http://hdl.handle.net/10993/134 Search this channel search http://orbilu.uni.lu/simple-search http://hdl.handle.net/10993/41626 Title: Intracellular recording of human cardiac action potentials on market-available multielectrode array platforms <br/> <br/>Author, co-author: Melle, Giovanni; Bruno, Giulia; Maccaferri, Nicolò; Iachetta, Giuseppina; Colistra, Nicolò; Barbaglia, Andrea; Dipalo, Michele; De Angelis, Francesco <br/> <br/>Abstract: High quality attenuated intracellular action potentials from large cell networks can be recorded on multi-electrode arrays by means of 3D vertical nanopillars using electrical pulses. However, most of the techniques require complex 3D nanostructures that prevent the straightforward translation into marketable products and the wide adoption in the scientific community. Moreover, 3D nanostructures are often delicate objects that cannot sustain several harsh use/cleaning cycles. On the contrary, laser optoacoustic poration allows the recording of action potentials on planar nanoporous electrodes made of noble metals. However, these constraints of the electrode material and morphology may also hinder the full exploitation of this methodology. Here, we show that optoacoustic poration is also very effective for porating cells on a large family of MEA electrode configurations, including robust electrodes made of nanoporous titanium nitride or disordered fractal-like gold nanostructures. This enables the recording of high quality cardiac action potentials in combination with optoacoustic poration, providing thus attenuated intracellular recordings on various already commercial devices used by a significant part of the research and industrial communities. http://hdl.handle.net/10993/41608 Title: Optimization ACE inhibition activity in hypertension based on random vector functional link and sine-cosine algorithm <br/> <br/>Author, co-author: Abd Elaziz, Mohammed; Hemedan, Ahmed; Ostaszewski, Marek; Schneider, Reinhard; Lu, Songfeng <br/> <br/>Abstract: Bioactive peptides from protein hydrolysates with antihypertensive properties have a great effect in health, which warrants their pharmaceutical use. Nevertheless, the process of their production may affect their efficacy. In this study, we investigate the inhibitory activities of various hydrolysates on angiotensin-converting enzyme (ACE) in relation to the chemical diversity of corresponding bioactive peptides. This depends on the enzyme specificity and process conditions used for the production of hydrolysates. In order to mitigate the uncontrolled chemical alteration in bioactive peptides, we propose a computational approach using the random vector functional link (RVFL) network based on the sine-cosine algorithm (SCA) to find optimal processing parameters, and to predict the ACE inhibition activity. The SCA is used to determine the optimal configuration of RVFL, improving the prediction performance. The experimental results show that the performance measures of the proposed model are better than the state-of-the-art methods. http://hdl.handle.net/10993/41535 Title: Multicenter Alzheimer's and Parkinson's disease immune biomarker verification study <br/> <br/>Author, co-author: Brosseron, Federic; Schneider, Reinhard <br/> <br/>Abstract: Multiple immunity biomarkers have been suggested as tracers of neuroinflammation in neurodegeneration. This study aimed to verify findings in cerebrospinal fluid (CSF) samples of Alzheimer's disease (AD) and Parkinson's disease (PD) subjects from the network of the European, Innovative Medicines Initiative–funded project AETIONOMY. http://hdl.handle.net/10993/41504 Title: DAISY: A Data Information System for accountability under the General Data Protection Regulation <br/> <br/>Author, co-author: Becker, Regina; Alper, Pinar; Groues, Valentin; Munoz, Sandrine; Jarosz, Yohan; Lebioda, Jacek; Rege, Kavita; Trefois, Christophe; Satagopam, Venkata; Schneider, Reinhard <br/> <br/>Abstract: The new European legislation on data protection, namely, the General Data Protection Regulation (GDPR), has introduced comprehensive requirements for the documentation about the processing of personal data as well as informing the data subjects of its use. GDPR’s accountability principle requires institutions, projects, and data hubs to document their data processings and demonstrate compliance with the GDPR. In response to this requirement, we see the emergence of commercial data-mapping tools, and institutions creating GDPR data register with such tools. One shortcoming of this approach is the genericity of tools, and their process-based model not capturing the project-based, collaborative nature of data processing in biomedical research.We have developed a software tool to allow research institutions to comply with the GDPR accountability requirement and map the sometimes very complex data flows in biomedical research. By analysing the transparency and record-keeping obligations of each GDPR principle, we observe that our tool effectively meets the accountability requirement.The GDPR is bringing data protection to center stage in research data management, necessitating dedicated tools, personnel, and processes. Our tool, DAISY, is tailored specifically for biomedical research and can help institutions in tackling the documentation challenge brought about by the GDPR. DAISY is made available as a free and open source tool on Github. DAISY is actively being used at the Luxembourg Centre for Systems Biomedicine and the ELIXIR-Luxembourg data hub. http://hdl.handle.net/10993/41479 Title: Quantum mechanics of proteins in explicit water: The role of plasmon-like solute-solvent interactions <br/> <br/>Author, co-author: Stoehr, Martin; Tkatchenko, Alexandre <br/> <br/>Abstract: Quantum-mechanical van der Waals dispersion interactions play an essential role in intraprotein and protein-water interactions—the two main factors affecting the structure and dynamics of proteins in water. Typically, these interactions are only treated phenomenologically, via pairwise potential terms in classical force fields. Here, we use an explicit quantum-mechanical approach of density-functional tight-binding combined with the many-body dispersion formalism and demonstrate the relevance of many-body van der Waals forces both to protein energetics and to protein-water interactions. In contrast to commonly used pairwise approaches, many-body effects substantially decrease the relative stability of native states in the absence of water. Upon solvation, the protein-water dispersion interaction counteracts this effect and stabilizes native conformations and transition states. These observations arise from the highly delocalized and collective character of the interactions, suggesting a remarkable persistence of electron correlation through aqueous environments and providing the basis for long-range interaction mechanisms in biomolecular systems. http://hdl.handle.net/10993/41477 Title: The top-down diffusion process of agroecological practices within farmer groups in Bilanga, Burkina Faso: barriers to agroecological knowledge creation? <br/> <br/>Author, co-author: Kapgen, Diane http://hdl.handle.net/10993/41476 Title: Impacts of Agroecology-based Development Programs on Smallholder Farmers’ Livelihoods in Eastern Burkina Faso <br/> <br/>Author, co-author: Kapgen, Diane http://hdl.handle.net/10993/41472 Title: Agroecology in Burkina Faso: A Smallholders' Livelihoods' Catalyst? <br/> <br/>Author, co-author: Kapgen, Diane http://hdl.handle.net/10993/41458 Title: A deep neural network approach to predicting clinical outcomes of neuroblastoma patients <br/> <br/>Author, co-author: Tranchevent, Leon-Charles; Azuaje, Francisco; Rajapakse, Jagath <br/> <br/>Abstract: Background The availability of high-throughput omics datasets from large patient cohorts has allowed the development of methods that aim at predicting patient clinical outcomes, such as survival and disease recurrence. Such methods are also important to better understand the biological mechanisms underlying disease etiology and development, as well as treatment responses. Recently, different predictive models, relying on distinct algorithms (including Support Vector Machines and Random Forests) have been investigated. In this context, deep learning strategies are of special interest due to their demonstrated superior performance over a wide range of problems and datasets. One of the main challenges of such strategies is the “small n large p” problem. Indeed, omics datasets typically consist of small numbers of samples and large numbers of features relative to typical deep learning datasets. Neural networks usually tackle this problem through feature selection or by including additional constraints during the learning process. Methods We propose to tackle this problem with a novel strategy that relies on a graph-based method for feature extraction, coupled with a deep neural network for clinical outcome prediction. The omics data are first represented as graphs whose nodes represent patients, and edges represent correlations between the patients’ omics profiles. Topological features, such as centralities, are then extracted from these graphs for every node. Lastly, these features are used as input to train and test various classifiers. Results We apply this strategy to four neuroblastoma datasets and observe that models based on neural networks are more accurate than state of the art models (DNN: 85%-87%, SVM/RF: 75%-82%). We explore how different parameters and configurations are selected in order to overcome the effects of the small data problem as well as the curse of dimensionality. Conclusions Our results indicate that the deep neural networks capture complex features in the data that help predicting patient clinical outcomes. http://hdl.handle.net/10993/41446 Title: The E6 protein from vaccinia virus is required for the formation of immature virions. <br/> <br/>Author, co-author: Boyd, Olga; Turner, Peter C.; Moyer, Richard W.; Condit, Richard C.; Moussatche, Nissin <br/> <br/>Abstract: An IPTG-inducible mutant in the E6R gene of vaccinia virus was used to study the role of the E6 virion core protein in viral replication. In the absence of the inducer, the mutant exhibited a normal pattern DNA replication, concatemer resolution and late gene expression, but it showed an inhibition of virion structural protein processing it failed to produce infectious particles. Electron microscopic analysis showed that in the absence of IPTG viral morphogenesis was arrested before IV formation: crescents, aberrant or empty IV-like structures, and large aggregated virosomes were observed throughout the cytoplasm. The addition of IPTG to release a 12-h block showed that virus infectious particles could be formed in the absence of de novo DNA synthesis. Our observations show that in the absence of E6 the association of viroplasm with viral membrane crescents is impaired. <br/> <br/>Commentary: Published by Elsevier Inc. http://hdl.handle.net/10993/41445 Title: Temperature-sensitive mutant in the vaccinia virus E6 protein produce virions that are transcriptionally inactive. <br/> <br/>Author, co-author: Boyd, Olga; Strahl, Audra L.; Rodeffer, Carson; Condit, Richard C.; Moussatche, Nissin <br/> <br/>Abstract: The vaccinia virus E6R gene encodes a late protein that is packaged into virion cores. A temperature-sensitive mutant was used to study the role of this protein in viral replicative cycle. Cts52 has a P226L missense mutation in the E6R gene, shows a two-log reduction in plaque formation, but displays normal patterns of gene expression, late protein processing and DNA replication during infection. Mutant virions produced at 40 degrees C were similar in their morphology to wt virions grown at 40 degrees C. The particle to infectivity ratio was 50 times higher in purified Cts52 grown at 40 degrees C when compared to the mutant grown at permissive temperature. In vitro characterization of Cts-52 particles grown at 40 degrees C revealed no differences in protein composition or in DNA content and the mutant virions could bind and enter cells. However, core particles prepared from Cts52 grown at 40 degrees C failed to transcribe in vitro. Our results show that E6 in the virion has either a direct or an indirect role in viral transcription. <br/> <br/>Commentary: Published by Elsevier Inc. http://hdl.handle.net/10993/41444 Title: Nectarine promotes longevity in Drosophila melanogaster. <br/> <br/>Author, co-author: Boyd, Olga; Weng, Peter; Sun, Xiaoping; Alberico, Thomas; Laslo, Mara; Obenland, David M.; Kern, Bradley; Zou, Sige <br/> <br/>Abstract: Fruits containing high antioxidant capacities and other bioactivities are ideal for promoting longevity and health span. However, few fruits are known to improve the survival and health span in animals, let alone the underlying mechanisms. Here we investigate the effects of nectarine, a globally consumed fruit, on life span and health span in Drosophila melanogaster. Wild-type flies were fed standard, dietary restriction (DR), or high-fat diet supplemented with 0-4% nectarine extract. We measured life span, food intake, locomotor activity, fecundity, gene expression changes, and oxidative damage indicated by the level of 4-hydroxynonenal-protein adduct in these flies. We also measured life span, locomotor activity, and oxidative damage in sod1 mutant flies on the standard diet supplemented with 0-4% nectarine. Supplementation with 4% nectarine extended life span, increased fecundity, and decreased expression of some metabolic genes, including a key gluconeogenesis gene, PEPCK, and oxidative stress-response genes, including peroxiredoxins, in female wild-type flies fed the standard, DR, or high-fat diet. Nectarine reduced oxidative damage in wild-type females fed the high-fat diet. Moreover, nectarine improved the survival of and reduced oxidative damage in female sod1 mutant flies. Together, these findings suggest that nectarine promotes longevity and health span partly by modulating glucose metabolism and reducing oxidative damage. <br/> <br/>Commentary: Published by Elsevier Inc. http://hdl.handle.net/10993/41434 Title: Synapse alterations precede neuronal damage and storage pathology in a human cerebral organoid model of CLN3-juvenile neuronal ceroid lipofuscinosis <br/> <br/>Author, co-author: Gomez Giro, Gemma; Arias-Fuenzalida, Jonathan; Jarazo, Javier; Zeuschner, Dagmar; Ali, Muhammad; Possemis, Nina; Bolognin, Silvia; Halder, Rashi; Jäger, Christian; Kuper, Willemijn; van Hasselt, Peter; Zaehres, Holm; del Sol Mesa, Antonio; van der Putten, Herman; Schoeler, Hans; Schwamborn, Jens Christian http://hdl.handle.net/10993/41428 Title: Testing for association between RNA-Seq and high-dimensional data <br/> <br/>Author, co-author: Rauschenberger, Armin; Jonker, Marianne A.; van de Wiel, Mark A.; Menezes, Renée X. <br/> <br/>Abstract: Background: Testing for association between RNA-Seq and other genomic data is challenging due to high variability of the former and high dimensionality of the latter. Results: Using the negative binomial distribution and a random-effects model, we develop an omnibus test that overcomes both difficulties. It may be conceptualised as a test of overall significance in regression analysis, where the response variable is overdispersed and the number of explanatory variables exceeds the sample size. Conclusions: The proposed test can detect genetic and epigenetic alterations that affect gene expression. It can examine complex regulatory mechanisms of gene expression. The R package globalSeq is available from Bioconductor. <br/> <br/>Commentary: https://bioconductor.org/packages/globalSeq/ http://hdl.handle.net/10993/41427 Title: Identification of pathogenic variant enriched regions across genes and gene families <br/> <br/>Author, co-author: Perez-Palma, Eduardo; May, Patrick; Iqbal, Sumaiya; Niestroj, Lisa-Marie; Du, Juanjiangmeng; Heyne, Henrike O.; Castrillon, Jessica A.; O'Donnell-Luna, Anne; Nürnberg, Peter; Palotie, Aarno; Daly, Mark; Lal, Dennis <br/> <br/>Abstract: Missense variant interpretation is challenging. Essential regions for protein function are conserved among gene family members, and genetic variants within these regions are potentially more likely to confer risk to disease. Here, we generated 2,871 gene family protein sequence alignments involving 9,990 genes and performed missense variant burden analyses to identify novel essential protein regions. We mapped 2,219,811 variants from the general population into these alignments and compared their distribution with 76,153 missense variants from patients. With this gene family approach, we identified 465 regions enriched for patient variants spanning 41,463 amino acids in 1,252 genes. As a comparison, testing the same genes individually we identified less patient variant enriched regions involving only 2,639 amino acids and 215 genes. Next, we selected de novo variants from 6,753 patients with neurodevelopmental disorders and 1,911 unaffected siblings, and observed an 8.33-fold enrichment of patient variants in our identified regions (95% C.I.=3.90-Inf, p-value = 2.72x10-11). Using the complete ClinVar variant set, we found that missense variants inside the identified regions are 106-fold more likely to be classified as pathogenic in comparison to benign classification (OR = 106.15, 95% C.I = 70.66-Inf, p-value < 2.2 x 10-16). All pathogenic variant enriched regions (PERs) identified are available online through the “PER viewer” a user-friendly online platform for interactive data mining, visualization and download. In summary, our gene family burden analysis approach identified novel pathogenic variant enriched regions in protein sequences. This annotation can empower variant interpretation. http://hdl.handle.net/10993/41426 Title: PDE6D Inhibitors with a New Design Principle Selectively Block K‑Ras Activity <br/> <br/>Author, co-author: Siddiqui, Farid A.; Alam, Catharina; Rosenqvist, Petja; Ora, Mikko; Sabt, Ahmed; Manoharan, Ganesh Babu; Bindu, Lakshman; Okutachi, Sunday Ojochegbe; Catillon, Marie; Taylor, Troy; Abdelhafez, Omaima M.; Lönnberg, Harri; Stephen, Andrew G.; Papageorgiou, Anastassios C.; Virta, Pasi; Abankwa, Daniel http://hdl.handle.net/10993/41421 Title: Synapse alterations precede neuronal damage and storage pathology in a human cerebral organoid model of CLN3-juvenile neuronal ceroid lipofuscinosis <br/> <br/>Author, co-author: Ali, Muhammad http://hdl.handle.net/10993/41418 Title: A Statistical View on Calcium Oscillations. <br/> <br/>Author, co-author: Powell, Jake; Falcke, Martin; Skupin, Alexander; Bellamy, Tomas C.; Kypraios, Theodore; Thul, Rüdiger <br/> <br/>Abstract: Transient rises and falls of the intracellular calcium concentration have been observed in numerous cell types and under a plethora of conditions. There is now a growing body of evidence that these whole-cell calcium oscillations are stochastic, which poses a significant challenge for modelling. In this review, we take a closer look at recently developed statistical approaches to calcium oscillations. These models describe the timing of whole-cell calcium spikes, yet their parametrisations reflect subcellular processes. We show how non-stationary calcium spike sequences, which e.g. occur during slow depletion of intracellular calcium stores or in the presence of time-dependent stimulation, can be analysed with the help of so-called intensity functions. By utilising Bayesian concepts, we demonstrate how values of key parameters of the statistical model can be inferred from single cell calcium spike sequences and illustrate what information whole-cell statistical models can provide about the subcellular mechanistic processes that drive calcium oscillations. In particular, we find that the interspike interval distribution of HEK293 cells under constant stimulation is captured by a Gamma distribution. http://hdl.handle.net/10993/41413 Title: SigHotSpotter: scRNA-seq-based computational tool to control cell subpopulation phenotypes for cellular rejuvenation strategies. <br/> <br/>Author, co-author: Ravichandran, Srikanth; Hartmann, Andras; Del Sol, Antonio <br/> <br/>Abstract: SUMMARY: Single-cell RNA-sequencing is increasingly employed to characterize disease or ageing cell subpopulation phenotypes. Despite exponential increase in data generation, systematic identification of key regulatory factors for controlling cellular phenotype to enable cell rejuvenation in disease or ageing remains a challenge. Here, we present SigHotSpotter, a computational tool to predict hotspots of signaling pathways responsible for the stable maintenance of cell subpopulation phenotypes, by integrating signaling and transcriptional networks. Targeted perturbation of these signaling hotspots can enable precise control of cell subpopulation phenotypes. SigHotSpotter correctly predicts the signaling hotspots with known experimental validations in different cellular systems. The tool is simple, user-friendly and is available as web-server or as stand-alone software. We believe SigHotSpotter will serve as a general purpose tool for the systematic prediction of signaling hotspots based on single-cell RNA-seq data, and potentiate novel cell rejuvenation strategies in the context of disease and ageing. AVAILABILITY AND IMPLEMENTATION: SigHotSpotter is at https://SigHotSpotter.lcsb.uni.lu as a web tool. Source code, example datasets and other information are available at https://gitlab.com/srikanth.ravichandran/sighotspotter. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. <br/> <br/>Commentary: (c) The Author(s) 2019. Published by Oxford University Press. http://hdl.handle.net/10993/41403 Title: Mitochondrial morphology provides a mechanism for energy buffering at synapses. <br/> <br/>Author, co-author: Garcia, Guadalupe Clara; Bartol, Thomas M.; Phan, Sébastien; Bushong, Eric A.; Perkins, Guy; Sejnowski, Terrence J.; Ellisman, Mark H.; Skupin, Alexander <br/> <br/>Abstract: Mitochondria as the main energy suppliers of eukaryotic cells are highly dynamic organelles that fuse, divide and are transported along the cytoskeleton to ensure cellular energy homeostasis. While these processes are well established, substantial evidence indicates that the internal structure is also highly variable in dependence on metabolic conditions. However, a quantitative mechanistic understanding of how mitochondrial morphology affects energetic states is still elusive. To address this question, we here present an agent-based multiscale model that integrates three-dimensional morphologies from electron microscopy tomography with the molecular dynamics of the main ATP producing components. We apply our modeling approach to mitochondria at the synapse which is the largest energy consumer within the brain. Interestingly, comparing the spatiotemporal simulations with a corresponding space-independent approach, we find minor spatial effects when the system relaxes toward equilibrium but a qualitative difference in fluctuating environments. These results suggest that internal mitochondrial morphology is not only optimized for ATP production but also provides a mechanism for energy buffering and may represent a mechanism for cellular robustness. IM