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Cell Systems

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https://www.readbyqxmd.com/read/28215528/a-systematic-evaluation-of-methods-for-tailoring-genome-scale-metabolic-models
#1
Sjoerd Opdam, Anne Richelle, Benjamin Kellman, Shanzhong Li, Daniel C Zielinski, Nathan E Lewis
Genome-scale models of metabolism can illuminate the molecular basis of cell phenotypes. Since some enzymes are only active in specific cell types, several algorithms use omics data to construct cell-line- and tissue-specific metabolic models from genome-scale models. However, these methods are often not rigorously benchmarked, and it is unclear how algorithm and parameter selection (e.g., gene expression thresholds, metabolic constraints) affects model content and predictive accuracy. To investigate this, we built hundreds of models of four different cancer cell lines using six algorithms, four gene expression thresholds, and three sets of metabolic constraints...
February 14, 2017: Cell Systems
https://www.readbyqxmd.com/read/28215527/chromosome-wise-protein-interaction-patterns-and-their-impact-on-functional-implications-of-large-scale-genomic-aberrations
#2
Isa Kristina Kirk, Nils Weinhold, Kirstine Belling, Niels Erik Skakkebæk, Thomas Skøt Jensen, Henrik Leffers, Anders Juul, Søren Brunak
Gene copy-number changes influence phenotypes through gene-dosage alteration and subsequent changes of protein complex stoichiometry. Human trisomies where gene copy numbers are increased uniformly over entire chromosomes provide generic cases for studying these relationships. In most trisomies, gene and protein level alterations have fatal consequences. We used genome-wide protein-protein interaction data to identify chromosome-specific patterns of protein interactions. We found that some chromosomes encode proteins that interact infrequently with each other, chromosome 21 in particular...
February 14, 2017: Cell Systems
https://www.readbyqxmd.com/read/28215526/canalization-of-c-%C3%A2-elegans-vulva-induction-against-anatomical-variability
#3
Guizela Huelsz-Prince, Jeroen Sebastiaan van Zon
It is a fundamental open question as to how embryos develop into complex adult organisms with astounding reproducibility, particularly because cells are inherently variable on the molecular level. During C. elegans vulva induction, the anchor cell induces cell fate in the vulva precursor cells in a distance-dependent manner. Surprisingly, we found that initial anchor cell position was highly variable and caused variability in cell fate induction. However, we observed that vulva induction was "canalized," i...
February 14, 2017: Cell Systems
https://www.readbyqxmd.com/read/28215525/explicit-modeling-of-sirna-dependent-on-and-off-target-repression-improves-the-interpretation-of-screening-results
#4
Andrea Riba, Mario Emmenlauer, Amy Chen, Frederic Sigoillot, Feng Cong, Christoph Dehio, Jeremy Jenkins, Mihaela Zavolan
RNAi is broadly used to map gene regulatory networks, but the identification of genes that are responsible for the observed phenotypes is challenging, as small interfering RNAs (siRNAs) simultaneously downregulate the intended on targets and many partially complementary off targets. Additionally, the scarcity of publicly available control datasets hinders the development and comparative evaluation of computational methods for analyzing the data. Here, we introduce PheLiM (https://github.com/andreariba/PheLiM), a method that uses predictions of siRNA on- and off-target downregulation to infer gene-specific contributions to phenotypes...
February 14, 2017: Cell Systems
https://www.readbyqxmd.com/read/28189581/construction-and-analysis-of-two-genome-scale-deletion-libraries-for-bacillus-subtilis
#5
Byoung-Mo Koo, George Kritikos, Jeremiah D Farelli, Horia Todor, Kenneth Tong, Harvey Kimsey, Ilan Wapinski, Marco Galardini, Angelo Cabal, Jason M Peters, Anna-Barbara Hachmann, David Z Rudner, Karen N Allen, Athanasios Typas, Carol A Gross
A systems-level understanding of Gram-positive bacteria is important from both an environmental and health perspective and is most easily obtained when high-quality, validated genomic resources are available. To this end, we constructed two ordered, barcoded, erythromycin-resistance- and kanamycin-resistance-marked single-gene deletion libraries of the Gram-positive model organism, Bacillus subtilis. The libraries comprise 3,968 and 3,970 genes, respectively, and overlap in all but four genes. Using these libraries, we update the set of essential genes known for this organism, provide a comprehensive compendium of B...
February 7, 2017: Cell Systems
https://www.readbyqxmd.com/read/28189580/automated-design-of-synthetic-cell-classifier-circuits-using-a-two-step-optimization-strategy
#6
Pejman Mohammadi, Niko Beerenwinkel, Yaakov Benenson
Cell classifiers are genetic logic circuits that transduce endogenous molecular inputs into cell-type-specific responses. Designing classifiers that achieve optimal differential response between specific cell types is a hard computational problem because it involves selection of endogenous inputs and optimization of both biochemical parameters and a logic function. To address this problem, we first derive an optimal set of biochemical parameters with the largest expected differential response over a diverse set of logic circuits, and second, we use these parameters in an evolutionary algorithm to select circuit inputs and optimize the logic function...
February 6, 2017: Cell Systems
https://www.readbyqxmd.com/read/28131824/a-dynamic-model-of-immune-responses-to-antigen-presentation-predicts-different-regions-of-tumor-or-pathogen-elimination
#7
Eduardo D Sontag
The immune system must discriminate between agents of disease and an organism's healthy cells. While the identification of an antigen as self/non-self is critically important, the dynamic features of antigen presentation may also determine the immune system's response. Here, we use a simple mathematical model of immune activation to explore the idea of antigen discrimination through dynamics. We propose that antigen presentation is coupled to two nodes, one regulatory and one effecting the immune response, through an incoherent feedforward loop and repressive feedback...
January 25, 2017: Cell Systems
https://www.readbyqxmd.com/read/28131823/in-situ-peroxidase-labeling-and-mass-spectrometry-connects-alpha-synuclein-directly-to-endocytic-trafficking-and-mrna-metabolism-in-neurons
#8
Chee Yeun Chung, Vikram Khurana, Song Yi, Nidhi Sahni, Ken H Loh, Pavan K Auluck, Valeriya Baru, Namrata D Udeshi, Yelena Freyzon, Steven A Carr, David E Hill, Marc Vidal, Alice Y Ting, Susan Lindquist
Synucleinopathies, including Parkinson's disease (PD), are associated with the misfolding and mistrafficking of alpha-synuclein (α-syn). Here, using an ascorbate peroxidase (APEX)-based labeling method combined with mass spectrometry, we defined a network of proteins in the immediate vicinity of α-syn in living neurons to shed light on α-syn function. This approach identified 225 proteins, including synaptic proteins, proteins involved in endocytic vesicle trafficking, the retromer complex, phosphatases and mRNA binding proteins...
January 25, 2017: Cell Systems
https://www.readbyqxmd.com/read/28131822/genome-scale-networks-link-neurodegenerative-disease-genes-to-%C3%AE-synuclein-through-specific-molecular-pathways
#9
Vikram Khurana, Jian Peng, Chee Yeun Chung, Pavan K Auluck, Saranna Fanning, Daniel F Tardiff, Theresa Bartels, Martina Koeva, Stephen W Eichhorn, Hadar Benyamini, Yali Lou, Andy Nutter-Upham, Valeriya Baru, Yelena Freyzon, Nurcan Tuncbag, Michael Costanzo, Bryan-Joseph San Luis, David C Schöndorf, M Inmaculada Barrasa, Sepehr Ehsani, Neville Sanjana, Quan Zhong, Thomas Gasser, David P Bartel, Marc Vidal, Michela Deleidi, Charles Boone, Ernest Fraenkel, Bonnie Berger, Susan Lindquist
Numerous genes and molecular pathways are implicated in neurodegenerative proteinopathies, but their inter-relationships are poorly understood. We systematically mapped molecular pathways underlying the toxicity of alpha-synuclein (α-syn), a protein central to Parkinson's disease. Genome-wide screens in yeast identified 332 genes that impact α-syn toxicity. To "humanize" this molecular network, we developed a computational method, TransposeNet. This integrates a Steiner prize-collecting approach with homology assignment through sequence, structure, and interaction topology...
January 25, 2017: Cell Systems
https://www.readbyqxmd.com/read/28089543/optimal-regulatory-circuit-topologies-for-fold-change-detection
#10
Miri Adler, Pablo Szekely, Avi Mayo, Uri Alon
Evolution repeatedly converges on only a few regulatory circuit designs that achieve a given function. This simplicity helps us understand biological networks. However, why so few circuits are rediscovered by evolution is unclear. We address this question for the case of fold-change detection (FCD): a response to relative changes of input rather than absolute changes. Two types of FCD circuits recur in biological systems-the incoherent feedforward and non-linear integral-feedback loops. We performed an analytical screen of all three-node circuits in a class comprising ∼500,000 topologies...
January 10, 2017: Cell Systems
https://www.readbyqxmd.com/read/28089542/parallelization-and-high-performance-computing-enables-automated-statistical-inference-of-multi-scale-models
#11
Nick Jagiella, Dennis Rickert, Fabian J Theis, Jan Hasenauer
Mechanistic understanding of multi-scale biological processes, such as cell proliferation in a changing biological tissue, is readily facilitated by computational models. While tools exist to construct and simulate multi-scale models, the statistical inference of the unknown model parameters remains an open problem. Here, we present and benchmark a parallel approximate Bayesian computation sequential Monte Carlo (pABC SMC) algorithm, tailored for high-performance computing clusters. pABC SMC is fully automated and returns reliable parameter estimates and confidence intervals...
January 10, 2017: Cell Systems
https://www.readbyqxmd.com/read/28125793/the-state-of-systems-genetics-in-2017
#12
Nitin S Baliga, Johan L M Björkegren, Jef D Boeke, Michael Boutros, Nigel P S Crawford, Aimée M Dudley, Charles R Farber, Allan Jones, Allan I Levey, Aldons J Lusis, H Craig Mak, Joseph H Nadeau, Marcus B Noyes, Enrico Petretto, Nicholas T Seyfried, Lars M Steinmetz, Sibylle C Vonesch
Cell Systems invited 16 experts to share their views on the field of systems genetics. In questions repeated in the headings, we asked them to define systems genetics, highlight its relevance to researchers outside the field, discuss what makes a strong systems genetics paper, and paint a picture of where the field is heading in the coming years. Their responses, ordered by the journal but otherwise unedited, make it clear that deciphering genotype to phenotype relationships is a central challenge of systems genetics and will require understanding how networks and higher-order properties of biological systems underlie complex traits...
January 25, 2017: Cell Systems
https://www.readbyqxmd.com/read/28125792/principles-of-systems-biology-no-13
#13
(no author information available yet)
This month: CRISPR flexes its massively parallel muscles (see also this month's editorial), two systems-level properties discovered in yeast, and a host of new tools and synthetic engineered systems.
January 25, 2017: Cell Systems
https://www.readbyqxmd.com/read/28125791/lessons-from-enzyme-kinetics-reveal-specificity-principles-for-rna-guided-nucleases-in-rna-interference-and-crispr-based-genome-editing
#14
REVIEW
Namita Bisaria, Inga Jarmoskaite, Daniel Herschlag
RNA-guided nucleases (RGNs) provide sequence-specific gene regulation through base-pairing interactions between a small RNA guide and target RNA or DNA. RGN systems, which include CRISPR-Cas9 and RNA interference (RNAi), hold tremendous promise as programmable tools for engineering and therapeutic purposes. However, pervasive targeting of sequences that closely resemble the intended target has remained a major challenge, limiting the reliability and interpretation of RGN activity and the range of possible applications...
January 25, 2017: Cell Systems
https://www.readbyqxmd.com/read/28125790/metabolism-centric-trans-omics
#15
Katsuyuki Yugi, Shinya Kuroda
Two recent studies in Cell and Science demonstrate the reconstruction of global mechanistic networks and identification of regulatory principles from multi-omics data.
January 25, 2017: Cell Systems
https://www.readbyqxmd.com/read/28125789/codon-clarity-or-conundrum
#16
Daniel P Aalberts, Gregory Boël, John F Hunt
Synonymous variations in protein-coding sequences alter protein expression dynamics, which has important implications for cellular physiology and evolutionary fitness, but disentangling the underlying molecular mechanisms remains challenging.
January 25, 2017: Cell Systems
https://www.readbyqxmd.com/read/28125788/inference-of-environmental-factor-microbe-and-microbe-microbe-associations-from-metagenomic-data-using-a-hierarchical-bayesian-statistical-model
#17
Yuqing Yang, Ning Chen, Ting Chen
The inference of associations between environmental factors and microbes and among microbes is critical to interpreting metagenomic data, but compositional bias, indirect associations resulting from common factors, and variance within metagenomic sequencing data limit the discovery of associations. To account for these problems, we propose metagenomic Lognormal-Dirichlet-Multinomial (mLDM), a hierarchical Bayesian model with sparsity constraints, to estimate absolute microbial abundance and simultaneously infer both conditionally dependent associations among microbes and direct associations between microbes and environmental factors...
January 25, 2017: Cell Systems
https://www.readbyqxmd.com/read/28125787/genotype-phenotype-mapping-meets-single-cell%C3%A2-biology
#18
EDITORIAL
H Craig Mak, Quincey Justman
No abstract text is available yet for this article.
January 25, 2017: Cell Systems
https://www.readbyqxmd.com/read/28065575/multiparametric-analysis-of-cell-shape-demonstrates-that-%C3%AE-pix-directly-couples-yap-activation-to-extracellular-matrix-adhesion
#19
Julia E Sero, Chris Bakal
Mechanical signals from the extracellular matrix (ECM) and cellular geometry regulate the nuclear translocation of transcriptional regulators such as Yes-associated protein (YAP). Elucidating how physical signals control the activity of mechanosensitive proteins poses a technical challenge, because perturbations that affect cell shape may also affect protein localization indirectly. Here, we present an approach that mitigates confounding effects of cell-shape changes, allowing us to identify direct regulators of YAP localization...
January 25, 2017: Cell Systems
https://www.readbyqxmd.com/read/28065574/a-blueprint-for-a-synthetic-genetic-feedback-controller-to-reprogram-cell-fate
#20
Domitilla Del Vecchio, Hussein Abdallah, Yili Qian, James J Collins
To artificially reprogram cell fate, experimentalists manipulate the gene regulatory networks (GRNs) that maintain a cell's phenotype. In practice, reprogramming is often performed by constant overexpression of specific transcription factors (TFs). This process can be unreliable and inefficient. Here, we address this problem by introducing a new approach to reprogramming based on mathematical analysis. We demonstrate that reprogramming GRNs using constant overexpression may not succeed in general. Instead, we propose an alternative reprogramming strategy: a synthetic genetic feedback controller that dynamically steers the concentration of a GRN's key TFs to any desired value...
January 25, 2017: Cell Systems
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