129 research outputs found

    Proteomic Fingerprint of Lung Fibrosis Progression and Response to Therapy in Bleomycin-Induced Mouse Model

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    Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by the aberrant accumulation of extracellular matrix in the lungs. nintedanib is one of the two FDA-approved drugs for IPF treatment; however, the exact pathophysiological mechanisms of fibrosis progression and response to therapy are still poorly understood. In this work, the molecular fingerprint of fibrosis progression and response to nintedanib treatment have been investigated by mass spectrometry-based bottom-up proteomics in paraffin-embedded lung tissues from bleomycin-induced (BLM) pulmonary fibrosis mice. Our proteomics results unveiled that (i) samples clustered depending on the tissue fibrotic grade (mild, moderate, and severe) and not on the time course after BLM treatment; (ii) the dysregulation of different pathways involved in fibrosis progression such as the complement coagulation cascades, advanced glycation end products (AGEs) and their receptors (RAGEs) signaling, the extracellular matrix-receptor interaction, the regulation of actin cytoskeleton, and ribosomes; (iii) Coronin 1A (Coro1a) as the protein with the highest correlation when evaluating the progression of fibrosis, with an increased expression from mild to severe fibrosis; and (iv) a total of 10 differentially expressed proteins (padj-value ≤ 0.05 and Fold change ≤-1.5 or ≥1.5), whose abundance varied in the base of the severity of fibrosis (mild and moderate), were modulated by the antifibrotic treatment with nintedanib, reverting their trend. Notably, nintedanib significantly restored lactate dehydrogenase B (Ldhb) expression but not lactate dehydrogenase A (Ldha). Notwithstanding the need for further investigations to validate the roles of both Coro1a and Ldhb, our findings provide an extensive proteomic characterization with a strong relationship with histomorphometric measurements. These results unveil some biological processes in pulmonary fibrosis and drug-mediated fibrosis therapy

    Applying neural networks for improving the MEG inverse solution

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    Magnetoencephalography (MEG) and electroencephalography (EEG) are appealing non-invasive methods for recording brain activity with high temporal resolution. However, locating the brain source currents from recordings picked up by the sensors on the scalp introduces an ill-posed inverse problem. The MEG inverse problem one of the most difficult inverse problems in medical imaging. The current standard in approximating the MEG inverse problem is to use multiple distributed inverse solutions – namely dSPM, sLORETA and L2 MNE – to estimate the source current distribution in the brain. This thesis investigates if these inverse solutions can be "post-processed" by a neural network to provide improved accuracy on source locations. Recently, deep neural networks have been used to approximate other ill-posed inverse medical imaging problems with accuracy comparable to current state-of- the-art inverse reconstruction algorithms. Neural networks are powerful tools for approximating problems with limited prior knowledge or problems that require high levels of abstraction. In this thesis a special case of a deep convolutional network, the U-Net, is applied to approximate the MEG inverse problem using the standard inverse solutions (dSPM, sLORETA and L2 MNE) as inputs. The U-Net is capable of learning non-linear relationships between the inputs and producing predictions about the site of single-dipole activation with higher accuracy than the L2 minimum-norm based inverse solutions with the following resolution metrics: dipole localization error (DLE), spatial dispersion (SD) and overall amplitude (OA). The U-Net model is stable and performs better in aforesaid resolution metrics than the inverse solutions with multi-dipole data previously unseen by the U-Net

    A single-cell transcriptomic atlas of the developing chicken limb

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    Through precise implementation of distinct cell type specification programs, differentially regulated in both space and time, complex patterns emerge during organogenesis. Thanks to its easy experimental accessibility, the developing chicken limb has long served as a paradigm to study vertebrate pattern formation. Through decades' worth of research, we now have a firm grasp on the molecular mechanisms driving limb formation at the tissue-level. However, to elucidate the dynamic interplay between transcriptional cell type specification programs and pattern formation at its relevant cellular scale, we lack appropriately resolved molecular data at the genome-wide level. Here, making use of droplet-based single-cell RNA-sequencing, we catalogue the developmental emergence of distinct tissue types and their transcriptome dynamics in the distal chicken limb, the so-called autopod, at cellular resolution.; Using single-cell RNA-sequencing technology, we sequenced a total of 17,628 cells coming from three key developmental stages of chicken autopod patterning. Overall, we identified 23 cell populations with distinct transcriptional profiles. Amongst them were small, albeit essential populations like the apical ectodermal ridge, demonstrating the ability to detect even rare cell types. Moreover, we uncovered the existence of molecularly distinct sub-populations within previously defined compartments of the developing limb, some of which have important signaling functions during autopod pattern formation. Finally, we inferred gene co-expression modules that coincide with distinct tissue types across developmental time, and used them to track patterning-relevant cell populations of the forming digits.; We provide a comprehensive functional genomics resource to study the molecular effectors of chicken limb patterning at cellular resolution. Our single-cell transcriptomic atlas captures all major cell populations of the developing autopod, and highlights the transcriptional complexity in many of its components. Finally, integrating our data-set with other single-cell transcriptomics resources will enable researchers to assess molecular similarities in orthologous cell types across the major tetrapod clades, and provide an extensive candidate gene list to functionally test cell-type-specific drivers of limb morphological diversification

    Towards AI-Assisted Disease Diagnosis: Learning Deep Feature Representations for Medical Image Analysis

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    Artificial Intelligence (AI) has impacted our lives in many meaningful ways. For our research, we focus on improving disease diagnosis systems by analyzing medical images using AI, specifically deep learning technologies. The recent advances in deep learning technologies are leading to enhanced performance for medical image analysis and computer-aided disease diagnosis. In this dissertation, we explore a major research area in medical image analysis - Image classification. Image classification is the process to assign an image a label from a fixed set of categories. For our research, we focus on the problem of Alzheimer\u27s Disease (AD) diagnosis from 3D structural Magnetic Resonance Imaging (sMRI) and Positron Emission Tomography (PET) brain scans. Alzheimer\u27s Disease is a severe neurological disorder. In this dissertation, we address challenges related to Alzheimer\u27s Disease diagnosis and propose several models for improved diagnosis. We focus on analyzing the 3D Structural MRI (sMRI) and Positron Emission Tomography (PET) brain scans to identify the current stage of Alzheimer\u27s Disease: Normal Controls (CN), Mild Cognitive Impairment (MCI), and Alzheimer\u27s Disease (AD). This dissertation demonstrates ways to improve the performance of a Convolutional Neural Network (CNN) for Alzheimer\u27s Disease diagnosis. Besides, we present approaches to solve the class-imbalance problem and improving classification performance with limited training data for medical image analysis. To understand the decision of the CNN, we present methods to visualize the behavior of a CNN model for disease diagnosis. As a case study, we analyzed brain PET scans of AD and CN patients to see how CNN discriminates among data samples of different classes. Additionally, this dissertation proposes a novel approach to generate synthetic medical images using Generative Adversarial Networks (GANs). Working with the limited dataset and small amount of annotated samples makes it difficult to develop a robust automated disease diagnosis model. Our proposed model can solve such issue and generate brain MRI and PET images for three different stages of Alzheimer\u27s Disease - Normal Control (CN), Mild Cognitive Impairment (MCI), and Alzheimer\u27s Disease (AD). Our proposed approach can be generalized to create synthetic data for other medical image analysis problems and help to develop better disease diagnosis model

    Addressing subjectivity in the classification of palaeoenvironmental remains with supervised deep learning convolutional neural networks

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    Archaeological object identifications have been traditionally undertaken through a comparative methodology where each artefact is identified through a subjective, interpretative act by a professional. Regarding palaeoenvironmental remains, this comparative methodology is given boundaries by using reference materials and codified sets of rules, but subjectivity is nevertheless present. The problem with this traditional archaeological methodology is that higher level of subjectivity in the identification of artefacts leads to inaccuracies, which then increases the potential for Type I and Type II errors in the testing of hypotheses. Reducing the subjectivity of archaeological identifications would improve the statistical power of archaeological analyses, which would subsequently lead to more impactful research. In this thesis, it is shown that the level of subjectivity in palaeoenvironmental research can be reduced by applying deep learning convolutional neural networks within an image recognition framework. The primary aim of the presented research is therefore to further the on-going paradigm shift in archaeology towards model-based object identifications, particularly within the realm of palaeoenvironmental remains. Although this thesis focuses on the identification of pollen grains and animal bones, with the latter being restricted to the astragalus of sheep and goats, there are wider implications for archaeology as these methods can easily be extended beyond pollen and animal remains. The previously published POLEN23E dataset is used as the pilot study of applying deep learning in pollen grain classification. In contrast, an image dataset of modern bones was compiled for the classification of sheep and goat astragali due to a complete lack of available bone image datasets and a double blind study with inexperienced and experienced zooarchaeologists was performed to have a benchmark to which image recognition models can be compared. In both classification tasks, the presented models outperform all previous formal modelling methods and only the best human analysts match the performance of the deep learning model in the sheep and goat astragalus separation task. Throughout the thesis, there is a specific focus on increasing trust in the models through the visualization of the models’ decision making and avenues of improvements to Grad-CAM are explored. This thesis makes an explicit case for the phasing out of the comparative methods in favour of a formal modelling framework within archaeology, especially in palaeoenvironmental object identification

    Statistical analysis of high-dimensional biomedical data: a gentle introduction to analytical goals, common approaches and challenges

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    International audienceBackground: In high-dimensional data (HDD) settings, the number of variables associated with each observation is very large. Prominent examples of HDD in biomedical research include omics data with a large number of variables such as many measurements across the genome, proteome, or metabolome, as well as electronic health records data that have large numbers of variables recorded for each patient. The statistical analysis of such data requires knowledge and experience, sometimes of complex methods adapted to the respective research questions. Methods: Advances in statistical methodology and machine learning methods offer new opportunities for innovative analyses of HDD, but at the same time require a deeper understanding of some fundamental statistical concepts. Topic group TG9 “High-dimensional data” of the STRATOS (STRengthening Analytical Thinking for Observational Studies) initiative provides guidance for the analysis of observational studies, addressing particular statistical challenges and opportunities for the analysis of studies involving HDD. In this overview, we discuss key aspects of HDD analysis to provide a gentle introduction for non-statisticians and for classically trained statisticians with little experience specific to HDD. Results: The paper is organized with respect to subtopics that are most relevant for the analysis of HDD, in particular initial data analysis, exploratory data analysis, multiple testing, and prediction. For each subtopic, main analytical goals in HDD settings are outlined. For each of these goals, basic explanations for some commonly used analysis methods are provided. Situations are identified where traditional statistical methods cannot, or should not, be used in the HDD setting, or where adequate analytic tools are still lacking. Many key references are provided. Conclusions: This review aims to provide a solid statistical foundation for researchers, including statisticians and non-statisticians, who are new to research with HDD or simply want to better evaluate and understand the results of HDD analyses

    Evaluating and Interpreting Deep Convolutional Neural Networks via Non-negative Matrix Factorization

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    With ever greater computational resources and more accessible software, deep neural networks have become ubiquitous across industry and academia. Their remarkable ability to generalize to new samples defies the conventional view, which holds that complex, over-parameterized networks would be prone to overfitting. This apparent discrepancy is exacerbated by our inability to inspect and interpret the high-dimensional, non-linear, latent representations they learn, which has led many to refer to neural networks as ``black-boxes''. The Law of Parsimony states that ``simpler solutions are more likely to be correct than complex ones''. Since they perform quite well in practice, a natural question to ask, then, is in what way are neural networks simple? We propose that compression is the answer. Since good generalization requires invariance to irrelevant variations in the input, it is necessary for a network to discard this irrelevant information. As a result, semantically similar samples are mapped to similar representations in neural network deep feature space, where they form simple, low-dimensional structures. Conversely, a network that overfits relies on memorizing individual samples. Such a network cannot discard information as easily. In this thesis we characterize the difference between such networks using the non-negative rank of activation matrices. Relying on the non-negativity of rectified-linear units, the non-negative rank is the smallest number that admits an exact non-negative matrix factorization. We derive an upper bound on the amount of memorization in terms of the non-negative rank, and show it is a natural complexity measure for rectified-linear units. With a focus on deep convolutional neural networks trained to perform object recognition, we show that the two non-negative factors derived from deep network layers decompose the information held therein in an interpretable way. The first of these factors provides heatmaps which highlight similarly encoded regions within an input image or image set. We find that these networks learn to detect semantic parts and form a hierarchy, such that parts are further broken down into sub-parts. We quantitatively evaluate the semantic quality of these heatmaps by using them to perform semantic co-segmentation and co-localization. In spite of the convolutional network we use being trained solely with image-level labels, we achieve results comparable or better than domain-specific state-of-the-art methods for these tasks. The second non-negative factor provides a bag-of-concepts representation for an image or image set. We use this representation to derive global image descriptors for images in a large collection. With these descriptors in hand, we perform two variations content-based image retrieval, i.e. reverse image search. Using information from one of the non-negative matrix factors we obtain descriptors which are suitable for finding semantically related images, i.e., belonging to the same semantic category as the query image. Combining information from both non-negative factors, however, yields descriptors that are suitable for finding other images of the specific instance depicted in the query image, where we again achieve state-of-the-art performance

    A blood atlas of COVID-19 defines hallmarks of disease severity and specificity.

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    Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete description of specific immune biomarkers. We present here a comprehensive multi-omic blood atlas for patients with varying COVID-19 severity in an integrated comparison with influenza and sepsis patients versus healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity involved cells, their inflammatory mediators and networks, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism, and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Systems-based integrative analyses including tensor and matrix decomposition of all modalities revealed feature groupings linked with severity and specificity compared to influenza and sepsis. Our approach and blood atlas will support future drug development, clinical trial design, and personalized medicine approaches for COVID-19

    Detecting and Correcting Batch Effects in High-Throughput Genomic Experiments

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    Batch effects are due to probe-specific systematic variation between groups of samples (batches) resulting from experimental features that are not of biological interest. Principal components analysis (PCA) is commonly used as a visual tool to determine whether batch effects exist after applying a global normalization method. However, PCA yields linear combinations of the variables that contribute maximum variance and thus will not necessarily detect batch effects if they are not the largest source of variability in the data. We present an extension of principal components analysis to quantify the existence of batch effects, called guided PCA (gPCA). We describe a test statistic that uses gPCA to test if a batch effect exists. We apply our proposed test statistic derived using gPCA to simulated data and to two copy number variation case studies: the first study consisted of 614 samples from a breast cancer family study using Illumina Human 660 bead-chip arrays whereas the second case study consisted of 703 samples from a family blood pressure study that used Affymetrix SNP Array 6.0. We demonstrate that our statistic has good statistical properties and is able to identify significant batch effects in two copy number variation case studies. We further compare existing batch effect correction methods and apply gPCA to test their effectiveness. We conclude that our novel statistic that utilizes guided principal components analysis to identify whether batch effects exist in high-throughput genomic data is effective. Although our examples pertain to copy number data, gPCA is general and can be used on other data types as well
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