these pathways activities. This revealed that the basal activity as well as the response against stressors of these pathways are altered in cells derived from patients having different mutations causative of PD. We performed a screen of repurposed drugs as well as of novel compounds to evaluate their impact in this altered developmental transition identifying a potential candidate to be further analysed in an in vivo context. [less ▲]

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See detailMesures d’instruction
Menetrey, Séverine UL

in Jurisclasseur Procédure Civile (2017)

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See detailContinuous gravimetric monitoring as an integrative tool for exploring hydrological processes in the Lomme Karst System (Belgium)
Watlet, A.; Van Camp, M. J.; Poulain, A. et al

Scientific Conference (2016)

Karst systems are highly heterogeneous which makes their hydrology difficult to understand. Geophysical techniques offer non-invasive and integrative methods that help interpreting such systems as a whole ... [more ▼]

Karst systems are highly heterogeneous which makes their hydrology difficult to understand. Geophysical techniques offer non-invasive and integrative methods that help interpreting such systems as a whole. Among these techniques, gravimetry has been increasingly used in the last decade to characterize the hydrological behavior of complex systems, e.g. karst environments or volcanoes. We present a continuous microgravimetric monitoring of 3 years in the karstic area of Rochefort (Belgium), that shows multiple occurrences of caves and karstic features. The gravity record includes measurements of a GWR superconducting gravimeter, a Micro-g LaCoste gPhone and an absolute FG5 gravimeter. Together with meteorological measurements and a surface/in-cave hydrogeological monitoring, we were able to improve the knowledge of hydrological processes. On the one hand, the data allowed identifying seasonal groundwater content changes in the unsaturated zone of the karst area, most likely to be linked to temporary groundwater storage occurring in the most karstified layers closed to the surface. Combined with additional geological information, modelling of the gravity signal based on the vertical potential of the gravitational attraction was then particularly useful to estimate the seasonal recharge leading to the temporary subsurface groundwater storage. On the other hand, the gravity monitoring of flash floods occurring in deeper layers after intense rainfall events informed on the effective porosity gradient of the limestones. Modelling was then helpful to identify the hydrogeological role played by the cave galleries with respect to the hosting limestones during flash floods. These results are also compared with measurements of an in-cave gravimetric monitoring performed with a gPhone spring gravimeter. An Electrical Resistivity Tomography monitoring is also conducted at site and brings additional information useful to verify the interpretation made with the gravimetric monitoring [less ▲]

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