| 1. |
- Rosendal, Ebba, et al.
(författare)
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Serine Protease Inhibitors Restrict Host Susceptibility to SARS-CoV-2 Infections
- 2022
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Ingår i: mBio. - : American Society for Microbiology. - 2161-2129 .- 2150-7511. ; 13:3
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Tidskriftsartikel (refereegranskat)abstract
- The coronavirus disease 2019, COVID-19, is a complex disease with a wide range of symptoms from asymptomatic infections to severe acute respiratory syndrome with lethal outcome. Individual factors such as age, sex, and comorbidities increase the risk for severe infections, but other aspects, such as genetic variations, are also likely to affect the susceptibility to SARS-CoV-2 infection and disease severity. Here, we used a human 3D lung cell model based on primary cells derived from multiple donors to identity host factors that regulate SARS-CoV-2 infection. With a transcriptomics-based approach, we found that less susceptible donors show a higher expression level of serine protease inhibitors SERPINA1, SERPINE1, and SERPINE2, identifying variation in cellular serpin levels as restricting host factors for SARS-CoV-2 infection. We pinpoint their antiviral mechanism of action to inhibition of the cellular serine protease, TMPRSS2, thereby preventing cleavage of the viral spike protein and TMPRSS2-mediated entry into the target cells. By means of single-cell RNA sequencing, we further locate the expression of the individual serpins to basal, ciliated, club, and goblet cells. Our results add to the importance of genetic variations as determinants for SARS-CoV-2 susceptibility and suggest that genetic deficiencies of cellular serpins might represent risk factors for severe COVID-19. Our study further highlights TMPRSS2 as a promising target for antiviral intervention and opens the door for the usage of locally administered serpins as a treatment against COVID-19.
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| 2. |
- Alinaghi, Masoumeh, et al.
(författare)
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Hierarchical time-series analysis of dynamic bioprocess systems
- 2022
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Ingår i: Biotechnology Journal. - : John Wiley & Sons. - 1860-6768 .- 1860-7314. ; 17:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Monoclonal antibodies (mAbs) are leading types of ‘blockbuster’ biotherapeutics worldwide; they have been successfully used to treat various cancers and chronic inflammatory and autoimmune diseases. Biotherapeutics process development and manufacturing are complicated due to lack of understanding the factors that impact cell productivity and product quality attributes. Understanding complex interactions between cells, media, and process parameters on the molecular level is essential to bring biomanufacturing to the next level. This can be achieved by analyzing cell culture metabolic levels connected to vital process parameters like viable cell density (VCD). However, VCD and metabolic profiles are dynamic parameters and inherently correlated with time, leading to a significant correlation without actual causality. Many time-series methods deal with such issues. However, with metabolic profiling, the number of measured variables vastly exceeds the number of experiments, making most of existing methods ill-suited and hard to interpret. Methods and MajorResults: Here we propose an alternative workflow using hierarchical dimension reduction to visualize and interpret the relation between evolution of metabolic profiles and dynamic process parameters. The first step of proposed method is focused on finding predictive relation between metabolic profiles and process parameter at all time points using OPLS regression. For each time point, the p(corr) obtained from OPLS model is considered as a differential metabogram and is further assessed using principal components analysis (PCA).Conclusions: Compared to traditional batch modeling, applying proposed methodology on metabolic data from Chinese Hamster Ovary (CHO) antibody production characterized the dynamic relation between metabolic profiles and critical process parameters.
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| 3. |
- Asim, Muhammad Nabeel, et al.
(författare)
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A robust and precise convnet for small non-coding rna classification (rpc-snrc)
- 2021
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Ingår i: IEEE Access. - 2169-3536. ; 9, s. 19379-19390
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Tidskriftsartikel (refereegranskat)abstract
- Small non-coding RNAs (ncRNAs) are attracting increasing attention as they are now considered potentially valuable resources in the development of new drugs intended to cure several human diseases. A prerequisite for the development of drugs targeting ncRNAs or the related pathways is the identification and correct classification of such ncRNAs. State-of-the-art small ncRNA classification methodologies use secondary structural features as input. However, such feature extraction approaches only take global characteristics into account and completely ignore co-relative effects of local structures. Furthermore, secondary structure based approaches incorporate high dimensional feature space which is computationally expensive. The present paper proposes a novel Robust and Precise ConvNet (RPC-snRC) methodology which classifies small ncRNAs into relevant families by utilizing their primary sequence. RPC-snRC methodology learns hierarchical representation of features by utilizing positioning and information on the occurrence of nucleotides. To avoid exploding and vanishing gradient problems, we use an approach similar to DenseNet in which gradient can flow straight from subsequent layers to previous layers. In order to assess the effectiveness of deeper architectures for small ncRNA classification, we also adapted two ResNet architectures having a different number of layers. Experimental results on a benchmark small ncRNA dataset show that the proposed methodology does not only outperform existing small ncRNA classification approaches with a significant performance margin of 10% but it also gives better results than adapted ResNet architectures. To reproduce the results Source code and data set is available at https://github.com/muas16/small-non-coding-RNA-classification.
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| 4. |
- Asim, Muhammad Nabeel, et al.
(författare)
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BoT-Net : a lightweight bag of tricks-based neural network for efficient LncRNA–miRNA interaction prediction
- 2022
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Ingår i: Interdisciplinary Sciences: Computational Life Sciences. - : Springer. - 1913-2751 .- 1867-1462. ; 14:4, s. 841-862
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Tidskriftsartikel (refereegranskat)abstract
- Background and objective: Interactions of long non-coding ribonucleic acids (lncRNAs) with micro-ribonucleic acids (miRNAs) play an essential role in gene regulation, cellular metabolic, and pathological processes. Existing purely sequence based computational approaches lack robustness and efficiency mainly due to the high length variability of lncRNA sequences. Hence, the prime focus of the current study is to find optimal length trade-offs between highly flexible length lncRNA sequences.Method: The paper at hand performs in-depth exploration of diverse copy padding, sequence truncation approaches, and presents a novel idea of utilizing only subregions of lncRNA sequences to generate fixed-length lncRNA sequences. Furthermore, it presents a novel bag of tricks-based deep learning approach “Bot-Net” which leverages a single layer long-short-term memory network regularized through DropConnect to capture higher order residue dependencies, pooling to retain most salient features, normalization to prevent exploding and vanishing gradient issues, learning rate decay, and dropout to regularize precise neural network for lncRNA–miRNA interaction prediction.Results: BoT-Net outperforms the state-of-the-art lncRNA–miRNA interaction prediction approach by 2%, 8%, and 4% in terms of accuracy, specificity, and matthews correlation coefficient. Furthermore, a case study analysis indicates that BoT-Net also outperforms state-of-the-art lncRNA–protein interaction predictor on a benchmark dataset by accuracy of 10%, sensitivity of 19%, specificity of 6%, precision of 14%, and matthews correlation coefficient of 26%.Conclusion: In the benchmark lncRNA–miRNA interaction prediction dataset, the length of the lncRNA sequence varies from 213 residues to 22,743 residues and in the benchmark lncRNA–protein interaction prediction dataset, lncRNA sequences vary from 15 residues to 1504 residues. For such highly flexible length sequences, fixed length generation using copy padding introduces a significant level of bias which makes a large number of lncRNA sequences very much identical to each other and eventually derail classifier generalizeability. Empirical evaluation reveals that within 50 residues of only the starting region of long lncRNA sequences, a highly informative distribution for lncRNA–miRNA interaction prediction is contained, a crucial finding exploited by the proposed BoT-Net approach to optimize the lncRNA fixed length generation process.
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| 5. |
- Asim, Muhammad Nabeel, et al.
(författare)
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EL-RMLocNet : An explainable LSTM network for RNA-associated multi-compartment localization prediction
- 2022
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Ingår i: Computational and Structural Biotechnology Journal. - : Elsevier. - 2001-0370. ; 20, s. 3986-4002
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Tidskriftsartikel (refereegranskat)abstract
- Subcellular localization of Ribonucleic Acid (RNA) molecules provide significant insights into the functionality of RNAs and helps to explore their association with various diseases. Predominantly developed single-compartment localization predictors (SCLPs) lack to demystify RNA association with diverse biochemical and pathological processes mainly happen through RNA co-localization in multiple compartments. Limited multi-compartment localization predictors (MCLPs) manage to produce decent performance only for target RNA class of particular sub-type. Further, existing computational approaches have limited practical significance and potential to optimize therapeutics due to the poor degree of model explainability. The paper in hand presents an explainable Long Short-Term Memory (LSTM) network “EL-RMLocNet”, predictive performance and interpretability of which are optimized using a novel GeneticSeq2Vec statistical representation learning scheme and attention mechanism for accurate multi-compartment localization prediction of different RNAs solely using raw RNA sequences. GeneticSeq2Vec generates optimized statistical vectors of raw RNA sequences by capturing short and long range relations of nucleotide k-mers. Using sequence vectors generated by GeneticSeq2Vec scheme, Long Short Term Memory layers extract most informative features, weighting of which on the basis of discriminative potential for accurate multi-compartment localization prediction is performed using attention layer. Through reverse engineering, weights of statistical feature space are mapped to nucleotide k-mers patterns to make multi-compartment localization prediction decision making transparent and explainable for different RNA classes and species. Empirical evaluation indicates that EL-RMLocNet outperforms state-of-the-art predictor for subcellular localization prediction of 4 different RNA classes by an average accuracy figure of 8% for Homo Sapiens species and 6% for Mus Musculus species. EL-RMLocNet is freely available as a web server at (https://sds_genetic_analysis.opendfki.de/subcellular_loc/).
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| 6. |
- Asim, Muhammad Nabeel, et al.
(författare)
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L2S-MirLoc : A Lightweight Two Stage MiRNA Sub-Cellular Localization Prediction Framework
- 2021
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Ingår i: Proceedings of the International Joint Conference on Neural Networks. - : IEEE. - 9780738133669 - 9781665439008 - 9781665445979
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Konferensbidrag (refereegranskat)abstract
- A comprehensive understanding of miRNA sub-cellular localization may leads towards better understanding of physiological processes and support the fixation of diverse irregularities present in a variety of organisms. To date, diverse computational methodologies have been proposed to automatically infer sub-cellular localization of miR-NAs solely using sequence information, however, existing approaches lack in performance. Considering the success of data transformation approaches in Natural Language Processing which primarily transform multi-label classification problem into multi-class classification problem, here, we introduce three different data transformation approaches namely binary relevance, label power set, and classifier chains. Using data transformation approaches, at 1st stage, multi-label miRNA sub-cellular localization problem is transformed into multi-class problem. Then, at 2nd stage, 3 different machine learning classifiers are used to estimate which classifier performs better with what data transformation approach for hand on task. Empirical evaluation on independent test set indicates that L2S-MirLoc selected combination based on binary relevance and deep random forest outperforms state-of-the-art performance values by significant margin.
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| 7. |
- Asim, Muhammad Nabeel, et al.
(författare)
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MirLocPredictor : A ConvNet-Based Multi-Label MicroRNA Subcellular Localization Predictor by Incorporating k-Mer Positional Information
- 2020
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Ingår i: Genes. - : MDPI. - 2073-4425 .- 2073-4425. ; 11:12
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs (miRNA) are small noncoding RNA sequences consisting of about 22 nucleotides that are involved in the regulation of almost 60% of mammalian genes. Presently, there are very limited approaches for the visualization of miRNA locations present inside cells to support the elucidation of pathways and mechanisms behind miRNA function, transport, and biogenesis. MIRLocator, a state-of-the-art tool for the prediction of subcellular localization of miRNAs makes use of a sequence-to-sequence model along with pretrained k-mer embeddings. Existing pretrained k-mer embedding generation methodologies focus on the extraction of semantics of k-mers. However, in RNA sequences, positional information of nucleotides is more important because distinct positions of the four nucleotides define the function of an RNA molecule. Considering the importance of the nucleotide position, we propose a novel approach (kmerPR2vec) which is a fusion of positional information of k-mers with randomly initialized neural k-mer embeddings. In contrast to existing k-mer-based representation, the proposed kmerPR2vec representation is much more rich in terms of semantic information and has more discriminative power. Using novel kmerPR2vec representation, we further present an end-to-end system (MirLocPredictor) which couples the discriminative power of kmerPR2vec with Convolutional Neural Networks (CNNs) for miRNA subcellular location prediction. The effectiveness of the proposed kmerPR2vec approach is evaluated with deep learning-based topologies (i.e., Convolutional Neural Networks (CNN) and Recurrent Neural Network (RNN)) and by using 9 different evaluation measures. Analysis of the results reveals that MirLocPredictor outperform state-of-the-art methods with a significant margin of 18% and 19% in terms of precision and recall.
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| 8. |
- Blaise, Benjamin J., et al.
(författare)
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Statistical analysis in metabolic phenotyping
- 2021
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Ingår i: Nature Protocols. - : Nature Publishing Group. - 1754-2189 .- 1750-2799. ; 16:9, s. 4299-4326
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Forskningsöversikt (refereegranskat)abstract
- Metabolic phenotyping is an important tool in translational biomedical research. The advanced analytical technologies commonly used for phenotyping, including mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy, generate complex data requiring tailored statistical analysis methods. Detailed protocols have been published for data acquisition by liquid NMR, solid-state NMR, ultra-performance liquid chromatography (LC-)MS and gas chromatography (GC-)MS on biofluids or tissues and their preprocessing. Here we propose an efficient protocol (guidelines and software) for statistical analysis of metabolic data generated by these methods. Code for all steps is provided, and no prior coding skill is necessary. We offer efficient solutions for the different steps required within the complete phenotyping data analytics workflow: scaling, normalization, outlier detection, multivariate analysis to explore and model study-related effects, selection of candidate biomarkers, validation, multiple testing correction and performance evaluation of statistical models. We also provide a statistical power calculation algorithm and safeguards to ensure robust and meaningful experimental designs that deliver reliable results. We exemplify the protocol with a two-group classification study and data from an epidemiological cohort; however, the protocol can be easily modified to cover a wider range of experimental designs or incorporate different modeling approaches. This protocol describes a minimal set of analyses needed to rigorously investigate typical datasets encountered in metabolic phenotyping.
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| 9. |
- de Sousa, Pedro F. M., 1977-
(författare)
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Chemometrics : Unravelling information from complex data generated by modern instruments
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chemometrics is a discipline dedicated to solving problems arising from complicated analytical systems, combining statistics, mathematics, and computational programming languages.This thesis is based on the work developed in four scientific projects published as papers in scientific journals. The studies developed in these projects have been essentially focused on a data analysis perspective, interpreting complicated data by means of algorithms, employing chemometrical methodologies. Several chemometrical approaches, based on multivariate data analysis and signal processing algorithms have been studied and employed in each project. Most of the data analysis problems studied these projects are related to liquid chromatography hyphenated to mass spectrometry systems, including tandem mass spectrometry. One of the projects has been related to spectrophotometric data.Chromatographic peak shifts have been attributed to lack of control of the nominal chromatographic parameters. The purpose of the work presented in Paper I was to study retention time data, obtained experimentally by provoking peak shifts with controlled effects, to demonstrate that there are patterns associated with such changing factors affecting chromatographic processes. PCR (Principal Component Regression) models were calculated for each compound (98 compounds), using the retention time data of each compound as responses (y), and the retention time data of the remaining compounds as regressors (X). The results demonstrate that the peak shifts of each compound across samples are correlated with the peak shifts of the other compounds in the chromatographic data. This work confirmed a previous work, where an algorithm was developed to improve alignment of peaks in large number of complex samples, based on peak shift patterns.Partial Least Squares (PLS) is one of the mostly used chemometrics techniques. In the work presented in Paper II, a previously reported modified PLS algorithm was studied. This algorithm was developed with the purpose of not generating overfitting models with increasing noise in X, which happens with the classical PLS. However, the results in less-noisy data were not as good as the classical PLS. From this study, we have developed another modified algorithm that does not overfit with increasing noise in X, and it converges with the solutions of the classical PLS in less-noisy data.DNA adductomics is a recent field in omics that studies modifications in the DNA. The goal of the project in Paper III was to develop a program with a graphical interface to interpret LC-MS/MS using a data independent acquisition method, to identify adducts in DNA nucleosides. The results were compared with those performed manually. The program detected over 150 potential adducts whereas manually, in a previous work, only about 25 were found. This program can detect adducts automatically in a matter of seconds.Cancer has been associated with processes that are related to exposure to pollutants and the consumption of certain food products. This process has been related to electrophilic compounds that react with DNA (adducts). When DNA modifications occur, often defense mechanisms in the cell are triggered often leading to the rupture of the cell. Fragments of DNA (micronuclei) are then roaming in the blood stream. In this work (Paper IV), electrophilic additions to hemoglobin (adducts) and the expression of micronuclei in blood samples from 50 children were studied. One of the goals of the project was to find correlations between the adducts in hemoglobin and the expression of micronuclei. PLS was used to model the data. However, the results were not conclusive (R2 = 0.60), i.e., there may be some trends, but there are other variables not modelled that may influence the variance in expression of micronuclei.
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| 10. |
- Edlund, Christoffer, et al.
(författare)
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LIVECell : a large-scale dataset for label-free live cell segmentation
- 2021
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Ingår i: Nature Methods. - : Nature Publishing Group. - 1548-7091 .- 1548-7105. ; 18:9, s. 1038-1045
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Light microscopy combined with well-established protocols of two-dimensional cell culture facilitates high-throughput quantitative imaging to study biological phenomena. Accurate segmentation of individual cells in images enables exploration of complex biological questions, but can require sophisticated imaging processing pipelines in cases of low contrast and high object density. Deep learning-based methods are considered state-of-the-art for image segmentation but typically require vast amounts of annotated data, for which there is no suitable resource available in the field of label-free cellular imaging. Here, we present LIVECell, a large, high-quality, manually annotated and expert-validated dataset of phase-contrast images, consisting of over 1.6 million cells from a diverse set of cell morphologies and culture densities. To further demonstrate its use, we train convolutional neural network-based models using LIVECell and evaluate model segmentation accuracy with a proposed a suite of benchmarks.
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