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in category systems biology

2,528 results found. For more information, click each entry to expand.

101: Stem cell differentiation is a stochastic process with memory
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Posted to bioRxiv 17 Jan 2017

Stem cell differentiation is a stochastic process with memory
2,030 downloads systems biology

Patrick S. Stumpf, Rosanna C.G. Smith, Michael Lenz, Andreas Schuppert, Franz-Josef Müller, Ann Babtie, Thalia E Chan, Michael P. H. Stumpf, Colin P. Please, Sam D. Howison, Fumio Arai, Ben D. MacArthur

Pluripotent stem cells are able to self-renew indefinitely in culture and differentiate into all somatic cell types in vivo. While much is known about the molecular basis of pluripotency, the molecular mechanisms of lineage commitment are complex and only partially understood. Here, using a combination of single cell profiling and mathematical modeling, we examine the differentiation dynamics of individual mouse embryonic stem cells (ESCs) as they progress from the ground state of pluripotency along the neuronal lineage. In accordance with previous reports we find that cells do not transit directly from the pluripotent state to the neuronal state, but rather first stochastically permeate an intermediate primed pluripotent state, similar to that found in the maturing epiblast in development. However, analysis of rate at which individual cells enter and exit this intermediate metastable state using a hidden Markov model reveals that the observed ESC and epiblast-like 'macrostates' conceal a chain of unobserved cellular 'microstates', which individual cells transit through stochastically in sequence. These hidden microstates ensure that individual cells spend well-defined periods of time in each functional macrostate and encode a simple form of epigenetic 'memory' that allows individual cells to record their position on the differentiation trajectory. To examine the generality of this model we also consider the differentiation of mouse hematopoietic stem cells along the myeloid lineage and observe remarkably similar dynamics, suggesting a general underlying process. Based upon these results we suggest a statistical mechanics view of cellular identities that distinguishes between functionally-distinct macrostates and the many functionally-similar molecular microstates associated with each macrostate. Taken together these results indicate that differentiation is a discrete stochastic process amenable to analysis using the tools of statistical mechanics.

102: Tellurium: A Python Based Modeling and Reproducibility Platform for Systems Biology
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Posted to bioRxiv 21 May 2016

Tellurium: A Python Based Modeling and Reproducibility Platform for Systems Biology
2,021 downloads systems biology

Herbert M. Sauro, J. Kyle Medley, Caroline Cannistra, Matthias König, Lucian Smith, Kaylene Stocking, Herbert M Sauro

In this article, we present Tellurium, a powerful Python-based integrated environment designed for model building, analysis, simulation and reproducibility in systems and synthetic biology. Tellurium is a modular, cross-platform, and open-source integrated development environment (IDE) composed of multiple libraries, plugins, and specialized modules and methods. Tellurium ensures exchangeability and reproducibility of computational models by supporting SBML (Systems Biology Markup Language), SED-ML (Simulation Experiment Description Markup Language), the COMBINE archive, and SBOL (Synthetic Biology Open Language). Tellurium is a self-contained modeling platform which comes with a fully configured Python distribution independent of other local Python installations on the target machine. The main interface is based on the Spyder IDE which has a highly accessible user interface akin to MATLAB (https://www.mathworks.com/). Tellurium uses libRoadRunner as the default SBML simulation engine due to its superior performance, scalability and ease of integration. libRoadRunner supports deterministic simulations, stochastic simulations and steady state analyses. Tellurium also includes Antimony, a human-readable model definition language which can be converted to and from SBML. Other standard Python scientific libraries such as NumPy, SciPy, and matplotlib are included by default. Additionally, we include several user-friendly plugins and advanced modules for a wide-variety of applications, ranging from visualization tools to complex algorithms for bifurcation analysis and multi-dimensional parameter scanning. By combining multiple libraries, plugins, and modules into a single package, Tellurium provides a unified but extensible solution for biological modeling and simulation.

103: Quantification of nuclear protein dynamics reveals chromatin remodeling during acute protein degradation
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Posted to bioRxiv 14 Jun 2018

Quantification of nuclear protein dynamics reveals chromatin remodeling during acute protein degradation
1,983 downloads systems biology

Alexander J. Federation, Vivek Nandakumar, Hao Wang, Brian C. Searle, Lindsay K Pino, Gennifer Merrihew, Ying S Ting, Nicholas Howard, Tanya Kutyavin, Michael J. MacCoss, John A Stamatoyannopoulos

Sequencing-based technologies cannot measure post-transcriptional dynamics of the nuclear proteome, but unbiased mass-spectrometry measurements of nuclear proteins remain difficult. In this work, we have combined facile nuclear sub-fractionation approaches with data-independent acquisition mass spectrometry to improve detection and quantification of nuclear proteins in human cells and tissues. Nuclei are isolated and subjected to a series of extraction conditions that enrich for nucleoplasm, euchromatin, heterochromatin and nuclear-membrane associated proteins. Using this approach, we can measure peptides from over 70% of the expressed nuclear proteome. As we are physically separating chromatin compartments prior to analysis, proteins can be assigned into functional chromatin environments that illuminate systems-wide nuclear protein dynamics. To validate the integrity of nuclear sub-compartments, immunofluorescence confirms the presence of key markers during chromatin extraction. We then apply this method to study the nuclear proteome-wide response to during pharmacological degradation of the BET bromodomain proteins. BET degradation leads to widespread changes in chromatin composition, and we discover global HDAC1/2-mediated remodeling of chromatin previously bound by BET bromodomains. In summary, we have developed a technology for reproducible, comprehensive characterization of the nuclear proteome to observe the systems-wide nuclear protein dynamics.

104: The fundamental principles of antibody repertoire architecture revealed by large-scale network analysis
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Posted to bioRxiv 05 Apr 2017

The fundamental principles of antibody repertoire architecture revealed by large-scale network analysis
1,981 downloads systems biology

Enkelejda Miho, Victor Greifft, Rok Roškar, Sai T. Reddy

The antibody repertoire is a vast and diverse collection of B-cell receptors and antibodies that confer protection against a plethora of pathogens. The architecture of the antibody repertoire, defined by the network similarity landscape of its sequences, is unknown. Here, we established a novel high-performance computing platform to construct large-scale networks from high-throughput sequencing data (>100 000 unique antibodies), in order to uncover the architecture of antibody repertoires. We identified three fundamental principles of antibody repertoire architecture across B-cell development: reproducibility, robustness and redundancy. Reproducibility of network structure explains clonal expansion and selection. Robustness ensures a functional immune response even under extensive loss of clones (50%). Redundancy in mutational pathways suggests that there is a pre-programmed evolvability in antibody repertoires. Our analysis provides guidelines for a quantitative network analysis of antibody repertoires, which can be applied to other facets of adaptive immunity (e.g., T cell receptors), and may direct the construction of synthetic repertoires for biomedical applications.

105: Gene regulation inference from single-cell RNA-seq data with linear differential equations and velocity inference
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Posted to bioRxiv 07 Nov 2018

Gene regulation inference from single-cell RNA-seq data with linear differential equations and velocity inference
1,964 downloads systems biology

Pierre-Cyril Aubin-Frankowski, Jean Philippe Vert

Single-cell RNA sequencing (scRNA-seq) offers new possibilities to infer gene regulation networks (GRN) for biological processes involving a notion of time, such as cell differentiation or cell cycles. It also raises many challenges due to the destructive measurements inherent to the technology. In this work we propose a new method named GRISLI for de novo GRN inference from scRNA-seq data. GRISLI infers a velocity vector field in the space of scRNA-seq data from profiles of individual data, and models the dynamics of cell trajectories with a linear ordinary differential equation to reconstruct the underlying GRN with a sparse regression procedure. We show on real data that GRISLI outperforms a recently proposed state-of-the-art method for GRN reconstruction from scRNA-seq data.

106: A Consensus Proteomic Analysis of Alzheimer’s Disease Brain and Cerebrospinal Fluid Reveals Early Changes in Energy Metabolism Associated with Microglia and Astrocyte Activation
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Posted to bioRxiv 13 Oct 2019

A Consensus Proteomic Analysis of Alzheimer’s Disease Brain and Cerebrospinal Fluid Reveals Early Changes in Energy Metabolism Associated with Microglia and Astrocyte Activation
1,949 downloads systems biology

Erik C.B. Johnson, Eric B. Dammer, Duc M. Duong, Lingyan Ping, Maotian Zhou, Luming Yin, Lenora A. Higginbotham, Andrew Guajardo, Bartholomew White, Juan C. Troncoso, Madhav Thambisetty, Thomas J. Montine, Edward B. Lee, John Q. Trojanowski, Thomas G Beach, Eric M. Reiman, Vahram Haroutunian, Minghui Wang, Eric Schadt, Bin Zhang, Dennis W. Dickson, Nilufer Ertekin-Taner, Todd E. Golde, Vladislav A. Petyuk, Philip L. De Jager, David A. Bennett, Thomas S. Wingo, Srikant Rangaraju, Ihab Hajjar, Joshua M. Shulman, James J. Lah, Allan I. Levey, Nicholas T. Seyfried

Our understanding of the biological changes in the brain associated with Alzheimer’s disease (AD) pathology and cognitive impairment remains incomplete. To increase our understanding of these changes, we analyzed dorsolateral prefrontal cortex of control, asymptomatic AD, and AD brains from four different centers by label-free quantitative mass spectrometry and weighted protein co-expression analysis to obtain a consensus protein co-expression network of AD brain. This network consisted of 13 protein co-expression modules. Six of these modules correlated with amyloid-β plaque burden, tau neurofibrillary tangle burden, cognitive function, and clinical functional status, and were altered in asymptomatic AD, AD, or in both disease states. These six modules reflected synaptic, mitochondrial, sugar metabolism, extracellular matrix, cytoskeletal, and RNA binding/splicing biological functions. The identified protein network modules were preserved in a community-based cohort analyzed by a different quantitative mass spectrometry approach. They were also preserved in temporal lobe and precuneus brain regions. Some of the modules were influenced by aging, and showed changes in other neurodegenerative diseases such as frontotemporal dementia and corticobasal degeneration. The module most strongly associated with AD pathology and cognitive impairment was the sugar metabolism module. This module was enriched in AD genetic risk factors, and was also highly enriched in microglia and astrocyte protein markers associated with an anti-inflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from the sugar metabolism module were increased in cerebrospinal fluid from asymptomatic AD and AD cases, highlighting their potential as biomarkers of the altered brain network. In this study of >2000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brain that may serve as therapeutic targets and fluid biomarkers for the disease.

107: Mechanistic modeling of the SARS-CoV-2 disease map
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Posted to bioRxiv 12 Apr 2020

Mechanistic modeling of the SARS-CoV-2 disease map
1,937 downloads systems biology

Kinza Rian, Marina Esteban-Medina, Marta R. Hidalgo, Cankut Çubuk, Matías M. Falco, Carlos Loucera, Devrim Gunyel, Marek Ostaszewski, María Peña-Chilet, Joaquín Dopazo

Here we present a web interface that implements a comprehensive mechanistic model of the SARS-CoV-2 disease map in which the detailed activity of the human signaling circuits related to the viral infection and the different antiviral responses, including immune and inflammatory activities, can be inferred from gene expression experiments. Moreover, given to the mechanistic properties of the model, the effect of potential interventions, such as knock-downs, over-expression or drug effects (currently the system models the effect of more than 8000 DrugBank drugs) can be studied in specific conditions. This tool, with the holistic, systems biology approach to the understanding of the complexities of the viral infection process, will become an important asset in the search for efficient antiviral treatments. The tool is freely available at: http://hipathia.babelomics.org/covid19/. ### Competing Interest Statement The authors have declared no competing interest.

108: Biological Self-organisation and Markov blankets
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Posted to bioRxiv 30 Nov 2017

Biological Self-organisation and Markov blankets
1,925 downloads systems biology

Ensor Rafael Palacios, Adeel Razi, Thomas Parr, Michael Kirchhoff, Karl Friston

Biological self-organisation is a process of spontaneous pattern formation; namely the emergence of coherent and stable systemic configurations that distinguish themselves from their environment. This process can occur at various spatial scales: from the microscopic (giving rise to cells) to the macroscopic (the emergence of organisms). Self-organisation at each level is essential to account for the hierarchical organisation of living organisms (organelles within cells, within tissues, within organs, etc.). In this paper, we pursue the idea that Markov blankets - statistical boundaries separating states that are external to a system from its internal states - emerge at every possible level of the description of the (living) system. Through simulations, we show that the concept of a Markov blanket is fundamental in defining biological systems and underwrites the nature and form of interactions between successive levels of hierarchical structure. We demonstrate the validity of our argument using simulations, based on the normative principle of variational free energy minimisation. Specifically, we adopt a top-down approach to provide a proof of concept for the claim that the self-organisation of Markov blankets (and blankets of blankets) underwrites the self-evidencing, autopoietic behaviour of living systems.

109: Protein phase separation provides long-term memory of transient spatial stimuli
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Posted to bioRxiv 16 Mar 2018

Protein phase separation provides long-term memory of transient spatial stimuli
1,924 downloads systems biology

Elliot Dine, Agnieszka A. Gil, Giselle Uribe, Clifford P. Brangwynne, Jared E. Toettcher

Protein/RNA clusters arise frequently in spatially-regulated biological processes, from the asymmetric distribution of P granules and PAR proteins in developing embryos to localized receptor oligomers in migratory cells. This co-occurrence suggests that protein clusters might possess intrinsic properties that make them a useful substrate for spatial regulation. Here, we demonstrate that protein droplets show a robust form of spatial memory, maintaining the spatial pattern of an inhibitor of droplet formation long after it has been removed. Despite this persistence, droplets can be highly dynamic, continuously exchanging monomers with the diffuse phase. We investigate the principles of biophysical spatial memory in three contexts: a computational model of phase separation; a novel optogenetic system where light can drive rapid, localized dissociation of liquid-like protein droplets; and membrane-localized signal transduction from clusters of receptor tyrosine kinases. Our results suggest that the persistent polarization underlying many cellular and developmental processes could arise through a simple biophysical process, without any additional requirement for biochemical positive and negative feedback loops.

110: Dynamics and spatial genomics of the nascent transcriptome in single mESCs by intron seqFISH
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Posted to bioRxiv 05 Jun 2018

Dynamics and spatial genomics of the nascent transcriptome in single mESCs by intron seqFISH
1,922 downloads systems biology

Sheel Shah, Yodai Takei, Wen Zhou, Eric Lubeck, Jina Yun, Noushin Koulena, Eric J. Liaw, Mina Amin, Long Cai

Recent single cell experiments have revealed significant heterogeneities at the levels of transcription, DNA methylation and chromosome organization in individual cells. However, existing method of profiling mRNAs effectively averages transcriptional dynamics over many hours due to hours-long life time of most mRNAs. To capture the instantaneous activity of the transcriptome that reflects the rapid regulatory changes in cells, we imaged up to 10,421 nascent transcription active sites (TAS) in single mouse embryonic stem cells using seqFISH followed by multiple rounds of single molecule FISH and immunofluorescence. We observed that nascent transcription active sites appear to be distributed on the surface of individual chromosome territories and are dispersed throughout the nucleus. In addition, there are significant variability in the number of active transcription sites in single cells, representing globally more active to quiescent states. These states interconverted on the time scale of 2 hours as determined by a single cell pulse-chase experiment. Thus, transcriptome level seqFISH experiments provide an unprecedented spatial and dynamic view of chromosome organization and global nascent transcription activity in single cells.

111: Experimental and computational framework for a dynamic protein atlas of human cell division
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Posted to bioRxiv 01 Dec 2017

Experimental and computational framework for a dynamic protein atlas of human cell division
1,905 downloads systems biology

Yin Cai, M. Julius Hossain, Jean-Karim Hériché, Antonio Z Politi, Nike Walther, Birgit Koch, Malte Wachsmuth, Bianca Nijmeijer, Moritz Kueblbeck, Marina Martinic Kavur, Rene Ladurner, Stephanie Alexander, Jan-Michael Peters, Jan Ellenberg

Essential biological functions of human cells, such as division, require the tight coordination of the activity of hundreds of proteins in space and time. While live cell imaging is a powerful tool to study the distribution and dynamics of individual proteins after fluorescence tagging, it has not yet been used to map protein networks due to the lack of systematic and quantitative experimental and computational approaches. Using the cell and nuclear boundaries as landmarks, we generated a 4D image data-driven, canonical, computational model for the morphological changes during mitotic progression of human cells. We show that this model can be used to integrate the dynamic distribution of 3D concentration data for many mitotic proteins imaged by absolutely calibrated fluorescence microscopy in a large number of dividing cells. Analysis of a pilot data set, containing 28 proteins of interest imaged in dividing cells, allowed us to automatically identify sub-cellular structures and quantify the timing and magnitude of protein fluxes between them, as well as predicting dynamic multi-molecular biological processes such as organelle dis/assembly. Our integrated experimental and computational method enables building a 4D protein atlas of the dividing human cell. As part of the MitoSys and Systems Microscopy consortia, we provide here an approach that is generic and allows the systematic mapping and mining of dynamic protein localization networks that drive cellular functions.

112: Dissection of the contribution of regulation mode to the properties of feedforward and feedback gene regulatory motifs.
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Posted to bioRxiv 06 Sep 2016

Dissection of the contribution of regulation mode to the properties of feedforward and feedback gene regulatory motifs.
1,904 downloads systems biology

Bharat Ravi Iyengar, Beena Pillai, K.V. Venkatesh, Chetan J Gadgil

We present a framework enabling dissection of the effects of motif structure (feedback or feedforward), nature of the controller (mRNA or protein), and regulation mode (transcriptional, post-transcriptional or translational) on the response to a step change in the input. We have used a common model framework for gene expression where both motif structures have an activating input and repressing regulator, with the same set of parameters to enable comparison of the responses. We studied the global sensitivity of the system properties such as steady-state gain, overshoot, peak time, and peak duration, to parameters. We find that, in all motifs, overshoot correlated negatively whereas peak duration varied concavely, with peak time. Differences in other system properties were found to be mainly dependent on the the nature of the regulator, than the motif structure. Protein mediated motifs showed a higher degree of adaptation; feedforward motifs exhibited perfect adaptation. RNA mediated motifs had a mild regulatory effect; they also exhibited lower peaking tendency and mean overshoot. Protein mediated feedforward motifs showed higher overshoot and lower peak time compared to corresponding feedback motifs.

113: Memote: A community-driven effort towards a standardized genome-scale metabolic model test suite
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Posted to bioRxiv 21 Jun 2018

Memote: A community-driven effort towards a standardized genome-scale metabolic model test suite
1,903 downloads systems biology

Christian Lieven, Moritz E. Beber, Brett G. Olivier, Frank T. Bergmann, Meric Ataman, Parizad Babaei, Jennifer A. Bartell, Lars M. Blank, Siddharth Chauhan, Kevin Correia, Christian Diener, Andreas Dräger, Birgitta E. Ebert, Janaka N. Edirisinghe, Jose P. Faria, Adam M. Feist, Georgios Fengos, Ronan M. T. Fleming, Beatriz García-Jiménez, Vassily Hatzimanikatis, Wout van Helvoirt, Christopher S. Henry, Henning Hermjakob, Markus J. Herrgård, Hyun Uk Kim, Zachary King, Jasper J. Koehorst, Steffen Klamt, Edda Klipp, Meiyappan Lakshmanan, Nicolas Gambardella Le Novère, Dong-Yup Lee, Sang Yup Lee, Sunjae Lee, Nathan E. Lewis, Hongwu Ma, Daniel Machado, Radhakrishnan Mahadevan, Paulo Maia, Adil Mardinoglu, Gregory L. Medlock, Jonathan M. Monk, Jens Nielsen, Lars K. Nielsen, J Nogales, Intawat Nookaew, Osbaldo Resendis-Antonio, Bernhard O Palsson, Jason Papin, Kiran R. Patil, Mark Poolman, Nathan D. Price, Anne Richelle, Isabel Rocha, Benjamin J. Sanchez, Peter J. Schaap, Rahuman S. Malik-Sheriff, Saeed Shoaie, Nikolaus Sonnenschein, Bas Teusink, Paulo Vilaça, Jon Olav Vik, Judith A. Wodke, Joana C. Xavier, Qianqian Yuan, Maksim Zakhartsev, Cheng Zhang

Several studies have shown that neither the formal representation nor the functional requirements of genome-scale metabolic models (GEMs) are precisely defined. Without a consistent standard, comparability, reproducibility, and interoperability of models across groups and software tools cannot be guaranteed. Here, we present memote (https://github.com/opencobra/memote) an open-source software containing a community-maintained, standardized set of metabolic model tests. The tests cover a range of aspects from annotations to conceptual integrity and can be extended to include experimental datasets for automatic model validation. In addition to testing a model once, memote can be configured to do so automatically, i.e., while building a GEM. A comprehensive report displays the model's performance parameters, which supports informed model development and facilitates error detection. Memote provides a measure for model quality that is consistent across reconstruction platforms and analysis software and simplifies collaboration within the community by establishing workflows for publicly hosted and version controlled models.

114: A Guide to the Quantitative Proteomic Profiles of the Cancer Cell Line Encyclopedia
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Posted to bioRxiv 03 Feb 2020

A Guide to the Quantitative Proteomic Profiles of the Cancer Cell Line Encyclopedia
1,902 downloads systems biology

David P. Nusinow, Steven P. Gygi

We recently reported the quantitative proteomics of 375 samples as part of the Cancer Cell Line Encyclopedia (Nusinow et al., 2020). Mass spectrometry-based proteomics data is broadly unfamiliar to most biologists in our experience, resulting in questions from analysts about how to use the data. From the proteomics community there was interest about how we normalized the data, as the scope of this project was so much larger than what has been commonly available. This paper serves as a guide to the data set to answer these questions and acts as a supplement to the main manuscript. The first part addresses users of the data, describing the experimental design, interpretation of the values, and dealing with standard issues in proteomics like multiple protein isoforms per gene and missing values. The second part of the manuscript details how we arrived at the normalization procedure reported in the paper, including the diagnostics used to assess multiple normalization schemes.

115: Random Walk With Restart On Multiplex And Heterogeneous Biological Networks
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Posted to bioRxiv 05 May 2017

Random Walk With Restart On Multiplex And Heterogeneous Biological Networks
1,895 downloads systems biology

Alberto Valdeolivas, Laurent Tichit, Claire Navarro, Sophie Perrin, Gaëlle Odelin, Nicolas Levy, Pierre Cau, Elisabeth Remy, Anaïs Baudot

Recent years have witnessed an exponential growth in the number of identified interactions between biological molecules. These interactions are usually represented as large and complex networks, calling for the development of appropriated tools to exploit the functional information they contain. Random walk with restart is the state-of-the-art guilt-by-association approach. It explores the network vicinity of gene/protein seeds to study their functions, based on the premise that nodes related to similar functions tend to lie close to each others in the networks. In the present study, we extended the random walk with restart algorithm to multiplex and heterogeneous networks. The walk can now explore different layers of physical and functional interactions between genes and proteins, such as protein-protein interactions and co-expression associations. In addition, the walk can also jump to a network containing different sets of edges and nodes, such as phenotype similarities between diseases. We devised a leave-one-out cross-validation strategy to evaluate the algorithms abilities to predict disease-associated genes. We demonstrate the increased performances of the multiplex-heterogeneous random walk with restart as compared to several random walks on monoplex or heterogeneous networks. Overall, our framework is able to leverage the different interaction sources to outperform current approaches. Finally, we applied the algorithm to predict genes candidate for being involved in the Wiedemann-Rautenstrauch syndrome, and to explore the network vicinity of the SHORT syndrome. The source code and the software are freely available at: https://github.com/alberto-valdeolivas/RWR-MH.

116: Gut microbiome activity contributes to individual variation in glycemic response in adults
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Posted to bioRxiv 19 May 2019

Gut microbiome activity contributes to individual variation in glycemic response in adults
1,890 downloads systems biology

Hal Tily, Ally Perlina, Eric Patridge, Stephanie Gline, Matvey Genkin, Vishakh Gopu, Haely Lindau, Alisson Sjue, Iordan Slavov, Niels Klitgord, Momchilo Vuyisich, Helen Messier, Guruduth Banavar

Limiting post-meal glycemic response is an important factor in reducing the risk of chronic metabolic diseases, and contributes to significant health benefits in people with elevated levels of blood sugar. In this study, we collected gut microbiome activity (i.e., metatranscriptomic ) data and measured the glycemic responses of 550 adults who consumed more than 30,000 meals from omnivore or vegetarian/gluten-free diets. We demonstrate that gut microbiome activity makes a statistically significant contribution to individual variation in glycemic response, in addition to anthropometric factors and the nutritional composition of foods. We describe predictive models (multilevel mixed-effects regression and gradient boosting machine) of variation in glycemic response among individuals ingesting the same foods. We introduce functional features aggregated from microbial activity data as candidates for association with mechanisms of glycemic control. In summary, we demonstrate for the first time that metatranscriptomic activity of the gut microbiome is correlated with glycemic response among adults.

117: Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation
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Posted to bioRxiv 16 Mar 2019

Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation
1,879 downloads systems biology

Erika Kelmer Sacramento, Joanna M Kirkpatrick, Mariateresa Mazzetto, Mario Baumgart, Aleksandar Bartolome, Simone Di Sanzo, Cinzia Caterino, Michele Sanguanini, Nikoletta Papaevgeniou, Maria Lefaki, Dorothee Childs, Sara Bagnoli, Eva Terzibasi Tozzini, Domenico Di Fraia, Natalie Romanov, Peter Sudmant, Wolfgang Huber, Niki Chondrogianni, Michele Vendruscolo, Alessandro Cellerino, Alessandro Ori

A progressive loss of protein homeostasis is characteristic of aging and a driver of neurodegeneration. To investigate this process quantitatively, we characterized proteome dynamics during brain aging in the short-lived vertebrate Nothobranchius furzeri combining transcriptomics and proteomics. We detected a progressive reduction in the correlation between protein and mRNA, mainly due to post-transcriptional mechanisms that account for over 40% of the age-regulated proteins. These changes cause a progressive loss of stoichiometry in several protein complexes, including ribosomes, which show impaired assembly / dis-assembly and are enriched in protein aggregates in old brains. Mechanistically, we show that reduction of proteasome activity is an early event during brain aging and is sufficient to induce proteomic signatures of aging and loss of stoichiometry in vivo . Using longitudinal transcriptomic data, we show that the magnitude of early life decline in proteasome levels is the major risk factor for mortality. Our work defines causative events in the aging process that can be targeted to prevent loss of protein homeostasis and delay the onset of age-related neurodegeneration. Highlights

118: Comprehensive discovery of subsample gene expression components by information explanation: therapeutic implications in cancer
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Posted to bioRxiv 11 Mar 2016

Comprehensive discovery of subsample gene expression components by information explanation: therapeutic implications in cancer
1,864 downloads systems biology

S. Pepke, G. Ver Steeg

Background De novo inference of clinically relevant gene function relationships from tumor RNA-seq remains a challenging task. Current methods typically either partition patient samples into a few subtypes or rely upon analysis of pairwise gene correlations (co-expression) that will miss some groups in noisy data. Leveraging higher dimensional information can be expected to increase the power to discern targetable pathways, but this is commonly thought to be an intractable computational problem. Methods In this work we adapt a recently developed machine learning algorithm, CorEx, that efficiently optimizes over multivariate mutual information for sensitive detection of complex gene relationships. The algorithm can be iteratively applied to generate a hierarchy of latent factors. Patients are stratified relative to each factor and combinatoric survival analyses are performed and interpreted in the context of biological function annotations and protein network interactions that might be utilized to match patients to multiple therapies. Results Analysis of ovarian tumor RNA-seq samples demonstrates the algorithm's power to infer well over one hundred biologically interpretable gene cohorts, several times more than standard methods such as hierarchical clustering and k-means. The CorEx factor hierarchy is also informative, with related but distinct gene clusters grouped by upper nodes. Some latent factors correlate with patient survival, including one for a pathway connected with the epithelial-mesenchymal transition in breast cancer that is regulated by a potentially druggable microRNA. Further, combinations of factors lead to a synergistic survival advantage in some cases. Conclusions In contrast to studies that attempt to partition patients into a small number of subtypes (typically 4 or fewer) for treatment purposes, our approach utilizes subgroup information for combinatoric transcriptional phenotyping. Considering only the 66 gene expression groups that are both found to have significant Gene Ontology enrichment and are small enough to indicate specific drug targets implies a computational phenotype for ovarian cancer that allows for 366 possible patient profiles, enabling truly personalized treatment. The findings here demonstrate a new technique that sheds light on the complexity of gene expression dependencies in tumors and could eventually enable the use of patient RNA-seq profiles for selection of personalized and effective cancer treatments.

119: PhysiCell: an Open Source Physics-Based Cell Simulator for 3-D Multicellular Systems
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Posted to bioRxiv 19 Nov 2016

PhysiCell: an Open Source Physics-Based Cell Simulator for 3-D Multicellular Systems
1,854 downloads systems biology

Ahmadreza Ghaffarizadeh, Randy Heiland, Samuel H. Friedman, Shannon Mumenthaler, Paul Macklin

Many multicellular systems problems can only be understood by studying how cells move, grow, divide, interact, and die. Tissue-scale dynamics emerge from systems of many interacting cells as they respond to and influence their microenvironment. The ideal "virtual laboratory" for such multicellular systems simulates both the biochemical microenvironment (the "stage") and many mechanically and biochemically interacting cells (the "players" upon the stage). PhysiCell — physics-based multicellular simulator — is an open source agent-based simulator that provides both the stage and the players for studying many interacting cells in dynamic tissue microenvironments. It builds upon a multi-substrate biotransport solver to link cell phenotype to multiple diffusing substrates and signaling factors. It includes biologically-driven sub-models for cell cycling, apoptosis, necrosis, solid and fluid volume changes, mechanics, and motility "out of the box." The C++ code has minimal dependencies, making it simple to maintain and deploy across platforms. PhysiCell has been parallelized with OpenMP, and its performance scales linearly with the number of cells. Simulations up to 10^5-10^6 cells are feasible on quad-core desktop workstations; larger simulations are attainable on single HPC compute nodes. We demonstrate PhysiCell by simulating the impact of necrotic core biomechanics, 3-D geometry, and stochasticity on the dynamics of hanging drop tumor spheroids and ductal carcinoma in situ (DCIS) of the breast. We demonstrate stochastic motility, chemical and contact-based interaction of multiple cell types, and the extensibility of PhysiCell with examples in synthetic multicellular systems (a "cellular cargo delivery" system, with application to anti-cancer treatments), cancer heterogeneity, and cancer immunology. PhysiCell is a powerful multicellular systems simulator that will be continually improved with new capabilities and performance improvements. It also represents a significant independent code base for replicating results from other simulation platforms. The PhysiCell source code, examples, documentation, and support are available under the BSD license at http://PhysiCell.MathCancer.org and http://PhysiCell.sf.net.

120: deepNF: Deep network fusion for protein function prediction
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Posted to bioRxiv 22 Nov 2017

deepNF: Deep network fusion for protein function prediction
1,828 downloads systems biology

Vladimir Gligorijević, Meet Barot, Richard Bonneau

The prevalence of high-throughput experimental methods has resulted in an abundance of large-scale molecular and functional interaction networks. The connectivity of these networks provide a rich source of information for inferring functional annotations for genes and proteins. An important challenge has been to develop methods for combining these heterogeneous networks to extract useful protein feature representations for function prediction. Most of the existing approaches for network integration use shallow models that cannot capture complex and highly-nonlinear network structures. Thus, we propose deepNF, a network fusion method based on Multimodal Deep Autoencoders to extract high-level features of proteins from multiple heterogeneous interaction networks. We apply this method to combine STRING networks to construct a common low-dimensional representation containing high-level protein features. We use separate layers for different network types in the early stages of the multimodal autoencoder, later connecting all the layers into a single bottleneck layer from which we extract features to predict protein function. We compare the cross-validation and temporal holdout predictive performance of our method with state-of-the-art methods, including the recently proposed method Mashup. Our results show that our method outperforms previous methods for both human and yeast STRING networks. We also show substantial improvement in the performance of our method in predicting GO terms of varying type and specificity.

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  • 20 Oct 2020: Support for sorting preprints using Twitter activity has been removed, at least temporarily, until a new source of social media activity data becomes available.
  • 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
  • 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
  • 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
  • 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
  • 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
  • 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
  • 22 Jan 2019: Nature just published an article about Rxivist and our data.
  • 13 Jan 2019: The Rxivist preprint is live!