mybib.bib

@article{Ahrends2014,
author = {Ahrends, R. and Ota, A. and Kovary, K. M. and Kudo, T. and Park, B. O. and Teruel, M. N.},
doi = {10.1126/science.1252079},
file = {:Users/kylekovary/Documents/Mendeley Desktop/Science/2014/Ahrends et al. - Controlling low rates of cell differentiation through noise and ultrahigh feedback. - 2014 - Science.pdf:pdf},
issn = {0036-8075},
journal = {Science},
mendeley-groups = {Thesis},
month = {jun},
number = {6190},
pages = {1384--1389},
title = {{Controlling low rates of cell differentiation through noise and ultrahigh feedback}},
url = {http://www.sciencemag.org/cgi/doi/10.1126/science.1252079 https://www.sciencemag.org/lookup/doi/10.1126/science.1252079},
volume = {344},
year = {2014}
}
@article{Abell2011,
abstract = {Despite large cell-to-cell variations in the concentrations of individual signaling proteins, cells transmit signals correctly. This phenomenon raises the question of what signaling systems do to prevent a predicted high failure rate. Here we combine quantitative modeling, RNA interference, and targeted selective reaction monitoring (SRM) mass spectrometry, and we show for the ubiquitous and fundamental calcium signaling system that cells monitor cytosolic and endoplasmic reticulum (ER) Ca(2+) levels and adjust in parallel the concentrations of the store-operated Ca(2+) influx mediator stromal interaction molecule (STIM), the plasma membrane Ca(2+) pump plasma membrane Ca-ATPase (PMCA), and the ER Ca(2+) pump sarco/ER Ca(2+)-ATPase (SERCA). Model calculations show that this combined parallel regulation in protein expression levels effectively stabilizes basal cytosolic and ER Ca(2+) levels and preserves receptor signaling. Our results demonstrate that, rather than directly controlling the relative level of signaling proteins in a forward regulation strategy, cells prevent transmission failure by sensing the state of the signaling pathway and using multiple parallel adaptive feedbacks.},
author = {Abell, Ellen and Ahrends, Robert and Bandara, Samuel and Park, Byung Ouk and Teruel, Mary N},
doi = {10.1073/pnas.1018266108},
file = {::},
isbn = {1091-6490 (Electronic)$\backslash$r0027-8424 (Linking)},
issn = {0027-8424},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
mendeley-groups = {Mass Spec,Misc,Thesis},
month = {aug},
number = {35},
pages = {14485--14490},
pmid = {21844332},
title = {{Parallel adaptive feedback enhances reliability of the Ca2+ signaling system.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21844332},
volume = {108},
year = {2011}
}
@article{Albeck2013,
abstract = {The EGF-stimulated ERK/MAPK pathway is a key conduit for cellular proliferation signals and a therapeutic target in many cancers. Here, we characterize two central quantitative aspects of this pathway: the mechanism by which signal strength is encoded and the response curve relating signal output to proliferation. Under steady-state conditions, we find that ERK is activated in discrete, asynchronous pulses with frequency and duration determined by extracellular concentrations of EGF spanning the physiological range. In genetically identical sister cells, cell-to-cell variability in pulse dynamics influences the decision to enter S phase. While targeted inhibition of EGFR reduces the frequency of ERK activity pulses, inhibition of MEK reduces their amplitude. Continuous response curves measured in multiple cell lines reveal that proliferation is effectively silenced only when ERK pathway output falls below a threshold of ∼10{\%}, indicating that high-dose targeting of the pathway is necessary to achieve therapeutic efficacy. {\textcopyright} 2013 Elsevier Inc.},
author = {Albeck, John G. and Mills, Gordon B. and Brugge, Joan S.},
doi = {10.1016/j.molcel.2012.11.002},
issn = {10972765},
journal = {Molecular Cell},
mendeley-groups = {Thesis},
pmid = {23219535},
title = {{Frequency-Modulated Pulses of ERK Activity Transmit Quantitative Proliferation Signals}},
year = {2013}
}
@article{Aoki2013,
abstract = {The extracellular signal-regulated kinase (ERK)plays a central role in the signaling cascades of cell growth. Here, we show that stochastic ERK activity pulses regulate cell proliferation rates in a cell density-dependent manner. A fluorescence resonance energy transfer (FRET) biosensor revealed that stochastic ERK activity pulses fired spontaneously or propagated from adjacent cells. Frequency, but not amplitude, of ERK activity pulses exhibited a bell-shaped response to the cell density and correlated with cell proliferation rates. Consistently, synthetic ERK activity pulses generated by a light-switchable CRaf protein accelerated cell proliferation. A mathematical model clarified that 80{\%} and 20{\%} of ERK activity pulses are generated by the noise and cell-to-cell propagation, respectively. Finally, RNA sequencing analysis of cells subjected to the synthetic ERK activity pulses suggested the involvement of serum responsive factor (SRF) transcription factors in the gene expression driven by the ERK activity pulses. {\textcopyright} 2013 Elsevier Inc.},
author = {Aoki, Kazuhiro and Kumagai, Yuka and Sakurai, Atsuro and Komatsu, Naoki and Fujita, Yoshihisa and Shionyu, Clara and Matsuda, Michiyuki},
doi = {10.1016/j.molcel.2013.09.015},
issn = {10972765},
journal = {Molecular Cell},
mendeley-groups = {Thesis},
pmid = {24140422},
title = {{Stochastic ERK activation induced by noise and cell-to-cell propagation regulates cell density-dependent proliferation}},
year = {2013}
}
@misc{Arshavsky2002,
abstract = {Phototransduction is the process by which a photon of light captured by a molecule of visual pigment generates an electrical response in a photoreceptor cell. Vertebrate rod phototransduction is one of the best-studied G protein signaling pathways. In this pathway the photoreceptor-specific G protein, transducin, mediates between the visual pigment, rhodopsin, and the effector enzyme, cGMP phosphodiesterase. This review focuses on two quantitative features of G protein signaling in phototransduction: signal amplification and response timing. We examine how the interplay between the mechanisms that contribute to amplification and those that govern termination of G protein activity determine the speed and the sensitivity of the cellular response to light.},
author = {Arshavsky, Vadim Y. and Lamb, Trevor D. and Pugh, Edward N.},
booktitle = {Annual Review of Physiology},
doi = {10.1146/annurev.physiol.64.082701.102229},
issn = {00664278},
keywords = {Amplification,Phosphodiesterase,Signal termination,Transducin},
mendeley-groups = {Thesis},
pmid = {11826267},
title = {{G proteins and phototransduction}},
year = {2002}
}
@article{Atgie1997,
abstract = {To evaluate the physiological functions of beta1-, beta2-, and beta3-adrenoceptors (ARs) in brown adipose tissue, the lipolytic and respiratory effects of various adrenergic agonists and antagonists were studied in rat brown adipocytes. The beta-agonists stimulated both lipolysis and respiration (8-10 times above basal levels), with the following order of potency (concentration eliciting 50{\%} of maximum response): CL-316243 (beta3) {\textgreater} BRL-37344 (beta3) {\textgreater} isoproterenol (mainly beta1/beta2) {\textgreater} norepinephrine (NE; mainly beta1/beta2) {\textgreater} epinephrine (mainly beta1/beta2) {\textgreater}{\textgreater} dobutamine (beta1) {\textgreater}{\textgreater} procaterol (beta2). Schild plot coefficients of competitive inhibition experiments using ICI-89406 (beta1 antagonist) revealed that more than one type of receptor mediates NE action. It is concluded from our results that 1) NE, at low plasma levels (1-25 nM), stimulates lipolysis and respiration mainly through beta1-ARs, 2) NE, at higher levels, stimulates lipolysis and respiration via both beta1- and beta3-ARs, 3) beta2-ARs play only a minor role, and 4) beta3-ARs may represent the physiological receptors for the high NE concentrations in the synaptic cleft, where the high-affinity beta1-ARs are presumably desensitized. It is also suggested that lipolysis represents the flux-generating step regulating mitochondrial respiration.},
author = {Atgie, C and D'Allaire, F and Bukowiecki, L J},
journal = {Am J Physiol.},
keywords = {Adipocytes/cytology/drug effects/physiology,Adrenergic alpha-Agonists/*pharmacology,Animals,Body Temperature Regulation/drug effects/*physiolo,Brown Fat/*physiology,Cells, Cultured,Dioxoles/pharmacology,Dobutamine/pharmacology,Epinephrine/pharmacology,Ethanolamines/pharmacology,Female,Isoproterenol/pharmacology,Lipolysis/drug effects/*physiology,Norepinephrine/pharmacology,Oxygen Consumption/drug effects,Procaterol/pharmacology,Rats,Rats, Sprague-Dawley,Receptors, Adrenergic, beta-1/*physiology,Receptors, Adrenergic, beta-2/physiology,Receptors, Adrenergic, beta-3,Receptors, Adrenergic, beta/*physiology,Research Support, Non-U.S. Gov't},
mendeley-groups = {Thesis},
title = {{Role of beta1- and beta3-adrenoceptors in the regulation of lipolysis and thermogenesis in rat brown adipocytes}},
year = {1997}
}
@article{Cappell2016,
abstract = {Proliferating cells must cross a point of no return before they replicate their DNA and divide. This commitment decision plays a fundamental role in cancer and degenerative diseases and has been proposed to be mediated by phosphorylation of retinoblastoma (Rb) protein. Here, we show that inactivation of the anaphase-promoting complex/cyclosome (APCCdh1) has the necessary characteristics to be the point of no return for cell-cycle entry. Our study shows that APCCdh1 inactivation is a rapid, bistable switch initiated shortly before the start of DNA replication by cyclin E/Cdk2 and made irreversible by Emi1. Exposure to stress between Rb phosphorylation and APCCdh1 inactivation, but not after APCCdh1 inactivation, reverted cells to a mitogen-sensitive quiescent state, from which they can later re-enter the cell cycle. Thus, APCCdh1 inactivation is the commitment point when cells lose the ability to return to quiescence and decide to progress through the cell cycle.},
author = {Cappell, Steven D and Chung, Mingyu and Jaimovich, Ariel and Spencer, Sabrina L and Meyer, Tobias},
doi = {10.1016/j.cell.2016.05.077},
issn = {10974172},
journal = {Cell},
mendeley-groups = {Thesis},
pmid = {27368103},
title = {{Irreversible APCCdh1 Inactivation Underlies the Point of No Return for Cell-Cycle Entry}},
year = {2016}
}
@article{Chang2008,
abstract = {Phenotypic cell-to-cell variability within clonal populations may be a manifestation of 'gene expression noise', or it may reflect stable phenotypic variants. Such 'non-genetic cell individuality' can arise from the slow fluctuations of protein levels in mammalian cells. These fluctuations produce persistent cell individuality, thereby rendering a clonal population heterogeneous. However, it remains unknown whether this heterogeneity may account for the stochasticity of cell fate decisions in stem cells. Here we show that in clonal populations of mouse haematopoietic progenitor cells, spontaneous 'outlier' cells with either extremely high or low expression levels of the stem cell marker Sca-1 (also known as Ly6a; ref. 9) reconstitute the parental distribution of Sca-1 but do so only after more than one week. This slow relaxation is described by a gaussian mixture model that incorporates noise-driven transitions between discrete subpopulations, suggesting hidden multi-stability within one cell type. Despite clonality, the Sca-1 outliers had distinct transcriptomes. Although their unique gene expression profiles eventually reverted to that of the median cells, revealing an attractor state, they lasted long enough to confer a greatly different proclivity for choosing either the erythroid or the myeloid lineage. Preference in lineage choice was associated with increased expression of lineage-specific transcription factors, such as a {\textgreater}200-fold increase in Gata1 (ref. 10) among the erythroid-prone cells, or a {\textgreater}15-fold increased PU.1 (Sfpi1) (ref. 11) expression among myeloid-prone cells. Thus, clonal heterogeneity of gene expression level is not due to independent noise in the expression of individual genes, but reflects metastable states of a slowly fluctuating transcriptome that is distinct in individual cells and may govern the reversible, stochastic priming of multipotent progenitor cells in cell fate decision. {\textcopyright}2008 Nature Publishing Group.},
author = {Chang, Hannah H. and Hemberg, Martin and Barahona, Mauricio and Ingber, Donald E. and Huang, Sui},
doi = {10.1038/nature06965},
issn = {14764687},
journal = {Nature},
mendeley-groups = {Thesis},
pmid = {18497826},
title = {{Transcriptome-wide noise controls lineage choice in mammalian progenitor cells}},
year = {2008}
}
@article{Cheong2011,
abstract = {Molecular noise restricts the ability of an individual cell to resolve input signals of different strengths and gather information about the external environment. Transmitting information through complex signaling networks with redundancies can overcome this limitation. We developed an integrative theoretical and experimental framework, based on the formalism of information theory, to quantitatively predict and measure the amount of information transduced by molecular and cellular networks. Analyzing tumor necrosis factor (TNF) signaling revealed that individual TNF signaling pathways transduce information sufficient for accurate binary decisions, and an upstream bottleneck limits the information gained via multiple integrated pathways. Negative feedback to this bottleneck could both alleviate and enhance its limiting effect, despite decreasing noise. Bottlenecks likewise constrain information attained by networks signaling through multiple genes or cells.},
author = {Cheong, Raymond and Rhee, Alex and Wang, Chiaochun Joanne and Nemenman, Ilya and Levchenko, Andre},
doi = {10.1126/science.1204553},
issn = {10959203},
journal = {Science},
mendeley-groups = {Thesis},
pmid = {21921160},
title = {{Information transduction capacity of noisy biochemical signaling networks}},
year = {2011}
}
@misc{Eldar2010,
abstract = {The genetic circuits that regulate cellular functions are subject to stochastic fluctuations, or 'noise', in the levels of their components. Noise, far from just a nuisance, has begun to be appreciated for its essential role in key cellular activities. Noise functions in both microbial and eukaryotic cells, in multicellular development, and in evolution. It enables coordination of gene expression across large regulons, as well as probabilistic differentiation strategies that function across cell populations. At the longest timescales, noise may facilitate evolutionary transitions. Here we review examples and emerging principles that connect noise, the architecture of the gene circuits in which it is present, and the biological functions it enables. We further indicate some of the important challenges and opportunities going forward. {\textcopyright} 2010 Macmillan Publishers Limited. All rights reserved.},
author = {Eldar, Avigdor and Elowitz, Michael B.},
booktitle = {Nature},
doi = {10.1038/nature09326},
issn = {14764687},
mendeley-groups = {Thesis},
pmid = {20829787},
title = {{Functional roles for noise in genetic circuits}},
year = {2010}
}
@article{Feinerman2008,
abstract = {In T cells, the stochasticity of protein expression could contribute to the useful diversification of biological functions within a clonal population or interfere with accurate antigen discrimination. Combining computer modeling and single-cell measurements, we examined how endogenous variation in the expression levels of signaling proteins might affect antigen responsiveness during T cell activation. We found that the CD8 co-receptor fine-tunes activation thresholds, whereas the soluble hematopoietic phosphatase 1 (SHP-1) digitally regulates cell responsiveness. Stochastic variation in the expression of these proteins generates substantial diversity of activation within a clonal population of T cells, but co-regulation of CD8 and SHP-1 levels ultimately limits this very diversity. These findings reveal how eukaryotic cells can draw on regulated variation in gene expression to achieve phenotypic variability in a controlled manner.},
author = {Feinerman, Ofer and Veiga, Jo{\"{e}}l and Dorfman, Jeffrey R. and Germain, Ronald N. and Altan-Bonnet, Gr{\'{e}}goire},
doi = {10.1126/science.1158013},
issn = {00368075},
journal = {Science},
mendeley-groups = {Thesis},
pmid = {18719282},
title = {{Variability and robustness in T cell activation from regulated heterogeneity in protein levels}},
year = {2008}
}
@incollection{Feng2016,
abstract = {Biology and especially systems biology projects increasingly require the capability to detect and quantify specific sets of proteins across multiple samples, for example the components of a biological pathway through a set of perturbation-response experiments. Targeted proteomics based on selected reaction monitoring (SRM) has emerged as an ideal tool to this purpose, and complements the discovery capabilities of shotgun proteomics methods. SRM experiments rely on the development of specific, quantitative mass spectrometric assays for each protein of interest and their application to the quantification of the protein set in various biological samples. SRM measurements are multiplexed, namely, multiple proteins can be quantified simultaneously, and are characterized by a high reproducibility and a broad dynamic range. We provide here a practical guide to the development of SRM assays targeting a set of proteins of interest and to their application to complex biological samples.},
author = {Feng, Yuehan and Picotti, Paola},
booktitle = {Methods in Molecular Biology},
doi = {10.1007/978-1-4939-3341-9_4},
issn = {10643745},
keywords = {Assay design,Assay validation,Protein quantitation,Selected reaction monitoring,Targeted proteomics},
mendeley-groups = {Thesis},
pmid = {26700040},
title = {{Selected reaction monitoring to measure proteins of interest in complex samples: A practical guide}},
year = {2016}
}
@misc{Ferrell1999,
abstract = {Fully grown Xenopus oocytes can remain in their immature state essentially indefinitely, or, in response to the steroid hormone progesterone, can be induced to develop into fertilizable eggs. This process is termed oocyte maturation. Oocyte maturation is initiated by a novel plasma membrane steroid hormone receptor. Progesterone brings about inhibition of adenylate cyclase and activation of the Mos/MEK1/p42 MAP kinase cascade, which ultimately brings about the activation of the universal M phase trigger Cdc2/cyclin B. Oocyte maturation provides an interesting example of how signaling cascades entrain the cell cycle clock to environmental changes.},
author = {Ferrell, James E.},
booktitle = {BioEssays},
doi = {10.1002/(SICI)1521-1878(199910)21:10<833::AID-BIES5>3.0.CO;2-P},
issn = {02659247},
mendeley-groups = {Thesis},
pmid = {10497333},
title = {{Xenopus oocyte maturation: New lessons from a good egg}},
year = {1999}
}
@article{Gaudet2012,
abstract = {Stochastic fluctuations in gene expression give rise to cell-to-cell variability in protein levels which can potentially cause variability in cellular phenotype. For TRAIL (TNF-related apoptosis-inducing ligand) variability manifests itself as dramatic differences in the time between ligand exposure and the sudden activation of the effector caspases that kill cells. However, the contribution of individual proteins to phenotypic variability has not been explored in detail. In this paper we use feature-based sensitivity analysis as a means to estimate the impact of variation in key apoptosis regulators on variability in the dynamics of cell death. We use Monte Carlo sampling from measured protein concentration distributions in combination with a previously validated ordinary differential equation model of apoptosis to simulate the dynamics of receptor-mediated apoptosis. We find that variation in the concentrations of some proteins matters much more than variation in others and that precisely which proteins matter depends both on the concentrations of other proteins and on whether correlations in protein levels are taken into account. A prediction from simulation that we confirm experimentally is that variability in fate is sensitive to even small increases in the levels of Bcl-2. We also show that sensitivity to Bcl-2 levels is itself sensitive to the levels of interacting proteins. The contextual dependency is implicit in the mathematical formulation of sensitivity, but our data show that it is also important for biologically relevant parameter values. Our work provides a conceptual and practical means to study and understand the impact of cell-to-cell variability in protein expression levels on cell fate using deterministic models and sampling from parameter distributions. {\textcopyright} 2012 Gaudet et al.},
author = {Gaudet, Suzanne and Spencer, Sabrina L. and Chen, William W. and Sorger, Peter K.},
doi = {10.1371/journal.pcbi.1002482},
issn = {1553734X},
journal = {PLoS Computational Biology},
mendeley-groups = {Thesis},
pmid = {22570596},
title = {{Exploring the contextual sensitivity of factors that determine cell-to-cell variability in receptor-mediated apoptosis}},
year = {2012}
}
@inproceedings{Grover2011,
abstract = {Using a microfluidic mass sensor, we have measured the density of single cells. We find that cell density is the most tightly regulated aspect of cell size: the cell-to-cell variation in density is almost 100 times smaller than the mass or volume variation. As a result, we can measure changes in cell density that are undetectable in cell mass or volume. We demonstrate this with four examples: distinguishing malaria-infected erythrocytes from healthy cells, discriminating transfused erythrocytes from an individual's own cells, identifying irreversibly-sickled cells from a patient with sickle-cell anemia, and identifying leukemia cells in the early stages of drug-induced apoptosis. Copyright {\textcopyright} (2011) by the Chemical and Biological Microsystems Society.},
author = {Grover, W. H. and Bryan, A. K. and Diez-Silva, M. and Suresh, S. and Higgins, J. M. and Manalis, S. R.},
booktitle = {15th International Conference on Miniaturized Systems for Chemistry and Life Sciences 2011, MicroTAS 2011},
isbn = {9781618395955},
keywords = {Cell density,Cell mass,Cell volume,Suspended MicroChannel resonator},
mendeley-groups = {Thesis},
title = {{Measuring single-cell density}},
year = {2011}
}
@article{Hide1993,
abstract = {Widespread experience indicates that application of suboptimal concentrations of stimulating ligands (secretagogues) to secretory cells elicits submaximal extents of secretion. Similarly, for permeabilized secretory cells, the extent of secretion is related to the concentration of applied intracellular effectors. We investigated the relationship between the extent of secretion from mast cells (assessed as the release of hexosaminidase) and the degranulation (exocytosis) responses of individual cells. For permeabilized mast cells stimulated by the effector combination Ca2+ plus GTP-$\gamma$-S and for intact cells stimulated by the Ca2+ ionophore ionomycin, we found that exocytosis has the characteristics of an all-or- none process at the level of the individual cell. With a suboptimal stimulus, the population comprised only totally degranulated cells and fully replete cells. In contrast, a suboptimal concentration of compound 48/80 applied to intact cells induced a partial degree of degranulation. This was determined by observing the morphological changes accompanying degranulation by light and electron microscopy and also as a reduction in the intensity of light scattered at 90°, indicative of a change in the cell-refractive index. These results may be explained by the existence of a threshold sensitivity to the combined effectors that is set at the level of individual cells and not at the granule level. We used flow cytometry to establish the relationship between the extent of degranulation in individual rat peritoneal mast cells and the extent of secretion in the population (measured as the percentage release of total hexosaminidase). For comparison, secretion was also elicited by applying the Ca2+ ionophore ionomycin or compound 48/80 to intact cells. For permeabilized cells and also for intact cells stimulated with the ionophore, levels of stimulation that generate partial secretion gave rise to bimodal frequency distributions of 90° light scatter. In contrast, a partial stimulus to secretion by compound 48/80 resulted in a single population of partially degranulated cells, the degree of degranulation varying across the cell population. The difference between the all-or-none responses of the permeabilized or ionophore-treated cells and the graded responses of cells activated by compound 48/80 is likely to stem from differences in the effective calcium stimulus. Whereas cells stimulated with receptor-directed agonists can undergo transient and localized Ca2+ changes, a homogeneous and persistent stimulus is sensed at every potential exocytotic site in the permeabilized cells.},
author = {Hide, I. and Bennett, J. P. and Pizzey, A. and Boonen, G. and Bar-Sagi, D. and Gomperts, B. D. and Tatham, P. E.R.},
doi = {10.1083/jcb.123.3.585},
issn = {00219525},
journal = {Journal of Cell Biology},
mendeley-groups = {Thesis},
pmid = {8227127},
title = {{Degranulation of individual mast cells in response to Ca2+ and guanine nucleotides: An all-or-none event}},
year = {1993}
}
@article{Hodgkin1952,
author = {Hodgkin, A. L. and Huxley, A. F.},
doi = {10.1113/jphysiol.1952.sp004764},
issn = {14697793},
journal = {The Journal of Physiology},
mendeley-groups = {Thesis},
pmid = {12991237},
title = {{A quantitative description of membrane current and its application to conduction and excitation in nerve}},
year = {1952}
}
@misc{Johnson2002,
abstract = {Multicellular organisms have three well-characterized subfamilies of mitogen-activated protein kinases (MAPKs) that control a vast array of physiological processes. These enzymes are regulated by a characteristic phosphorelay system in which a series of three protein kinases phosphorylate and activate one another. The extracellular signal-regulated kinases (ERKs) function in the control of cell division, and inhibitors of these enzymes are being explored as anticancer agents. The c-Jun amino-terminal kinases (JNKs) are critical regulators of transcription, and JNK inhibitors may be effective in control of rheumatoid arthritis. The p38 MAPKs are activated by inflammatory cytokines and environmental stresses and may contribute to diseases like asthma and autoimmunity.},
author = {Johnson, Gary L. and Lapadat, Razvan},
booktitle = {Science},
doi = {10.1126/science.1072682},
issn = {00368075},
mendeley-groups = {Thesis},
pmid = {12471242},
title = {{Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases}},
year = {2002}
}
@misc{Jukam2010,
abstract = {Neural cell fate programs must generate an enormous number of neurons with distinct adult functions. The decision to choose one neuronal subtype from two alternatives - a binary fate decision - is one way to diversify neuronal subtypes during nervous system development. Recent progress has been made in describing the genetic programs that define late-stage neuronal identity. Here, we review mechanisms that control how such fate decisions generate two different postmitotic, terminally differentiated neuronal subtypes. We survey examples from Caenorhabditis elegans and Drosophila that demonstrate different modes of binary neuronal fate specification that depend on cell division, lineage, stochastic gene expression, or extracellular signals. Comparison of these strategies reveals that, although organisms use diverse approaches to generate neural diversity, some common themes do exist. {\textcopyright} 2009 Elsevier Ltd. All rights reserved.},
author = {Jukam, David and Desplan, Claude},
booktitle = {Current Opinion in Neurobiology},
doi = {10.1016/j.conb.2009.11.002},
issn = {09594388},
mendeley-groups = {Thesis},
pmid = {20022236},
title = {{Binary fate decisions in differentiating neurons}},
year = {2010}
}
@article{Kafri2013,
abstract = {Biologists have long been concerned about what constrains variation in cell size, but progress in this field has been slow and stymied by experimental limitations. Here we describe a new method, ergodic rate analysis (ERA), that uses single-cell measurements of fixed steady-state populations to accurately infer the rates of molecular events, including rates of cell growth. ERA exploits the fact that the number of cells in a particular state is related to the average transit time through that state. With this method, it is possible to calculate full time trajectories of any feature that can be labelled in fixed cells, for example levels of phosphoproteins or total cellular mass. Using ERA we find evidence for a size-discriminatory process at the G1/S transition that acts to decrease cell-to-cell size variation. {\textcopyright} 2013 Macmillan Publishers Limited. All rights reserved.},
author = {Kafri, Ran and Levy, Jason and Ginzberg, Miriam B. and Oh, Seungeun and Lahav, Galit and Kirschner, Marc W.},
doi = {10.1038/nature11897},
issn = {00280836},
journal = {Nature},
mendeley-groups = {Thesis},
pmid = {23446419},
title = {{Dynamics extracted from fixed cells reveal feedback linking cell growth to cell cycle}},
year = {2013}
}
@article{Kalmar2009,
abstract = {There is evidence that pluripotency of mouse embryonic stem (ES) cells is associated with the activity of a network of transcription factors with Sox2, Oct4, and Nanog at the core. Using fluorescent reporters for the expression of Nanog, we observed that a population of ES cells is best described by a dynamic distribution of Nanog expression characterized by two peaks defined by high (HN) and low (LN) Nanog expression. Typically, the LN state is 5{\%}-20{\%} of the total population, depending on the culture conditions. Modelling of the activity of Nanog reveals that a simple network of Oct4/Sox2 and Nanog activity can account for the observed distribution and its properties as long as the transcriptional activity is tuned by transcriptional noise. The model also predicts that the LN state is unstable, something that is born out experimentally. While in this state, cells can differentiate. We suggest that transcriptional fluctuations in Nanog expression are an essential element of the pluripotent state and that the function of Sox2, Oct4, and Nanog is to act as a network that promotes and maintains transcriptional noise to interfere with the differentiation signals. {\textcopyright} 2009 Kalmar et al.},
author = {Kalmar, Tibor and Lim, Chea and Hayward, Penelope and Mu{\~{n}}oz-Descalzo, Silvia and Nichols, Jennifer and Garcia-Ojalvo, Jordi and Arias, Alfonso Martinez},
doi = {10.1371/journal.pbio.1000149},
issn = {15449173},
journal = {PLoS Biology},
mendeley-groups = {Thesis},
pmid = {19582141},
title = {{Regulated fluctuations in Nanog expression mediate cell fate decisions in embryonic stem cells}},
year = {2009}
}
@article{Kar2009,
abstract = {The DNA replication - division cycle of eukaryotic cells is controlled by a complex network of regulatory proteins, called cyclin-dependent kinases, and their activators and inhibitors. Although comprehensive and accurate deterministic models of the control system are available for yeast cells, reliable stochastic simulations have not been carried out because the full reaction network has yet to be expressed in terms of elementary reaction steps. As a first step in this direction, we present a simplified version of the control system that is suitable for exact stochastic simulation of intrinsic noise caused by molecular fluctuations and extrinsic noise because of unequal division. The model is consistent with many characteristic features of noisy cell cycle progression in yeast populations, including the observation that mRNAs are present in very low abundance (≈1 mRNA molecule per cell for each expressed gene). For the control system to operate reliably at such low mRNA levels, some specific mRNAs in our model must have very short half-lives ({\textless}1 min). If these mRNA molecules are longer-lived (perhaps 2 min), then the intrinsic noise in our simulations is too large, and there must be some additional noise suppression mechanisms at work in cells.},
author = {Kar, Sandip and Baumann, William T. and Paul, Mark R. and Tyson, John J.},
doi = {10.1073/pnas.0810034106},
issn = {00278424},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
keywords = {Cyclin-dependent kinase,Gene expression,Network dynamics,Stochastic model,mRNA turnover},
mendeley-groups = {Thesis},
pmid = {19246388},
title = {{Exploring the roles of noise in the eukaryotic cell cycle}},
year = {2009}
}
@article{Katakam2001,
abstract = {Hyper-insulinemia, a primary feature of insulin resistance, is associated with increased endothelin-1 (ET-1) activity. This study determined the vascular response to ET-1 and receptor binding characteristics in small mesenteric arteries of insulin-resistant (IR) rats. Rats were randomized to control (C) (n = 32) or IR (n = 32) groups. The response to ET-1 was assessed (in vitro) in arteries with (Endo+) and without (Endo-) endothelium. In addition, arteries (Endo+) were pretreated with the ETB antagonist A-192621 or the ETA antagonist A-127722. Finally, binding characteristics of [125I]ET-1 were determined. Results showed that in Endo+ arteries the maximal relaxation (Emax) to ET-1 was similar between C and IR groups; however, the concentration at 50{\%} of maximum relaxation (EC50) was decreased in IR arteries. In Endo-arteries, the Emax to ET-1 was enhanced in both groups. Pretreatment with A-192621 enhanced the Emax and EC50 to ET-1 in both groups. In contrast, A-127722 inhibited the ET-1 response in all arteries in a concentration-dependent manner; however, a greater ET-1 response was seen at each concentration in IR arteries. Maximal binding of [125I]ET-1 was increased in IR versus C arteries although the dissociation constant values were similar. In conclusion, we found the vasoconstrictor response to ET-1 is enhanced in IR arteries due to an enhanced expression of ET receptors and underlying endothelial dysfunction.},
author = {Katakam, Prasad V.G. and Pollock, Jennifer S. and Pollock, David M. and Ujhelyi, Michael R. and Miller, Allison W.},
doi = {10.1152/ajpheart.2001.280.2.h522},
issn = {03636135},
journal = {American Journal of Physiology - Heart and Circulatory Physiology},
keywords = {ETA,ETB,Hyperinsulinemia},
mendeley-groups = {Thesis},
pmid = {11158947},
title = {{Enhanced endothelin-1 response and receptor expression in small mesenteric arteries of insulin-resistant rats}},
year = {2001}
}
@article{Kimura2007,
abstract = {The aim of this study was to evaluate cutaneous vasodilation and sweating responses to exogenous administration of acetylcholine (ACh) and methacholine (MCh), which have different sensitivities to endogenous cholinesterase. Four intradermal microdialysis probes were placed in dorsal forearm skin: two sites were perfused with ACh (1 × 10-7-1 M) and the other two with the same molar concentrations of MCh. Sweat rate (SR) and cutaneous blood flow were simultaneously assessed directly over each microdialysis membrane. Dose-response curves were constructed, and the effective concentration of the drug resulting in 50{\%} of the maximal response (EC50) was identified. For SR and cutaneous vascular conductance (CVC), there were no significant differences in EC50 between sites receiving the same drug: -1.52 ± 0.18 and -1.19 ± 0.09 log-molar concentration of ACh at distal and proximal sites, respectively, and -2.35 ± 0.24 and -2.42 ± 0.23 log-molar concentration of MCh at distal and proximal sites, respectively, for SR (P {\textgreater} 0.05) and -3.87 ± 0.32 and -3.97 ± 0.27 log-molar concentration of ACh at distal and proximal sites, respectively, and -4.78 ± 0.17 and -4.46 ± 0.16 log-molar concentration of MCh at distal and proximal sites, respectively, for CVC (P {\textgreater} 0.05). However, the EC 50 for CVC and SR was significantly lower at the MCh than at the ACh sites. A second procedure was performed to confirm that differences in responses between ACh and MCh could be attributed to different cholinesterase sensitivities. Similarly, four microdialysis membranes were placed in dorsal forearm skin: two sites were perfused with ACh and other two with MCh. However, one of each of the ACh and MCh sites was also perfused with 10 $\mu$M neostigmine (an acetylcholinesterase inhibitor). Neostigmine at the ACh site induced a leftward shift (i.e., lower EC50) of the SR and CVC dose-response curves compared with the site treated with ACh alone, resulting in no difference in the EC50 for SR and CVC between the ACh +- neostigmine and the MCh site. These results suggest that elevations in SR and CVC occur earlier with MCh than with ACh treatment because of differences in cholinesterase susceptibility between these drugs. Copyright {\textcopyright} 2007 the American Physiological Society.},
author = {Kimura, Kenichi and Low, David A. and Keller, David M. and Davis, Scott L. and Crandall, Craig G.},
doi = {10.1152/japplphysiol.01069.2006},
issn = {87507587},
journal = {Journal of Applied Physiology},
keywords = {Microdialysis,Sweating,Thermoregulation},
mendeley-groups = {Thesis},
pmid = {17234802},
title = {{Cutaneous blood flow and sweat rate responses to exogenous administration of acetylcholine and methacholine}},
year = {2007}
}
@article{Komatsu2011,
abstract = {Biosensors based on the principle of F{\"{o}}rster (or fluorescence) resonance energy transfer (FRET) have shed new light on the spatiotemporal dynamics of signaling molecules. Among them, intramolecular FRET biosensors have been increasingly used due to their high sensitivity and user-friendliness. Time-consuming optimizations by trial and error, however, obstructed the development of intramolecular FRET biosensors. Here we report an optimized backbone for rapid development of highly sensitive intramolecular FRET biosensors. The key concept is to exclude the "orientation-dependent" FRET and to render the biosensors completely "distance-dependent" with a long, flexible linker. We optimized a pair of fluorescent proteins for distance-dependent biosensors, and then developed a long, flexible linker ranging from 116 to 244 amino acids in length, which reduced the basal FRET signal and thereby increased the gain of the FRET biosensors. Computational simulations provided insight into the mechanisms by which this optimized system was the rational strategy for intramolecular FRET biosensors. With this backbone system, we improved previously reported FRET biosensors of PKA, ERK, JNK, EGFR/Abl, Ras, and Rac1. Furthermore, this backbone enabled us to develop novel FRET biosensors for several kinases of RSK, S6K, Akt, and PKC and to perform quantitative evaluation of kinase inhibitors in living cells. {\textcopyright} 2011 Komatsu et al.},
author = {Komatsu, Naoki and Aoki, Kazuhiro and Yamada, Masashi and Yukinaga, Hiroko and Fujita, Yoshihisa and Kamioka, Yuji and Matsuda, Michiyuki},
doi = {10.1091/mbc.E11-01-0072},
issn = {10591524},
journal = {Molecular Biology of the Cell},
mendeley-groups = {Thesis},
pmid = {21976697},
title = {{Development of an optimized backbone of FRET biosensors for kinases and GTPases}},
year = {2011}
}
@incollection{Krauchunas2013,
abstract = {Egg activation is the final transition that an oocyte goes through to become a developmentally competent egg. This transition is usually triggered by a calcium-based signal that is often, but not always, initiated by fertilization. Activation encompasses a number of changes within the egg. These include changes to the egg's membranes and outer coverings to prevent polyspermy and to support the developing embryo, as well as resumption and completion of the meiotic cell cycle, mRNA polyadenylation, translation of new proteins, and the degradation of specific maternal mRNAs and proteins. The transition from an arrested, highly differentiated cell, the oocyte, to a developmentally active, totipotent cell, the activated egg or embryo, represents a complete change in cellular state. This is accomplished by altering ion concentrations and by widespread changes in both the proteome and the suite of mRNAs present in the cell. Here, we review the role of calcium and zinc in the events of egg activation, and the importance of macromolecular changes during this transition. The latter include the degradation and translation of proteins, protein posttranslational regulation through phosphorylation, and the degradation, of maternal mRNAs. {\textcopyright} 2013 Elsevier Inc.},
author = {Krauchunas, Amber R. and Wolfner, Mariana F.},
booktitle = {Current Topics in Developmental Biology},
doi = {10.1016/B978-0-12-416024-8.00010-6},
issn = {00702153},
keywords = {Calcium,Fertilization,Maternal mRNAs and proteins,Oocyte-to-embryo transition,Phosphorylation,Proteome},
mendeley-groups = {Thesis},
title = {{Molecular Changes During Egg Activation}},
year = {2013}
}
@article{Ludwig2012,
abstract = {For many research questions in modern molecular and systems biology, information about absolute protein quantities is imperative. This information includes, for example, kinetic modeling of processes, protein turnover determinations, stoichiometric investigations of protein complexes, or quantitative comparisons of different proteins within one sample or across samples. To date, the vast majority of proteomic studies are limited to providing relative quantitative comparisons of protein levels between limited numbers of samples. Here we describe and demonstrate the utility of a targeting MS technique for the estimation of absolute protein abundance in unlabeled and nonfractionated cell lysates. The method is based on selected reaction monitoring (SRM) mass spectrometry and the "best flyer" hypothesis, which assumes that the specific MS signal intensity of the most intense tryptic peptides per protein is approximately constant throughout a whole proteome. SRM-targeted best flyer peptides were selected for each protein from the peptide precursor ion signal intensities from directed MS data. The most intense transitions per peptide were selected from full MS/MS scans of crude synthetic analogs. We used Monte Carlo cross-validation to systematically investigate the accuracy of the technique as a function of the number of measured best flyer peptides and the number of SRM transitions per peptide. We found that a linear model based on the two most intense transitions of the three best flying peptides per proteins (TopPep3/TopTra2) generated optimal results with a cross-correlated mean fold error of 1.8 and a squared Pearson coefficient R2 of 0.88. Applying the optimized model to lysates of the microbe Leptospira interrogans, we detected significant protein abundance changes of 39 target proteins upon antibiotic treatment, which correlate well with literature values. The described method is generally applicable and exploits the inherent performance advantages of SRM, such as high sensitivity, selectivity, reproducibility, and dynamic range, and estimates absolute protein concentrations of selected proteins at minimized costs. {\textcopyright} 2012 by The American Society for Biochemistry and Molecular Biology, Inc.},
author = {Ludwig, Christina and Claassen, Manfred and Schmidt, Alexander and Aebersold, Ruedi},
doi = {10.1074/mcp.M111.013987},
issn = {15359484},
journal = {Molecular and Cellular Proteomics},
mendeley-groups = {Thesis},
pmid = {22101334},
title = {{Estimation of absolute protein quantities of unlabeled samples by selected reaction monitoring mass spectrometry}},
year = {2012}
}
@article{McShane2016,
abstract = {Do young and old protein molecules have the same probability to be degraded? We addressed this question using metabolic pulse-chase labeling and quantitative mass spectrometry to obtain degradation profiles for thousands of proteins. We find that {\textgreater}10{\%} of proteins are degraded non-exponentially. Specifically, proteins are less stable in the first few hours of their life and stabilize with age. Degradation profiles are conserved and similar in two cell types. Many non-exponentially degraded (NED) proteins are subunits of complexes that are produced in super-stoichiometric amounts relative to their exponentially degraded (ED) counterparts. Within complexes, NED proteins have larger interaction interfaces and assemble earlier than ED subunits. Amplifying genes encoding NED proteins increases their initial degradation. Consistently, decay profiles can predict protein level attenuation in aneuploid cells. Together, our data show that non-exponential degradation is common, conserved, and has important consequences for complex formation and regulation of protein abundance.},
author = {McShane, Erik and Sin, Celine and Zauber, Henrik and Wells, Jonathan N. and Donnelly, Neysan and Wang, Xi and Hou, Jingyi and Chen, Wei and Storchova, Zuzana and Marsh, Joseph A. and Valleriani, Angelo and Selbach, Matthias},
doi = {10.1016/j.cell.2016.09.015},
issn = {10974172},
journal = {Cell},
keywords = {aneuploidy,bioorthogonal amino acid tagging,gene copy-number alterations,metabolic labeling,posttranslational control,protein complex assembly,protein degradation,proteomics,pulse chase experiment,trisomy},
mendeley-groups = {Thesis},
pmid = {27720452},
title = {{Kinetic Analysis of Protein Stability Reveals Age-Dependent Degradation}},
year = {2016}
}
@article{Nash2001,
abstract = {The pleckstrin homology domain of phospholipase C$\delta$1 (PHPLC$\delta$) binds Ins(1,4,5)P3 and PtdIns(4,5)P2 specifically, and can be used to detect changes in Ins(1,4,5)P3 in single cells. A fusion construct of PHPLC$\delta$ and enhanced green fluorescent protein (EGFP-PHPLC$\delta$) associates with the plasma membrane due to its association with PtdIns(4,5)P2. However, PHPLC$\delta$ has greater affinity for Ins(1,4,5)P3 than PtdIns(4,5)P2, and translocates to the cytosol as Ins(1,4,5)P3 levels rise. Prolonged activation of group I metabotropic glutamate receptor 1$\alpha$ expressed in Chinese-hamster ovary cells or endogenous M3 muscarinic receptors in SH-SY5Y neuroblastoma cells gave an initial transient peak in translocation, followed by a sustained plateau phase. This closely followed changes in cell population Ins(1,4,5)P3 mass, but not PtdIns(4,5)P2 levels, which decreased monophasically, as determined by radioreceptor assay. Translocation thus provides a real-time method to follow increases in Ins(1,4,5)P3. Graded changes in Ins(1,4,5)P3 in Chinese-hamster ovary-lac-mGlu1$\alpha$ cells could be detected with increasing glutamate concentrations, and dual loading with fura 2 and EGFP-PHPLC$\delta$ showed that changes in intracellular Ca2+ concentration closely paralleled Ins(1,4,5)P3 production. Moreover, Ins(1,4,5)P3 accumulation and intracellular Ca2+ mobilization within single cells is graded in nature and dependent on both agonist concentration and receptor density.},
author = {Nash, Mark S. and Young, Kenneth W. and Willars, Gary B. and Challiss, R. A.John and Nahorski, Stefan R.},
doi = {10.1042/0264-6021:3560137},
issn = {02646021},
journal = {Biochemical Journal},
keywords = {Group I metabotropic glutamate receptor 1$\alpha$,M3 muscarinic receptor,Pleckstrin homology domain},
mendeley-groups = {Thesis},
pmid = {11336645},
title = {{Single-cell imaging of graded ins(1,4,5)P3 production following G-protein-coupled-receptor activation}},
year = {2001}
}
@misc{Niepel2009,
abstract = {Recent advances in single-cell assays have focused attention on the fact that even members of a genetically identical group of cells or organisms in identical environments can exhibit variability in drug sensitivity, cellular response, and phenotype. Underlying much of this variability is stochasticity in gene expression, which can produce unique proteomes even in genetically identical cells. Here we discuss the consequences of non-genetic cell-to-cell variability in the cellular response to drugs and its potential impact for the treatment of human disease. {\textcopyright} 2009 Elsevier Ltd. All rights reserved.},
author = {Niepel, Mario and Spencer, Sabrina L. and Sorger, Peter K.},
booktitle = {Current Opinion in Chemical Biology},
doi = {10.1016/j.cbpa.2009.09.015},
issn = {13675931},
mendeley-groups = {Thesis},
pmid = {19833543},
title = {{Non-genetic cell-to-cell variability and the consequences for pharmacology}},
year = {2009}
}
@article{Padovan-Merhar2015,
abstract = {Individual mammalian cells exhibit large variability in cellular volume, even with the same absolute DNA content, and so must compensate for differences inDNA concentration in order to maintain constant concentration of gene expression products. Using single-molecule counting and computational image analysis, we show that transcript abundance correlates with cellular volume at the single-cell level due to increased global transcription in larger cells. Cell fusion experiments establish that increased cellular content itself can directly increase transcription. Quantitative analysis shows that this mechanism measures the ratio of cellular volume to DNA content, most likely through sequestration of a transcriptional factor to DNA. Analysis of transcriptional bursts reveals a separate mechanism for gene dosage compensation after DNA replication that enables proper transcriptional output during early and late S phase. Our results provide a framework for quantitatively understanding the relationships among DNA content, cell size, and gene expression variability in single cells.},
author = {Padovan-Merhar, Olivia and Nair, Gautham P. and Biaesch, Andrew G. and Mayer, Andreas and Scarfone, Steven and Foley, Shawn W. and Wu, Angela R. and Churchman, L. Stirling and Singh, Abhyudai and Raj, Arjun},
doi = {10.1016/j.molcel.2015.03.005},
issn = {10974164},
journal = {Molecular Cell},
mendeley-groups = {Thesis},
pmid = {25866248},
title = {{Single Mammalian Cells Compensate for Differences in Cellular Volume and DNA Copy Number through Independent Global Transcriptional Mechanisms}},
year = {2015}
}
@article{Peshkin2015,
abstract = {A biochemical explanation of development from the fertilized egg to the adult requires an understanding of the proteins and RNAs expressed over time during embryogenesis. We present a comprehensive characterization of protein and mRNA dynamics across early development in Xenopus. Surprisingly, we find that most protein levels change little and duplicated genes are expressed similarly. While the correlation between protein and mRNA levels is poor, a mass action kinetics model parameterized using protein synthesis and degradation rates regresses protein dynamics to RNA dynamics, corrected for initial protein concentration. This study provides detailed data for absolute levels of {\~{}}10,000 proteins and {\~{}}28,000 transcripts via a convenient web portal, a rich resource for developmental biologists. It underscores the lasting impact of maternal dowry, finds surprisingly few cases where degradation alone drives a change in protein level, and highlights the importance of transcription in shaping the dynamics of the embryonic proteome.},
author = {Peshkin, Leonid and W{\"{u}}hr, Martin and Pearl, Esther and Haas, Wilhelm and Freeman, Robert M. and Gerhart, John C. and Klein, Allon M. and Horb, Marko and Gygi, Steven P. and Kirschner, Marc W.},
doi = {10.1016/j.devcel.2015.10.010},
issn = {18781551},
journal = {Developmental Cell},
mendeley-groups = {Thesis},
pmid = {26555057},
title = {{On the Relationship of Protein and mRNA Dynamics in Vertebrate Embryonic Development}},
year = {2015}
}
@misc{Picotti2012,
abstract = {Selected reaction monitoring (SRM) is a targeted mass spectrometry technique that is emerging in the field of proteomics as a complement to untargeted shotgun methods. SRM is particularly useful when predetermined sets of proteins, such as those constituting cellular networks or sets of candidate biomarkers, need to be measured across multiple samples in a consistent, reproducible and quantitatively precise manner. Here we describe how SRM is applied in proteomics, review recent advances, present selected applications and provide a perspective on the future of this powerful technology. {\textcopyright} 2012 Nature America, Inc. All rights reserved.},
author = {Picotti, Paola and Aebersold, Ruedi},
booktitle = {Nature Methods},
doi = {10.1038/nmeth.2015},
issn = {15487091},
mendeley-groups = {Thesis},
pmid = {22669653},
title = {{Selected reaction monitoring-based proteomics: Workflows, potential, pitfalls and future directions}},
year = {2012}
}
@misc{Raj2008,
abstract = {Gene expression is a fundamentally stochastic process, with randomness in transcription and translation leading to cell-to-cell variations in mRNA and protein levels. This variation appears in organisms ranging from microbes to metazoans, and its characteristics depend both on the biophysical parameters governing gene expression and on gene network structure. Stochastic gene expression has important consequences for cellular function, being beneficial in some contexts and harmful in others. These situations include the stress response, metabolism, development, the cell cycle, circadian rhythms, and aging. {\textcopyright} 2008 Elsevier Inc. All rights reserved.},
author = {Raj, Arjun and van Oudenaarden, Alexander},
booktitle = {Cell},
doi = {10.1016/j.cell.2008.09.050},
issn = {00928674},
mendeley-groups = {Thesis},
pmid = {18957198},
title = {{Nature, Nurture, or Chance: Stochastic Gene Expression and Its Consequences}},
year = {2008}
}
@article{Rankin1997,
abstract = {Activated Xenopus laevis eggs undergo a series of surface contractions in response to cell-cycle progression but fail to cleave unless the sperm centrosome is present. These surface contraction waves (SCWs) begin at the animal pole and progress around the egg, occur every cell cycle and precede cleavage [1-3]. The SCWs are biphasic, comprising a relaxation phase (SCWa) and a contraction phase (SCWb). To investigate how these events are linked to the underlying cell cycle, we studied the temporal and spatial relationship between the SCWs and previously characterized biochemical markers of cell-cycle progression. We found that the relaxation phase was a response to activated maturation-promoting factor (MPF). In contrast, the contraction phase required inactivation of MPF and was blocked when MPF activity was maintained at elevated levels. We also found that a wave of MPF activity traveled within the cell from the animal to the vegetal hemisphere. Taken together, these experiments suggest that the SCWs are a local response to a wave of MPF activation and inactivatlon. The egg cytoplasm, therefore, is metachronous in terms of cell-cycle progression; multiple cell-cycle states are present and spatially distinct within the egg at the same time.},
author = {Rankin, Susannah and Kirschner, Marc W.},
doi = {10.1016/S0960-9822(06)00192-8},
issn = {09609822},
journal = {Current Biology},
mendeley-groups = {Thesis},
pmid = {9197242},
title = {{The surface contraction waves of Xenopus eggs reflect the metachronous cell-cycle state of the cytoplasm}},
year = {1997}
}
@article{Seger1995,
abstract = {The transmission of extracellular signals into their intracellular targets is mediated by a network of interacting proteins that regulate a large number of cellular processes. Cumulative efforts from many laboratories over the past decade have allowed the elucidation of one such signaling mechanism, which involves activations of several membranal signaling molecules followed by a sequential stimulation of several cytoplasmic protein kinases collectively known as mitogen-activated protein kinase (MAPK) signaling cascade. Up to six tiers in this cascade contribute to the amplification and specificity of the transmitted signals that eventually activate several regulatory molecules in the cytoplasm and in the nucleus to initiate cellular processes such as proliferation, differentiation, and development. Moreover, because many oncogenes have been shown to encode proteins that transmit mitogenic signals upstream of this cascade, the MAPK pathway provides a simple unifying explanation for the mechanism of action of most, if not all, nonnuclear oncogenes. The pattern of MAPK cascade is not restricted to growth factor signaling and it is now known that signaling pathways initiated by phorbol esters, ionophors, heat shock, and ligands for seven transmembrane receptors use distinct MAPK cascades with little or no cross-reactivity between them. In this review we emphasize primarily the first MAPK cascade to be discovered that uses the MEK and ERK isoforms and describe their involvement in different cellular processes.},
author = {Seger, Rony and Krebs, Edwin G.},
doi = {10.1096/fasebj.9.9.7601337},
issn = {0892-6638},
journal = {The FASEB Journal},
mendeley-groups = {Thesis},
pmid = {7601337},
title = {{The MAPK signaling cascade}},
year = {1995}
}
@article{Selimkhanov2014,
abstract = {Stochasticity inherent to biochemical reactions (intrinsic noise) and variability in cellular states (extrinsic noise) degrade information transmitted through signaling networks. We analyzed the ability of temporal signal modulation-that is, dynamics-to reduce noise-induced information loss. In the extracellular signal-regulated kinase (ERK), calcium (Ca2+), and nuclear factor kappa-B (NF-kB) pathways, response dynamics resulted in significantly greater information transmission capacities compared to nondynamic responses. Theoretical analysis demonstrated that signaling dynamics has a key role in overcoming extrinsic noise. Experimental measurements of information transmission in the ERK network under varying signal-to-noise levels confirmed our predictions and showed that signaling dynamics mitigate, and can potentially eliminate, extrinsic noise-induced information loss. By curbing the information-degrading effects of cell-to-cell variability, dynamic responses substantially increase the accuracy of bichemical signaling networks.},
author = {Selimkhanov, Jangir and Taylor, Brooks and Yao, Jason and Pilko, Anna and Albeck, John and Hoffmann, Alexander and Tsimring, Lev and Wollman, Roy},
doi = {10.1126/science.1254933},
issn = {10959203},
journal = {Science},
mendeley-groups = {Thesis},
pmid = {25504722},
title = {{Accurate information transmission through dynamic biochemical signaling networks}},
year = {2014}
}
@article{Sigal2006,
abstract = {Protein expression is a stochastic process that leads to phenotypic variation among cells. The cell-cell distribution of protein levels in microorganisms has been well characterized but little is known about such variability in human cells. Here, we studied the variability of protein levels in human cells, as well as the temporal dynamics of this variability, and addressed whether cells with higher than average protein levels eventually have lower than average levels, and if so, over what timescale does this mixing occur. We measured fluctuations over time in the levels of 20 endogenous proteins in living human cells, tagged by the gene for yellow fluorescent protein at their chromosomal loci. We found variability with a standard deviation that ranged, for different proteins, from about 15{\%} to 30{\%} of the mean. Mixing between high and low levels occurred for all proteins, but the mixing time was longer than two cell generations (more than 40 h) for many proteins. We also tagged pairs of proteins with two colours, and found that the levels of proteins in the same biological pathway were far more correlated than those of proteins in different pathways. The persistent memory for protein levels that we found might underlie individuality in cell behaviour and could set a timescale needed for signals to affect fully every member of a cell population. {\textcopyright}2006 Nature Publishing Group.},
author = {Sigal, Alex and Milo, Ron and Cohen, Ariel and Geva-Zatorsky, Naama and Klein, Yael and Liron, Yuvalal and Rosenfeld, Nitzan and Danon, Tamar and Perzov, Natalie and Alon, Uri},
doi = {10.1038/nature05316},
issn = {14764687},
journal = {Nature},
mendeley-groups = {Thesis},
pmid = {17122776},
title = {{Variability and memory of protein levels in human cells}},
year = {2006}
}
@article{Spalding2008,
abstract = {Obesity is increasing in an epidemic manner in most countries and constitutes a public health problem by enhancing the risk for cardiovascular disease and metabolic disorders such as type 2 diabetes. Owing to the increase in obesity, life expectancy may start to decrease in developed countries for the first time in recent history. The factors determining fat mass in adult humans are not fully understood, but increased lipid storage in already developed fat cells (adipocytes) is thought to be most important. Here we show that adipocyte number is a major determinant for the fat mass in adults. However, the number of fat cells stays constant in adulthood in lean and obese individuals, even after marked weight loss, indicating that the number of adipocytes is set during childhood and adolescence. To establish the dynamics within the stable population of adipocytes in adults, we have measured adipocyte turnover by analysing the integration of 14C derived from nuclear bomb tests in genomic DNA. Approximately 10{\%} of fat cells are renewed annually at all adult ages and levels of body mass index. Neither adipocyte death nor generation rate is altered in early onset obesity, suggesting a tight regulation of fat cell number in this condition during adulthood. The high turnover of adipocytes establishes a new therapeutic target for pharmacological intervention in obesity. {\textcopyright}2008 Nature Publishing Group.},
author = {Spalding, Kirsty L. and Arner, Erik and Westermark, P{\aa}l O. and Bernard, Samuel and Buchholz, Bruce A. and Bergmann, Olaf and Blomqvist, Lennart and Hoffstedt, Johan and N{\"{a}}slund, Erik and Britton, Tom and Concha, Hernan and Hassan, Moustapha and Ryd{\'{e}}n, Mikael and Fris{\'{e}}n, Jonas and Arner, Peter},
doi = {10.1038/nature06902},
issn = {14764687},
journal = {Nature},
mendeley-groups = {Thesis},
pmid = {18454136},
title = {{Dynamics of fat cell turnover in humans}},
year = {2008}
}
@article{Spencer2009,
abstract = {In microorganisms, noise in gene expression gives rise to cell-to-cell variability in protein concentrations. In mammalian cells, protein levels also vary and individual cells differ widely in their responsiveness to uniform physiological stimuli. In the case of apoptosis mediated by TRAIL (tumour necrosis factor (TNF)-related apoptosis-inducing ligand) it is common for some cells in a clonal population to die while others survivea striking divergence in cell fate. Among cells that die, the time between TRAIL exposure and caspase activation is highly variable. Here we image sister cells expressing reporters of caspase activation and mitochondrial outer membrane permeabilization after exposure to TRAIL. We show that naturally occurring differences in the levels or states of proteins regulating receptor-mediated apoptosis are the primary causes of cell-to-cell variability in the timing and probability of death in human cell lines. Protein state is transmitted from mother to daughter, giving rise to transient heritability in fate, but protein synthesis promotes rapid divergence so that sister cells soon become no more similar to each other than pairs of cells chosen at random. Our results have implications for understanding fractional killing of tumour cells after exposure to chemotherapy, and for variability in mammalian signal transduction in general. {\textcopyright} 2009 Macmillan Publishers Limited.},
author = {Spencer, Sabrina L. and Gaudet, Suzanne and Albeck, John G. and Burke, John M. and Sorger, Peter K.},
doi = {10.1038/nature08012},
issn = {00280836},
journal = {Nature},
mendeley-groups = {Thesis},
pmid = {19363473},
title = {{Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis}},
year = {2009}
}
@article{Stewart-Ornstein2012,
abstract = {Stochasticity is a hallmark of cellular processes, and different classes of genes show large differences in their cell-to-cell variability (noise). To decipher the sources and consequences of this noise, we systematically measured pairwise correlations between large numbers of genes, including those with high variability. We find that there is substantial pathway variability shared across similarly regulated genes. This induces quantitative correlations in the expression of functionally related genes such as those involved in the Msn2/4 stress response pathway, amino-acid biosynthesis, and mitochondrial maintenance. Bioinformatic analyses and genetic perturbations suggest that fluctuations in PKA and Tor signaling contribute to pathway-specific variability. Our results argue that a limited number of well-delineated " noise regulons" operate across a yeast cell and that such coordinated fluctuations enable a stochastic but coherent induction of functionally related genes. Finally, we show that pathway noise is a quantitative tool for exploring pathway features and regulatory relationships in un-stimulated systems. {\textcopyright} 2012 Elsevier Inc..},
author = {Stewart-Ornstein, Jacob and Weissman, Jonathan S. and El-Samad, Hana},
doi = {10.1016/j.molcel.2011.11.035},
issn = {10972765},
journal = {Molecular Cell},
mendeley-groups = {Thesis},
pmid = {22365828},
title = {{Cellular Noise Regulons Underlie Fluctuations in Saccharomyces cerevisiae}},
year = {2012}
}
@misc{Stryer1991,
author = {Stryer, L.},
booktitle = {Journal of Biological Chemistry},
issn = {00219258},
mendeley-groups = {Thesis},
pmid = {1710212},
title = {{Visual excitation and recovery}},
year = {1991}
}
@article{Sturm2010,
abstract = {Three-tiered kinase modules, such as the Raf-MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase)-ERK (extracellular signal-regulated kinase) mitogen-activated protein kinase pathway, are widespread in biology, suggesting that this structure conveys evolutionarily advantageous properties. We show that the three-tiered kinase amplifier module combined with negative feedback recapitulates the design principles of a negative feedback amplifier (NFA), which is used in electronic circuits to confer robustness, output stabilization, and linearization of nonlinear signal amplification. We used mathematical modeling and experimental validation to demonstrate that the ERK pathway has properties of an NFA that (i) converts intrinsic switch-like activation kinetics into graded linear responses, (ii) conveys robustness to changes in rates of reactions within the NFA module, and (iii) stabilizes outputs in response to drug-induced perturbations of the amplifier. These properties determine biological behavior, including activation kinetics and the response to drugs. {\textcopyright} 2008 American Association for the Advancement of Science.},
author = {Sturm, Oliver E. and Orton, Richard and Grindlay, Joan and Birtwistle, Marc and Vyshemirsky, Vladislav and Gilbert, David and Calder, Muffy and Pitt, Andrew and Kholodenko, Boris and Kolch, Walter},
doi = {10.1126/scisignal.2001212},
issn = {19450877},
journal = {Science Signaling},
mendeley-groups = {Thesis},
pmid = {21177493},
title = {{The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier}},
year = {2010}
}
@article{Suderman2017,
abstract = {Signal transduction networks allow eukaryotic cells to make decisions based on information about intracellular state and the environment. Biochemical noise significantly diminishes the fidelity of signaling: Networks examined to date seem to transmit less than 1 bit of information. It is unclear how networks that control critical cell-fate decisions (e.g., cell division and apoptosis) can function with such low levels of information transfer. Here, we use theory, experiments, and numerical analysis to demonstrate an inherent trade-off between the information transferred in individual cells and the information available to control population-level responses. Noise in receptormediated apoptosis reduces information transfer to approximately 1 bit at the single-cell level but allows 3-4 bits of information to be transmitted at the population level. For processes such as eukaryotic chemotaxis, in which single cells are the functional unit, we find high levels of information transmission at a single-cell level. Thus, low levels of information transfer are unlikely to represent a physical limit. Instead, we propose that signaling networks exploit noise at the single-cell level to increase population-level information transfer, allowing extracellular ligands, whose levels are also subject to noise, to incrementally regulate phenotypic changes. This is particularly critical for discrete changes in fate (e.g., life vs. death) for which the key variable is the fraction of cells engaged. Our findings provide a framework for rationalizing the high levels of noise in metazoan signaling networks and have implications for the development of drugs that target these networks in the treatment of cancer and other diseases.},
author = {Suderman, Ryan and Bachman, John A. and Smith, Adam and Sorger, Peter K. and Deeds, Eric J.},
doi = {10.1073/pnas.1615660114},
issn = {10916490},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
keywords = {Apoptosis,Cellular heterogeneity,Information theory,Signal transduction},
mendeley-groups = {Thesis},
pmid = {28500273},
title = {{Fundamental trade-offs between information flow in single cells and cellular populations}},
year = {2017}
}
@article{Suel2007,
abstract = {The dynamic process of differentiation depends on the architecture, quantitative parameters, and noise of underlying genetic circuits. However, it remains unclear how these elements combine to control cellular behavior. We analyzed the probabilistic and transient differentiation of Bacillus subtilis cells into the state of competence. A few key parameters independently tuned the frequency of initiation and the duration of competence episodes and allowed the circuit to access different dynamic regimes, including oscillation. Altering circuit architecture showed that the duration of competence events can be made more precise. We used an experimental method to reduce global cellular noise and showed that noise levels are correlated with frequency of differentiation events. Together, the data reveal a noise-dependent circuit that is remarkably resilient and tunable in terms of its dynamic behavior.},
author = {S{\"{u}}el, G{\"{u}}rol M. and Kulkarni, Rajan P. and Dworkin, Jonathan and Garcia-Ojalvo, Jordi and Elowitz, Michael B.},
doi = {10.1126/science.1137455},
issn = {00368075},
journal = {Science},
mendeley-groups = {Thesis},
pmid = {17379809},
title = {{Tunability and noise dependence in differentiation dynamics}},
year = {2007}
}
@misc{Symmons2016,
abstract = {The field of single-cell biology has morphed from a philosophical digression at its inception, to a playground for quantitative biologists, to a major area of biomedical research. The last several years have witnessed an explosion of new technologies, allowing us to apply even more of the modern molecular biology toolkit to single cells. Conceptual progress, however, has been comparatively slow. Here, we provide a framework for classifying both the origins of the differences between individual cells and the consequences of those differences. We discuss how the concept of "random" differences is context dependent, and propose that rigorous definitions of inputs and outputs may bring clarity to the discussion. We also categorize ways in which probabilistic behavior may influence cellular function, highlighting studies that point to exciting future directions in the field.},
author = {Symmons, Orsolya and Raj, Arjun},
booktitle = {Molecular Cell},
doi = {10.1016/j.molcel.2016.05.023},
issn = {10974164},
mendeley-groups = {Thesis},
pmid = {27259209},
title = {{What's Luck Got to Do with It: Single Cells, Multiple Fates, and Biological Nondeterminism}},
year = {2016}
}
@article{Tkach2014,
abstract = {Variability within isogenic T cell populations yields heterogeneous ‘local' signaling responses to shared antigenic stimuli, but responding clones may communicate ‘global' antigen load through paracrine messengers, such as cytokines. Such coordination of individual cell responses within multicellular populations is critical for accurate collective reactions to shared environmental cues. However, cytokine production may saturate as a function of antigen input, or be dominated by the precursor frequency of antigen-specific T cells. Surprisingly, we found that T cells scale their collective output of IL-2 to total antigen input over a large dynamic range, independently of population size. Through experimental quantitation and computational modeling, we demonstrate that this scaling is enforced by an inhibitory cross-talk between antigen and IL-2 signaling, and a nonlinear acceleration of IL-2 secretion per cell. Our study reveals how time-integration of these regulatory loops within individual cell signaling generates scaled collective responses and can be leveraged for immune monitoring.},
author = {Tkach, Karen E. and Barik, Debashis and Voisinne, Guillaume and Malandro, Nicole and Hathorn, Matthew M. and Cotari, Jesse W. and Vogel, Robert and Merghoub, Taha and Wolchok, Jedd and Krichevsky, Oleg and Altan-Bonnet, Gr{\'{e}}goire},
doi = {10.7554/eLife.01944},
issn = {2050-084X},
journal = {eLife},
mendeley-groups = {Thesis},
month = {apr},
pmid = {24719192},
title = {{T cells translate individual, quantal activation into collective, analog cytokine responses via time-integrated feedbacks}},
url = {https://elifesciences.org/articles/01944},
volume = {3},
year = {2014}
}
@article{Tsai2014,
abstract = {During the early development of Xenopus laevis embryos, the first mitotic cell cycle is long ({\~{}}85 min) and the subsequent 11 cycles are short ({\~{}}30 min) and clock-like. Here we address the question of how the Cdk1 cell cycle oscillator changes between these two modes of operation. We found that the change can be attributed to an alteration in the balance between Wee1/Myt1 and Cdc25. The change in balance converts a circuit that acts like a positive-plus-negative feedback oscillator, with spikes of Cdk1 activation, to one that acts like a negative-feedback-only oscillator, with a shorter period and smoothly varying Cdk1 activity. Shortening the first cycle, by treating embryos with the Wee1A/Myt1 inhibitor PD0166285, resulted in a dramatic reduction in embryo viability, and restoring the length of the first cycle in inhibitor-treated embryos with low doses of cycloheximide partially rescued viability. Computations with an experimentally parameterized mathematical model show that modest changes in the Wee1/Cdc25 ratio can account for the observed qualitative changes in the cell cycle. The high ratio in the first cycle allows the period to be long and tunable, and decreasing the ratio in the subsequent cycles allows the oscillator to run at a maximal speed. Thus, the embryo rewires its feedback regulation to meet two different developmental requirements during early development. {\textcopyright} 2014 Tsai et al.},
author = {Tsai, Tony Y.C. and Theriot, Julie A. and Ferrell, James E.},
doi = {10.1371/journal.pbio.1001788},
issn = {15457885},
journal = {PLoS Biology},
mendeley-groups = {Thesis},
pmid = {24523664},
title = {{Changes in Oscillatory Dynamics in the Cell Cycle of Early Xenopus laevis Embryos}},
year = {2014}
}
@article{Yang2017,
abstract = {Regulation of cell proliferation is necessary for immune responses, tissue repair, and upkeep of organ function to maintain human health. When proliferating cells complete mitosis, a fraction of newly born daughter cells immediately enter the next cell cycle, while the remaining cells in the same population exit to a transient or persistent quiescent state. Whether this choice between two cell-cycle pathways is due to natural variability in mitogen signalling or other underlying causes is unknown. Here we show that human cells make this fundamental cell-cycle entry or exit decision based on competing memories of variable mitogen and stress signals. Rather than erasing their signalling history at cell-cycle checkpoints before mitosis, mother cells transmit DNA damage-induced p53 protein and mitogen-induced cyclin D1 (CCND1) mRNA to newly born daughter cells. After mitosis, the transferred CCND1 mRNA and p53 protein induce variable expression of cyclin D1 and the CDK inhibitor p21 that almost exclusively determines cell-cycle commitment in daughter cells. We find that stoichiometric inhibition of cyclin D1-CDK4 activity by p21 controls the retinoblastoma (Rb) and E2F transcription program in an ultrasensitive manner. Thus, daughter cells control the proliferation-quiescence decision by converting the memories of variable mitogen and stress signals into a competition between cyclin D1 and p21 expression. We propose a cell-cycle control principle based on natural variation, memory and competition that maximizes the health of growing cell populations.},
author = {Yang, Hee Won and Chung, Mingyu and Kudo, Takamasa and Meyer, Tobias},
doi = {10.1038/nature23880},
issn = {0028-0836},
journal = {Nature},
mendeley-groups = {Thesis},
month = {sep},
number = {7672},
pages = {404--408},
pmid = {28869970},
title = {{Competing memories of mitogen and p53 signalling control cell-cycle entry}},
url = {http://www.nature.com/articles/nature23880},
volume = {549},
year = {2017}
}
@article{Spencer2013,
abstract = {Tissue homeostasis in metazoans is regulated by transitions of cells between quiescence and proliferation. The hallmark of proliferating populations is progression through the cell cycle, which is driven by cyclin-dependent kinase (CDK) activity. Here, we introduce a live-cell sensor for CDK2 activity and unexpectedly found that proliferating cells bifurcate into two populations as they exit mitosis. Many cells immediately commit to the next cell cycle by building up CDK2 activity from an intermediate level, while other cells lack CDK2 activity and enter a transient state of quiescence. This bifurcation is directly controlled by the CDK inhibitor p21 and is regulated by mitogens during a restriction window at the end of the previous cell cycle. Thus, cells decide at the end of mitosis to either start the next cell cycle by immediately building up CDK2 activity or to enter a transient G0-like state by suppressing CDK2 activity. {\textcopyright} 2013 Elsevier Inc.},
author = {Spencer, Sabrina L. and Cappell, Steven D. and Tsai, Feng-Chiao and Overton, K. Wesley and Wang, Clifford L. and Meyer, Tobias},
doi = {10.1016/j.cell.2013.08.062},
issn = {00928674},
journal = {Cell},
mendeley-groups = {Thesis},
month = {oct},
number = {2},
pages = {369--383},
title = {{The Proliferation-Quiescence Decision Is Controlled by a Bifurcation in CDK2 Activity at Mitotic Exit}},
url = {https://linkinghub.elsevier.com/retrieve/pii/S0092867413011434},
volume = {155},
year = {2013}
}
@article{Kovary2018,
abstract = {{\textcopyright} 2018 The Authors. Published under the terms of the CC BY 4.0 license Due to noise in the synthesis and degradation of proteins, the concentrations of individual vertebrate signaling proteins were estimated to vary with a coefficient of variation (CV) of approximately 25{\%} between cells. Such high variation is beneficial for population-level regulation of cell functions but abolishes accurate single-cell signal transmission. Here, we measure cell-to-cell variability of relative protein abundance using quantitative proteomics of individual Xenopus laevis eggs and cultured human cells and show that variation is typically much lower, in the range of 5–15{\%}, compatible with accurate single-cell transmission. Focusing on bimodal ERK signaling, we show that variation and covariation in MEK and ERK expression improves controllability of the percentage of activated cells, demonstrating how variation and covariation in expression enables population-level control of binary cell-fate decisions. Together, our study argues for a control principle whereby low expression variation enables accurate control of analog single-cell signaling, while increased variation, covariation, and numbers of pathway components are required to widen the stimulus range over which external inputs regulate binary cell activation to enable precise control of the fraction of activated cells in a population.},
author = {Kovary, K.M. and Taylor, Brooks and Zhao, M.L. and Teruel, M.N.},
doi = {10.15252/msb.20177997},
file = {:Users/kylekovary/Documents/Mendeley Desktop/Molecular Systems Biology/2018/Kovary et al. - Expression variation and covariation impair analog and enable binary signaling control - 2018 - Molecular Systems Biolog.pdf:pdf},
issn = {17444292},
journal = {Molecular Systems Biology},
keywords = {MAPK/MEK/ERK signaling,SRM-MS,cellular heterogeneity,selected reaction monitoring mass spectrometry,single-cell proteomics},
mendeley-groups = {Thesis},
number = {5},
pages = {e7997},
pmid = {29759982},
title = {{Expression variation and covariation impair analog and enable binary signaling control}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/29759982 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC5951153},
volume = {14},
year = {2018}
}

@article{Foreman2020,
abstract = {Gene expression variability in mammalian systems plays an important role in physiological and pathophysiological conditions. This variability can come from differential regulation related to cell state (extrinsic) and allele-specific transcriptional bursting (intrinsic). Yet, the relative contribution of these two distinct sources is unknown. Here we exploit the qualitative difference in the patterns of covariance between these two sources to quantify their relative contributions to expression variance in mammalian cells. Using multiplexed error robust RNA fluorescent in situ hybridization (MERFISH) we measured the multivariate gene expression distribution of 150 genes related to Ca2+ signaling coupled with the dynamic Ca2+ response of live cells to ATP. We show that after controlling for cellular phenotypic states such as size, cell cycle stage, and Ca2+ response to ATP, the remaining variability is effectively at the Poisson limit for most genes. These findings demonstrate that the majority of expression variability results from cell state differences and that the contribution of transcriptional bursting is relatively minimal.},
author = {Foreman, Robert and Wollman, Roy},
doi = {10.15252/msb.20199146},
file = {:Users/kylekovary/Documents/Mendeley Desktop/Molecular Systems Biology/2020/Foreman, Wollman - Mammalian gene expression variability is explained by underlying cell state - 2020 - Molecular Systems Biology.pdf:pdf},
issn = {1744-4292},
journal = {Molecular Systems Biology},
keywords = {ca 2,gene expression,merfish,signaling,single cell,transcrip-},
number = {2},
pages = {1--13},
title = {{Mammalian gene expression variability is explained by underlying cell state}},
volume = {16},
year = {2020}
}

@article{Foreman2020,
abstract = {Gene expression variability in mammalian systems plays an important role in physiological and pathophysiological conditions. This variability can come from differential regulation related to cell state (extrinsic) and allele-specific transcriptional bursting (intrinsic). Yet, the relative contribution of these two distinct sources is unknown. Here we exploit the qualitative difference in the patterns of covariance between these two sources to quantify their relative contributions to expression variance in mammalian cells. Using multiplexed error robust RNA fluorescent in situ hybridization (MERFISH) we measured the multivariate gene expression distribution of 150 genes related to Ca2+ signaling coupled with the dynamic Ca2+ response of live cells to ATP. We show that after controlling for cellular phenotypic states such as size, cell cycle stage, and Ca2+ response to ATP, the remaining variability is effectively at the Poisson limit for most genes. These findings demonstrate that the majority of expression variability results from cell state differences and that the contribution of transcriptional bursting is relatively minimal.},
author = {Foreman, Robert and Wollman, Roy},
doi = {10.15252/msb.20199146},
file = {:Users/kylekovary/Documents/Mendeley Desktop/Molecular Systems Biology/2020/Foreman, Wollman - Mammalian gene expression variability is explained by underlying cell state - 2020 - Molecular Systems Biology.pdf:pdf},
issn = {1744-4292},
journal = {Molecular Systems Biology},
keywords = {ca 2,gene expression,merfish,signaling,single cell,transcrip-},
number = {2},
pages = {1--13},
title = {{Mammalian gene expression variability is explained by underlying cell state}},
volume = {16},
year = {2020}
}

@article{Li2014,
abstract = {Quantitative views of cellular functions require precise measures of rates of biomolecule production, especially proteins—the direct effectors of biological processes. Here, we present a genome-wide approach, based on ribosome profiling, for measuring absolute protein synthesis rates. The resultant E. coli data set transforms our understanding of the extent to which protein synthesis is precisely controlled to optimize function and efficiency. Members of multiprotein complexes are made in precise proportion to their stoichiometry, whereas components of functional modules are produced differentially according to their hierarchical role. Estimates of absolute protein abundance also reveal principles for optimizing design. These include how the level of different types of transcription factors is optimized for rapid response and how a metabolic pathway (methionine biosynthesis) balances production cost with activity requirements. Our studies reveal how general principles, important both for understanding natural systems and for synthesizing new ones, emerge from quantitative analyses of protein synthesis.},
author = {Li, Gene-Wei and Burkhardt, David and Gross, Carol and Weissman, Jonathan S.},
doi = {10.1016/J.CELL.2014.02.033},
file = {:Users/kylekovary/Documents/Mendeley Desktop/Cell/2014/Li et al. - Quantifying Absolute Protein Synthesis Rates Reveals Principles Underlying Allocation of Cellular Resources - 2014 - Cell.pdf:pdf},
issn = {0092-8674},
journal = {Cell},
month = {apr},
number = {3},
pages = {624--635},
publisher = {Cell Press},
title = {{Quantifying Absolute Protein Synthesis Rates Reveals Principles Underlying Allocation of Cellular Resources}},
url = {https://www.sciencedirect.com/science/article/pii/S0092867414002323},
volume = {157},
year = {2014}
}

@article{Shi2017,
author = {Shi, Zhen and Fujii, Kotaro and Kovary, Kyle M. and Genuth, Naomi R. and R{\"{o}}st, Hannes L. and Teruel, Mary N. and Barna, Maria},
doi = {10.1016/j.molcel.2017.05.021},
file = {:Users/kylekovary/Documents/Mendeley Desktop/Molecular Cell/2017/Shi et al. - Heterogeneous Ribosomes Preferentially Translate Distinct Subpools of mRNAs Genome-wide - 2017 - Molecular Cell.pdf:pdf},
issn = {10972765},
journal = {Molecular Cell},
mendeley-groups = {Thesis},
month = {jul},
number = {1},
pages = {71--83.e7},
title = {{Heterogeneous Ribosomes Preferentially Translate Distinct Subpools of mRNAs Genome-wide}},
url = {https://linkinghub.elsevier.com/retrieve/pii/S1097276517303611},
volume = {67},
year = {2017}
}

@article{Gut2018,
abstract = {Obtaining highly multiplexed protein measurements across multiple length scales has enormous potential for biomedicine. Here, we measured, by iterative indirect immunofluorescence imaging (4i), 40-plex protein readouts from biological samples at high-throughput from the millimeter to the nanometer scale. This approach simultaneously captures properties apparent at the population, cellular, and subcellular levels, including microenvironment, cell shape, and cell cycle state. It also captures the detailed morphology of organelles, cytoskeletal structures, nuclear subcompartments, and the fate of signaling receptors in thousands of single cells in situ. We used computer vision and systems biology approaches to achieve unsupervised comprehensive quantification of protein subcompartmentalization within various multicellular, cellular, and pharmacological contexts. Thus, highly multiplexed subcellular protein maps can be used to identify functionally relevant single-cell states.},
author = {Gut, Gabriele and Herrmann, Markus D. and Pelkmans, Lucas},
doi = {10.1126/science.aar7042},
issn = {0036-8075},
journal = {Science},
month = {aug},
number = {6401},
pages = {eaar7042},
pmid = {30072512},
title = {{Multiplexed protein maps link subcellular organization to cellular states}},
url = {https://www.sciencemag.org/lookup/doi/10.1126/science.aar7042},
volume = {361},
year = {2018}
}

@article{Bendall2011,
abstract = {Flow cytometry is an essential tool for dissecting the functional complexity of hematopoiesis. We used single-cell "mass cytometry" to examine healthy human bone marrow, measuring 34 parameters simultaneously in single cells (binding of 31 antibodies, viability, DNA content, and relative cell size). The signaling behavior of cell subsets spanning a defined hematopoietic hierarchy was monitored with 18 simultaneous markers of functional signaling states perturbed by a set of ex vivo stimuli and inhibitors. The data set allowed for an algorithmically driven assembly of related cell types defined by surface antigen expression, providing a superimposable map of cell signaling responses in combination with drug inhibition. Visualized in this manner, the analysis revealed previously unappreciated instances of both precise signaling responses that were bounded within conventionally defined cell subsets and more continuous phosphorylation responses that crossed cell population boundaries in unexpected manners yet tracked closely with cellular phenotype. Collectively, such single-cell analyses provide system-wide views of immune signaling in healthy human hematopoiesis, against which drug action and disease can be compared for mechanistic studies and pharmacologic intervention.},
author = {Bendall, Sean C and Simonds, Erin F and Qiu, Peng and Amir, El-ad D and Krutzik, Peter O and Finck, Rachel and Bruggner, Robert V and Melamed, Rachel and Trejo, Angelica and Ornatsky, Olga I and Balderas, Robert S and Plevritis, Sylvia K and Sachs, Karen and Pe'er, Dana and Tanner, Scott D and Nolan, Garry P},
doi = {10.1126/science.1198704},
file = {:Users/kylekovary/Documents/Mendeley Desktop/Science (New York, N.Y.)/2011/Bendall et al. - Single-cell mass cytometry of differential immune and drug responses across a human hematopoietic continuum. - 2011 - S.pdf:pdf},
issn = {1095-9203},
journal = {Science},
keywords = {Algorithms,Antibodies,Antigens,B-Lymphocytes,B-Lymphocytes: drug effects,B-Lymphocytes: immunology,B-Lymphocytes: metabolism,Bone Marrow Cells,Bone Marrow Cells: cytology,Bone Marrow Cells: drug effects,Bone Marrow Cells: immunology,Bone Marrow Cells: metabolism,Cytokines,Cytokines: metabolism,Flow Cytometry,Flow Cytometry: methods,Hematopoiesis,Humans,Immunophenotyping,Lanthanoid Series Elements,Leukocytes,Lymphocyte Activation,Lymphocyte Subsets,Lymphocyte Subsets: drug effects,Lymphocyte Subsets: immunology,Lymphocyte Subsets: metabolism,Mass Spectrometry,Mononuclear,Mononuclear: drug effects,Mononuclear: immunology,Mononuclear: metabolism,Phosphorylation,Protein Kinase Inhibitors,Protein Kinase Inhibitors: pharmacology,Protein-Tyrosine Kinases,Protein-Tyrosine Kinases: antagonists {\&} inhibitors,Pyrimidines,Pyrimidines: pharmacology,Signal Transduction,Signal Transduction: drug effects,Single-Cell Analysis,Single-Cell Analysis: methods,Surface,Surface: analysis,T-Lymphocytes,T-Lymphocytes: drug effects,T-Lymphocytes: immunology,T-Lymphocytes: metabolism,Thiazoles,Thiazoles: pharmacology,Transition Elements},
mendeley-groups = {Misc},
month = {may},
number = {6030},
pages = {687--96},
pmid = {21551058},
title = {{Single-cell mass cytometry of differential immune and drug responses across a human hematopoietic continuum.}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3273988{\&}tool=pmcentrez{\&}rendertype=abstract},
volume = {332},
year = {2011}
}

@article{Budnik2018,
abstract = {Cellular heterogeneity is important to biological processes, including cancer and development. However, proteome heterogeneity is largely unexplored because of the limitations of existing methods for quantifying protein levels in single cells. To alleviate these limitations, we developed Single Cell ProtEomics by Mass Spectrometry (SCoPE-MS), and validated its ability to identify distinct human cancer cell types based on their proteomes. We used SCoPE-MS to quantify over a thousand proteins in differentiating mouse embryonic stem (ES) cells. The single-cell proteomes enabled us to deconstruct cell populations and infer protein abundance relationships. Comparison between single-cell proteomes and transcriptomes indicated coordinated mRNA and protein covariation. Yet many genes exhibited functionally concerted and distinct regulatory patterns at the mRNA and the protein levels, suggesting that post-transcriptional regulatory mechanisms contribute to proteome remodeling during lineage specification, especially for developmental genes. SCoPE-MS is broadly applicable to measuring proteome configurations of single cells and linking them to functional phenotypes, such as cell type and differentiation potentials.},
author = {Budnik, Bogdan and Levy, Ezra and Harmange, Guillaume and Slavov, Nikolai},
doi = {10.1186/s13059-018-1547-5},
file = {:Users/kylekovary/Documents/Mendeley Desktop/Genome Biology/2018/Budnik et al. - SCoPE-MS mass spectrometry of single mammalian cells quantifies proteome heterogeneity during cell differentiation - 201.pdf:pdf},
issn = {1474760X},
journal = {Genome Biology},
keywords = {Animal Genetics and Genomics,Bioinformatics,Evolutionary Biology,Human Genetics,Microbial Genetics and Genomics,Plant Genetics and Genomics},
month = {dec},
number = {1},
pages = {161},
publisher = {BioMed Central},
title = {{SCoPE-MS: mass spectrometry of single mammalian cells quantifies proteome heterogeneity during cell differentiation}},
url = {https://genomebiology.biomedcentral.com/articles/10.1186/s13059-018-1547-5},
volume = {19},
year = {2018}
}

@article{Macosko2015,
abstract = {Cells, the basic units of biological structure and function, vary broadly in type and state. Single-cell genomics can characterize cell identity and function, but limitations of ease and scale have prevented its broad application. Here we describe Drop-seq, a strategy for quickly profiling thousands of individual cells by separating them into nanoliter-sized aqueous droplets, associating a different barcode with each cell's RNAs, and sequencing them all together. Drop-seq analyzes mRNA transcripts from thousands of individual cells simultaneously while remembering transcripts' cell of origin. We analyzed transcriptomes from 44,808 mouse retinal cells and identified 39 transcriptionally distinct cell populations, creating a molecular atlas of gene expression for known retinal cell classes and novel candidate cell subtypes. Drop-seq will accelerate biological discovery by enabling routine transcriptional profiling at single-cell resolution. Video Abstract},
archivePrefix = {arXiv},
arxivId = {15334406},
author = {Macosko, Evan Z. and Basu, Anindita and Satija, Rahul and Nemesh, James and Shekhar, Karthik and Goldman, Melissa and Tirosh, Itay and Bialas, Allison R. and Kamitaki, Nolan and Martersteck, Emily M. and Trombetta, John J. and Weitz, David A. and Sanes, Joshua R. and Shalek, Alex K. and Regev, Aviv and McCarroll, Steven A.},
doi = {10.1016/j.cell.2015.05.002},
eprint = {15334406},
file = {:Users/kylekovary/Documents/Mendeley Desktop/Cell/2015/Macosko et al. - Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets - 2015 - Cell.pdf:pdf},
isbn = {1097-4172 (Electronic)$\backslash$r0092-8674 (Linking)},
issn = {10974172},
journal = {Cell},
number = {5},
pages = {1202--1214},
pmid = {26000488},
publisher = {Elsevier},
title = {{Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets}},
url = {http://dx.doi.org/10.1016/j.cell.2015.05.002},
volume = {161},
year = {2015}
}

@article{Wuhr2014,
abstract = {BACKGROUND: Mass spectrometry-based proteomics enables the global identification and quantification of proteins and their posttranslational modifications in complex biological samples. However, proteomic analysis requires a complete and accurate reference set of proteins and is therefore largely restricted to model organisms with sequenced genomes.

RESULTS: Here, we demonstrate the feasibility of deep genome-free proteomics by using a reference proteome derived from heterogeneous mRNA data. We identify more than 11,000 proteins with 99{\%} confidence from the unfertilized Xenopus laevis egg and estimate protein abundance with approximately 2-fold precision. Our reference database outperforms the provisional gene models based on genomic DNA sequencing and references generated by other methods. Surprisingly, we find that many proteins in the egg lack mRNA support and that many of these proteins are found in blood or liver, suggesting that they are taken up from the blood plasma, together with yolk, during oocyte growth and maturation, potentially contributing to early embryogenesis.

CONCLUSION: To facilitate proteomics in nonmodel organisms, we make our platform available as an online resource that converts heterogeneous mRNA data into a protein reference set. Thus, we demonstrate the feasibility and power of genome-free proteomics while shedding new light on embryogenesis in vertebrates.},
author = {W{\"{u}}hr, Martin and Freeman, Robert M and Presler, Marc and Horb, Marko E and Peshkin, Leonid and Gygi, Steven P and Kirschner, Marc W},
doi = {10.1016/j.cub.2014.05.044},
file = {:Users/kylekovary/Documents/Mendeley Desktop/Current biology CB/2014/W{\"{u}}hr et al. - Deep proteomics of the Xenopus laevis egg using an mRNA-derived reference database. - 2014 - Current biology CB.pdf:pdf},
issn = {1879-0445},
journal = {Current biology : CB},
mendeley-groups = {Misc},
month = {jul},
number = {13},
pages = {1467--75},
pmid = {24954049},
title = {{Deep proteomics of the Xenopus laevis egg using an mRNA-derived reference database.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/24954049},
volume = {24},
year = {2014}
}

@article{Presler2017,
abstract = {Fertilization triggers release from meiotic arrest and initiates events that prepare for the ensuing developmental program. Protein degradation and phosphorylation are known to regulate protein activity during this process. However, the full extent of protein loss and phospho-regulation is still unknown. We examined absolute protein and phospho-site dynamics after fertilization by mass spectrometry-based proteomics. To do this, we developed a new approach for calculating the stoichiometry of phospho-sites from multiplexed proteomics that is compatible with dynamic, stable and multi-site phosphorylation. Overall, the data suggest that degradation is limited to a few low abundance proteins. However, this degradation promotes extensive dephosphorylation that occurs over a wide range of abundances during meiotic exit. We also show that eggs release a large amount of protein into the medium just after fertilization, most likely related to the blocks to polyspermy. Concomitantly, there is a substantial increase in phosphorylation likely tied to calcium activated kinases. We identify putative degradation targets as well as new components of the block to polyspermy. The analytical approaches demonstrated here are broadly applicable to studies of dynamic biological systems.},
author = {Presler, Marc and {Van Itallie}, Elizabeth and Klein, Allon M and Kunz, Ryan and Coughlin, Margaret L. and Peshkin, Leonid and Gygi, Steven P and W{\"{u}}hr, Martin and Kirschner, Marc W},
doi = {10.1073/pnas.1709207114},
file = {:Users/kylekovary/Documents/Mendeley Desktop/Proceedings of the National Academy of Sciences/2017/Presler et al. - Proteomics of phosphorylation and protein dynamics during fertilization and meiotic exit in the Xenopus egg - 2017 - Pr.pdf:pdf},
issn = {0027-8424},
journal = {Proceedings of the National Academy of Sciences},
pages = {201709207},
pmid = {29183978},
title = {{Proteomics of phosphorylation and protein dynamics during fertilization and meiotic exit in the Xenopus egg}},
url = {http://www.pnas.org/lookup/doi/10.1073/pnas.1709207114},
year = {2017}
}

@article{Dworkin1989a,
abstract = {32P-labeled glucose 6-phosphate and phosphoenolpyruvate were injected into oocytes, fertilized eggs, and early embryos of Xenopus laevis, and the 32P label was followed into glycolytic enzymes and acid-soluble metabolites. The kinetics of labeling of phosphoglucomutase and phosphoglyceromutase and the formation of specific metabolites were used to measure carbon flux through glycolytic intermediates in these cells. In full-grown stage VI oocytes, fertilized eggs, and cells of cleaving embryos, carbon metabolism is in the glycogenic direction. Glycolytic intermediates injected into these cells were metabolized into UDP-glucose and then presumably into glycogen. Carbon flow between phosphoenolpyruvate and glucose 6-phosphate does not utilize fructose 1,6-bisphosphatase; rather, it may depend largely on enzymes of the pentose phosphate pathway. Maturation and fertilization of the oocyte did not result in a change in the qualitative pattern of metabolites formed. Pyruvate kinase, although abundant in oocytes and embryos, is essentially inactive in these cells. Pyruvate kinase also appears to be inactive in small previtellogenic stage II oocytes; however, in these cells injected glycolytic intermediates were not metabolized to UDP-glucose. {\textcopyright} 1989.},
author = {Dworkin, Mark B. and Dworkin-Rastl, Eva},
doi = {10.1016/0012-1606(89)90246-7},
file = {:Users/kylekovary/Documents/Mendeley Desktop/Developmental Biology/1989/Dworkin, Dworkin-Rastl - Metabolic regulation during early frog development Glycogenic flux in Xenopus oocytes, eggs, and embryos - 1989.pdf:pdf},
issn = {00121606},
journal = {Developmental Biology},
number = {2},
pages = {512--523},
title = {{Metabolic regulation during early frog development: Glycogenic flux in Xenopus oocytes, eggs, and embryos}},
volume = {132},
year = {1989}
}

@article{Dworkin1989b,
abstract = {32P-labeled glucose 6-phosphate, [32P]phosphoenolpyruvate, and [$\gamma$-32P]ATP were injected into oocytes and fertilized eggs of Xenopus laevis, and the incorporation of the 32P label was followed into phospholipids. Several classes of phospholipids incorporated 32P label from the injected glycolytic intermediates, including lysophosphatidic acid, phosphatidic acid, phosphatidylinositol, and phosphatidylinositol phosphates, inferring de novo synthesis of these lipids from dihydroxyacetone phosphate or glycerol 3-phosphate. Injection of [$\gamma$-32P]ATP into oocytes and fertilized eggs led to labeling of phosphatidylinositol phosphate and phosphatidylinositol bisphosphate, indicating an active phosphatidylinositol cycle in resting oocytes and fertilized eggs. Maturation and fertilization of the oocyte led to a qualitative change in phosphatidylinositol metabolism, increased labeling of phosphatidylinositol phosphate compared to phosphatidylinositol bisphosphate (either from glycerol 3-phosphate or from ATP). This change occurs late in the maturation process, and the new pattern of phosphatidylinositol metabolism is maintained during the rapid cleavage stages of early embryogenesis. {\textcopyright} 1989.},
author = {Dworkin, Mark B. and Dworkin-Rastl, Eva},
doi = {10.1016/0012-1606(89)90247-9},
file = {:Users/kylekovary/Documents/Mendeley Desktop/Developmental Biology/1989/Dworkin, Dworkin-Rastl - Metabolic regulation during early frog development Flow of glycolytic carbon into phospholipids in Xenopus oocy.pdf:pdf},
issn = {00121606},
journal = {Developmental Biology},
number = {2},
pages = {524--528},
title = {{Metabolic regulation during early frog development: Flow of glycolytic carbon into phospholipids in Xenopus oocytes and fertilized eggs}},
volume = {132},
year = {1989}
}

@article{Nutt2005,
author = {Nutt, Leta K and Margolis, Seth S and Jensen, Mette and Herman, Catherine E and Dunphy, William G. and Rathmell, Jeffrey C and Kornbluth, Sally},
doi = {10.1016/j.cell.2005.07.032},
file = {:Users/kylekovary/Documents/Mendeley Desktop/Cell/2005/Nutt et al. - Metabolic Regulation of Oocyte Cell Death through the CaMKII-Mediated Phosphorylation of Caspase-2 - 2005 - Cell.pdf:pdf},
isbn = {9196811005},
issn = {00928674},
journal = {Cell},
month = {oct},
number = {1},
pages = {89--103},
title = {{Metabolic Regulation of Oocyte Cell Death through the CaMKII-Mediated Phosphorylation of Caspase-2}},
url = {https://linkinghub.elsevier.com/retrieve/pii/S0092867405008020},
volume = {123},
year = {2005}
}

@article{Labhsetwar2013,
abstract = {Stochastic gene expression can lead to phenotypic differences among cells even in isogenic populations growing under macroscopically identical conditions. Here, we apply flux balance analysis in investigating the effects of single-cell proteomics data on the metabolic behavior of an in silico Escherichia coli population. We use the latest metabolic reconstruction integrated with transcriptional regulatory data to model realistic cells growing in a glucose minimal medium under aerobic conditions. The modeled population exhibits a broad distribution of growth rates, and principal component analysis was used to identify well-defined subpopulations that differ in terms of their pathway use. The cells differentiate into slow-growing acetate-secreting cells and fast-growing CO2-secreting cells, and a large population growing at intermediate rates shift from glycolysis to Entner–Doudoroff pathway use. Constraints imposed by integrating regulatory data have a large impact on NADH oxidizing pathway use within the cell. Finally, we find that stochasticity in the expression of only a few genes may be sufficient to capture most of the metabolic variability of the entire population.},
author = {Labhsetwar, Piyush and Cole, John Andrew and Roberts, Elijah and Price, Nathan D. and Luthey-Schulten, Zaida A.},
doi = {10.1073/PNAS.1222569110},
file = {:Users/kylekovary/Documents/Mendeley Desktop/Proceedings of the National Academy of Sciences/2013/Labhsetwar et al. - Heterogeneity in protein expression induces metabolic variability in a modeled Escherichia coli population - 2013 -.pdf:pdf},
issn = {0027-8424},
journal = {Proceedings of the National Academy of Sciences},
month = {aug},
number = {34},
pages = {14006--14011},
pmid = {23908403},
publisher = {National Academy of Sciences},
title = {{Heterogeneity in protein expression induces metabolic variability in a modeled Escherichia coli population}},
url = {https://www.pnas.org/content/110/34/14006.short},
volume = {110},
year = {2013}
}

@article{Hu2008,
abstract = {CateGOrizer: A Web-Based Program to Batch Analyze Gene Ontology Classification Categories, Online J Bioinformatics 9(2):108-112, 2008. With the accelerating rate at which gene-associated research data are accumulated, there is a growing need for batch analysis of large-scale sequence annotations such as Gene Ontology (GO). A frustrating problem with GO annotation has been the inability to properly count the occurrences of GO terms within certain parental categories under a given classification method such as GO Slim. The GO term occurrence count by category can also be time consuming when all possible paths are searched with looped structured query language (SQL). The CateGOrizer we present here is designed to overcome these problems. The CateGOrizer utilizes pre-computed transitive closure paths, performs GO classification count under any given GO slim through a web interface. Our approach has significantly reduced the run time and improved flexibility in comparison to peer programs. However, users are advised to take caution when choosing a proper classification system, to design a strategy objectively count GO terms and properly interpret the results.},
author = {Hu, Zhi-Liang and Bao, J and Reecy, JM},
journal = {Online Journal of Bioinformatics},
title = {{CateGOrizer: A Web-Based Program to Batch Analyze Gene Ontology Classification Categories}},
year = {2008}
}

@article{Jorgensen2009,
abstract = {Little is known about how metabolism changes during development. For most animal embryos, yolk protein is a principal source of nutrition, particularly of essential amino acids. Within eggs, yolk is stored inside large organelles called yolk platelets (YPs). We have gained insight into embryonic nutrition in the African clawed frog Xenopus laevis by studying YPs. Amphibians follow the ancestral pattern in which all embryonic cells inherit YPs from the egg cytoplasm. These YPs are consumed intracellularly at some point during embryogenesis, but it was not known when, where or how yolk consumption occurs. We have identified the novel yolk protein Seryp by biochemical and mass spectrometric analyses of purified YPs. Within individual YPs, Seryp is degraded to completion earlier than the major yolk proteins, thereby providing a molecular marker for YPs engaged in yolk proteolysis. We demonstrate that yolk proteolysis is a quantal process in which a subset of dormant YPs within embryonic cells are reincorporated into the endocytic system and become terminal degradative compartments. Yolk consumption is amongst the earliest aspects of differentiation. The rate of yolk consumption is also highly tissue specific, suggesting that nutrition in early amphibian embryos is tissue autonomous. But yolk consumption does not appear to be triggered by embryonic cells declining to a critically small size. Frog embryos offer a promising platform for the in vivo analysis of metabolism.},
author = {Jorgensen, Paul and Steen, Judith A.J. and Steen, Hanno and Kirschner, Marc W.},
doi = {10.1242/dev.032425},
file = {:Users/kylekovary/Documents/Mendeley Desktop/Development/2009/Jorgensen et al. - The mechanism and pattern of yolk consumption provide insight into embryonic nutrition in Xenopus - 2009 - Developmen.pdf:pdf},
issn = {09501991},
journal = {Development},
keywords = {Cell size,EP45,PNiXa,Seryp,Vitellogenin,Xenopus,Yolk},
number = {9},
pages = {1539--1548},
title = {{The mechanism and pattern of yolk consumption provide insight into embryonic nutrition in Xenopus}},
volume = {136},
year = {2009}
}

@article{Lu2006,
abstract = {We reconstituted bilayer nuclear membranes, multilayer membranes, and organelles from mixtures of Xenopus laevis egg extracts and demembranated Xenopus sperm nuclei. Varying proportions of the cytosolic and vesicular fractions from the eggs were used in the reconstitution mixtures. A cytosol:vesicle ratio of 10:1 promoted reassembly of the normal bilayer nuclear membrane with inserted nuclear pore complexes around the decondensed Xenopus sperm chromatin. A cytosol:vesicle ratio of 5:1 caused decondensed and dispersed sperm chromatin to be either surrounded by or divided by unusual multilayer membrane structures with inlaid pore complexes. A cytosol:vesicle ratio of 2.5:1 promoted reconstitution of mitochondria, endoplasmic reticulum networks, and Golgi apparatus. During reassembly of the endoplasmic reticulum and Golgi apparatus, vesicular fragments of the corresponding organelles fused together and changed their shape to form flattened cisternae, which were then stacked one on top of another. {\textcopyright} 2006 IBCB, SIBS, CAS All rights reserved.},
author = {Lu, Ping and Zheng, Hui and Zhai, Zhonghe},
doi = {10.1038/sj.cr.7310066},
file = {:Users/kylekovary/Documents/Mendeley Desktop/Cell Research/2006/Lu, Zheng, Zhai - In vitro reassembly of nuclear envelopes and organelles in Xenopus egg extracts - 2006 - Cell Research.pdf:pdf},
issn = {10010602},
journal = {Cell Research},
keywords = {Cell-free system,Endoplasmic reticulum,Golgi apparatus,Mitochondria,Nuclear reconstitution,Xenopus egg extracts},
number = {7},
pages = {632--640},
title = {{In vitro reassembly of nuclear envelopes and organelles in Xenopus egg extracts}},
volume = {16},
year = {2006}
}

@article{Yao2019,
abstract = {Proliferating cells often have increased glucose consumption and lactate excretion relative to the same cells in the quiescent state, a phenomenon known as the Warburg effect. Despite an increase in glycolysis, however, here we show that non-transformed mouse fibroblasts also increase oxidative phosphorylation (OXPHOS) by nearly two-fold and mitochondrial coupling efficiency by {\~{}}30{\%} during proliferation. Both increases are supported by mitochondrial fusion. Impairing mitochondrial fusion by knocking down mitofusion-2 (Mfn2) was sufficient to attenuate proliferation, while overexpressing Mfn2 increased proliferation. Interestingly, impairing mitochondrial fusion decreased OXPHOS but did not deplete ATP levels. Instead, inhibition caused cells to transition from excreting aspartate to consuming it. Transforming fibroblasts with the Ras oncogene induced mitochondrial biogenesis, which further elevated OXPHOS. Notably, transformed fibroblasts continued to have elongated mitochondria and their proliferation remained sensitive to inhibition of Mfn2. Our results suggest that cell proliferation requires increased OXPHOS as supported by mitochondrial fusion.},
author = {Yao, Cong Hui and Wang, Rencheng and Wang, Yahui and Kung, Che Pei and Weber, Jason D. and Patti, Gary J.},
doi = {10.7554/eLife.41351},
file = {:Users/kylekovary/Documents/Mendeley Desktop/eLife/2019/Yao et al. - Mitochondrial fusion supports increased oxidative phosphorylation during cell proliferation - 2019 - eLife.pdf:pdf},
issn = {2050084X},
journal = {eLife},
keywords = {cancer,cancer biology,cell biology,cell proliferation,human,metabolism,mitochondrial fusion,mouse,oxidative phosphorylation,warburg effect},
pages = {1--19},
pmid = {30694178},
title = {{Mitochondrial fusion supports increased oxidative phosphorylation during cell proliferation}},
volume = {8},
year = {2019}
}

@article{Kang2019,
abstract = {The energetic demands of a cell are believed to increase during mitosis 1–7. As cells transit from G2 into mitosis, mitochondrial electron transport chain (ETC) activity increases 4,8,9, and cellular ATP levels progressively decrease until the metaphase-anaphase transition 3,7,10, consistent with elevated consumption. The rates of ATP synthesis during mitosis, however, have not been quantified. Here, we monitor mitochondrial membrane potential of single lymphocytes and demonstrate that cyclin-dependent kinase 1 (CDK1) activity causes mitochondrial hyperpolarization from G2/M until the metaphase-anaphase transition. By using an electrical circuit model of mitochondria, we quantify the time-dynamics of mitochondrial membrane potential under normal and perturbed conditions to extract mitochondrial ATP synthesis rates in mitosis. We found that mitochondrial ATP synthesis decreases by approximately 50 {\%} during early mitosis, when CDK1 is active, and increases back to G2 levels during cytokinesis. Consistently, acute inhibition of mitochondrial ATP synthesis failed to delay cell division. Our results provide a quantitative understanding of mitochondrial bioenergetics in mitosis and challenge the traditional dogma that cell division is a highly energy demanding process.},
author = {Kang, Joon Ho and Katsikis, Georgios and Stockslager, Max A and Lim, Daniel and Yaffe, Michael B and Manalis, Scott R and Miettinen, Teemu P},
doi = {10.1101/772244},
journal = {bioRxiv},
month = {jan},
pages = {772244},
title = {{Time-dynamics of mitochondrial membrane potential reveal an inhibition of ATP synthesis in mitosis}},
url = {http://biorxiv.org/content/early/2019/09/18/772244.abstract},
year = {2019}
}

@article{Tsuboi2020,
abstract = {Mitochondria are dynamic organelles that must precisely control their protein composition according to cellular energy demand. Although nuclear-encoded mRNAs can be localized to the mitochondrial surface, the importance of this localization is unclear. As yeast switch to respiratory metabolism, there is an increase in the fraction of the cytoplasm that is mitochondrial. Our data point to this change in mitochondrial volume fraction increasing the localization of certain nuclear-encoded mRNAs to the surface of the mitochondria. We show that mitochondrial mRNA localization is necessary and sufficient to increase protein production to levels required during respiratory growth. Furthermore, we find that ribosome stalling impacts mRNA sensitivity to mitochondrial volume fraction and counterintuitively leads to enhanced protein synthesis by increasing mRNA localization to mitochondria. This points to a mechanism by which cells are able to use translation elongation and the geometric constraints of the cell to fine-tune organelle-specific gene expression through mRNA localization.},
author = {Tsuboi, Tatsuhisa and Viana, Matheus P and Xu, Fan and Yu, Jingwen and Chanchani, Raghav and Arceo, Ximena G and Tutucci, Evelina and Choi, Joonhyuk and Chen, Yang S and Singer, Robert H and Rafelski, Susanne M and Zid, Brian M},
doi = {10.7554/eLife.57814},
file = {:Users/kylekovary/Documents/Mendeley Desktop/eLife/2020/Tsuboi et al. - Mitochondrial volume fraction and translation duration impact mitochondrial mRNA localization and protein synthesis - 20.pdf:pdf},
issn = {2050-084X},
journal = {eLife},
month = {aug},
number = {529289},
pages = {1--24},
title = {{Mitochondrial volume fraction and translation duration impact mitochondrial mRNA localization and protein synthesis}},
url = {https://elifesciences.org/articles/57814},
volume = {9},
year = {2020}
}

@article{Taniguchi2010,
abstract = {Protein and messenger RNA (mRNA) copy numbers vary from cell to cell in isogenic bacterial populations. However, these molecules often exist in low copy numbers and are difficult to detect in single cells. We carried out quantitative system-wide analyses of protein and mRNA expression in individual cells with single-molecule sensitivity using a newly constructed yellow fluorescent protein fusion library for Escherichia coli. We found that almost all protein number distributions can be described by the gamma distribution with two fitting parameters which, at low expression levels, have clear physical interpretations as the transcription rate and protein burst size. At high expression levels, the distributions are dominated by extrinsic noise. We found that a single cell's protein and mRNA copy numbers for any given gene are uncorrelated.},
author = {Taniguchi, Yuichi and Choi, Paul J and Li, Gene-Wei and Chen, Huiyi and Babu, Mohan and Hearn, Jeremy and Emili, Andrew and Xie, X Sunney},
doi = {10.1126/science.1188308},
file = {:Users/kylekovary/Documents/Mendeley Desktop/Science/2010/Taniguchi et al. - Quantifying E. coli proteome and transcriptome with single-molecule sensitivity in single cells. - 2010 - Science.pdf:pdf},
issn = {1095-9203},
journal = {Science},
keywords = {Escherichia coli,Escherichia coli Proteins,Escherichia coli Proteins: analysis,Escherichia coli Proteins: metabolism,Escherichia coli: chemistry,Escherichia coli: genetics,Escherichia coli: metabolism,Gene Expression,Gene Expression Profiling,Gene Library,In Situ Hybridization, Fluorescence,Luminescent Proteins,Microfluidic Analytical Techniques,Microscopy, Fluorescence,Protein Biosynthesis,Proteome,Proteome: analysis,RNA Stability,RNA, Bacterial,RNA, Bacterial: analysis,RNA, Bacterial: genetics,RNA, Bacterial: metabolism,RNA, Messenger,RNA, Messenger: analysis,RNA, Messenger: genetics,Saccharomyces cerevisiae,Saccharomyces cerevisiae: chemistry,Saccharomyces cerevisiae: genetics,Saccharomyces cerevisiae: metabolism,Transcription, Genetic},
month = {jul},
number = {5991},
pages = {533--8},
pmid = {20671182},
title = {{Quantifying E. coli proteome and transcriptome with single-molecule sensitivity in single cells.}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2922915{\&}tool=pmcentrez{\&}rendertype=abstract},
volume = {329},
year = {2010}
}

@article{Ozbudak2002,
abstract = {Stochastic mechanisms are ubiquitous in biological systems. Biochemical reactions that involve small numbers of molecules are intrinsically noisy, being dominated by large concentration fluctuations. This intrinsic noise has been implicated in the random lysis/lysogeny decision of bacteriophage-lambda, in the loss of synchrony of circadian clocks and in the decrease of precision of cell signals. We sought to quantitatively investigate the extent to which the occurrence of molecular fluctuations within single cells (biochemical noise) could explain the variation of gene expression levels between cells in a genetically identical population (phenotypic noise). We have isolated the biochemical contribution to phenotypic noise from that of other noise sources by carrying out a series of differential measurements. We varied independently the rates of transcription and translation of a single fluorescent reporter gene in the chromosome of Bacillus subtilis, and we quantitatively measured the resulting changes in the phenotypic noise characteristics. We report that of these two parameters, increased translational efficiency is the predominant source of increased phenotypic noise. This effect is consistent with a stochastic model of gene expression in which proteins are produced in random and sharp bursts. Our results thus provide the first direct experimental evidence of the biochemical origin of phenotypic noise, demonstrating that the level of phenotypic variation in an isogenic population can be regulated by genetic parameters.},
archivePrefix = {arXiv},
arxivId = {NIHMS150003},
author = {Ozbudak, Ertugrul M and Thattai, Mukund and Kurtser, Iren and Grossman, Alan D and van Oudenaarden, Alexander},
doi = {10.1038/ng869},
eprint = {NIHMS150003},
file = {:Users/kylekovary/Documents/Mendeley Desktop/Nature genetics/2002/Ozbudak et al. - Regulation of noise in the expression of a single gene. - 2002 - Nature genetics.pdf:pdf},
isbn = {1061-4036 (Print)$\backslash$n1061-4036 (Linking)},
issn = {10614036},
journal = {Nature genetics},
number = {1},
pages = {69--73},
pmid = {11967532},
title = {{Regulation of noise in the expression of a single gene.}},
volume = {31},
year = {2002}
}

@article{Elowitz2002,
abstract = {Clonal populations of cells exhibit substantial phenotypic variation. Such heterogeneity can be essential for many biological processes and is conjectured to arise from stochasticity, or noise, in gene expression. We constructed strains of Escherichia coli that enable detection of noise and discrimination between the two mechanisms by which it is generated. Both stochasticity inherent in the biochemical process of gene expression (intrinsic noise) and fluctuations in other cellular components (extrinsic noise) contribute substantially to overall variation. Transcription rate, regulatory dynamics, and genetic factors control the amplitude of noise. These results establish a quantitative foundation for modeling noise in genetic networks and reveal how low intracellular copy numbers of molecules can fundamentally limit the precision of gene regulation.},
author = {Elowitz, Michael B. and Levine, Arnold J. and Siggia, Eric D. and Swain, Peter S.},
doi = {10.1126/science.1070919},
issn = {00368075},
journal = {Science},
pmid = {12183631},
title = {{Stochastic gene expression in a single cell}},
year = {2002}
}

@article{Blake2003,
abstract = {Transcription in eukaryotic cells has been described as quantal, with pulses of messenger RNA produced in a probabilistic manner. This description reflects the inherently stochastic nature of gene expression, known to be a major factor in the heterogeneous response of individual cells within a clonal population to an inducing stimulus. Here we show in Saccharomyces cerevisiae that stochasticity (noise) arising from transcription contributes significantly to the level of heterogeneity within a eukaryotic clonal population, in contrast to observations in prokaryotes, and that such noise can be modulated at the translational level. We use a stochastic model of transcription initiation specific to eukaryotes to show that pulsatile mRNA production, through reinitiation, is crucial for the dependence of noise on transcriptional efficiency, highlighting a key difference between eukaryotic and prokaryotic sources of noise. Furthermore, we explore the propagation of noise in a gene cascade network and demonstrate experimentally that increased noise in the transcription of a regulatory protein leads to increased cell-cell variability in the target gene output, resulting in prolonged bistable expression states. This result has implications for the role of noise in phenotypic variation and cellular differentiation.},
author = {Blake, William J. and K{\ae}rn, Mads and Cantor, Charles R. and Collins, J. J.},
doi = {10.1038/nature01546},
issn = {00280836},
journal = {Nature},
pmid = {12687005},
title = {{Noise in eukaryotic gene expression}},
year = {2003}
}

@article{Raser2004,
abstract = {Noise, or random fluctuations, in gene expression may produce variability in cellular behavior. To measure the noise intrinsic to eukaryotic gene expression, we quantified the differences in expression of two alleles in a diploid cell. We found that such noise is gene-specific and not dependent on the regulatory pathway or absolute rate of expression. We propose a model in which the balance between promoter activation and transcription influences the variability in messenger RNA levels. To confirm the predictions of our model, we identified both cis- and trans-acting mutations that alter the noise of gene expression. These mutations suggest that noise is an evolvable trait that can be optimized to balance fidelity and diversity in eukaryotic gene expression.},
author = {Raser, Jonathan M. and O'Shea, Erin K.},
doi = {10.1126/science.1098641},
issn = {00368075},
journal = {Science},
pmid = {15166317},
title = {{Control of stochasticity in eukaryotic gene expression}},
year = {2004}
}

@article{Golding2005,
abstract = {Protein levels have been shown to vary substantially between individual cells in clonal populations. In prokaryotes, the contribution to such fluctuations from the inherent randomness of gene expression has largely been attributed to having just a few transcripts of the corresponding mRNAs. By contrast, eukaryotic studies tend to emphasize chromatin remodeling and burst-like transcription. Here, we study single-cell transcription in Escherichia coli by measuring mRNA levels in individual living cells. The results directly demonstrate transcriptional bursting, similar to that indirectly inferred for eukaryotes. We also measure mRNA partitioning at cell division and correlate mRNA and protein levels in single cells. Partitioning is approximately binomial, and mRNA-protein correlations are weaker earlier in the cell cycle, where cell division has recently randomized the relative concentrations. Our methods further extend protein-based approaches by counting the integer-valued number of transcript with single-molecule resolution. This greatly facilitates kinetic interpretations in terms of the integer-valued random processes that produce the fluctuations. {\textcopyright}2005 Elsevier Inc.},
author = {Golding, Ido and Paulsson, Johan and Zawilski, Scott M. and Cox, Edward C.},
doi = {10.1016/j.cell.2005.09.031},
issn = {00928674},
journal = {Cell},
pmid = {16360033},
title = {{Real-time kinetics of gene activity in individual bacteria}},
year = {2005}
}