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18 Publications

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    Menon Lab
    10/11/13 | Dynamic Bayesian clustering.
    Fowler A, Menon V, Heard NA
    Journal of bioinformatics and computational biology. 2013 Oct;11(5):1342001. doi: 10.1142/S0219720013420018

    Clusters of time series data may change location and memberships over time; in gene expression data, this occurs as groups of genes or samples respond differently to stimuli or experimental conditions at different times. In order to uncover this underlying temporal structure, we consider dynamic clusters with time-dependent parameters which split and merge over time, enabling cluster memberships to change. These interesting time-dependent structures are useful in understanding the development of organisms or complex organs, and could not be identified using traditional clustering methods. In cell cycle data, these time-dependent structure may provide links between genes and stages of the cell cycle, whilst in developmental data sets they may highlight key developmental transitions.

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    Menon Lab
    10/09/13 | The influence of synaptic weight distribution on neuronal population dynamics.
    Iyer R, Menon V, Buice M, Koch C, Mihalas S
    PLoS computational biology. 2013 Oct;9(10):e1003248. doi: 10.1371/journal.pcbi.1003248

    The manner in which different distributions of synaptic weights onto cortical neurons shape their spiking activity remains open. To characterize a homogeneous neuronal population, we use the master equation for generalized leaky integrate-and-fire neurons with shot-noise synapses. We develop fast semi-analytic numerical methods to solve this equation for either current or conductance synapses, with and without synaptic depression. We show that its solutions match simulations of equivalent neuronal networks better than those of the Fokker-Planck equation and we compute bounds on the network response to non-instantaneous synapses. We apply these methods to study different synaptic weight distributions in feed-forward networks. We characterize the synaptic amplitude distributions using a set of measures, called tail weight numbers, designed to quantify the preponderance of very strong synapses. Even if synaptic amplitude distributions are equated for both the total current and average synaptic weight, distributions with sparse but strong synapses produce higher responses for small inputs, leading to a larger operating range. Furthermore, despite their small number, such synapses enable the network to respond faster and with more stability in the face of external fluctuations.

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    Menon Lab
    11/24/11 | Multi-scale correlation structure of gene expression in the brain.
    Hawrylycz M, Ng L, Page D, Morris J, Lau C, Faber S, Faber V, Sunkin S, Menon V, Lein E, Jones A
    Neural networks : the official journal of the International Neural Network Society. 2011 Nov;24(9):933-42. doi: 10.1016/j.neunet.2011.06.012

    The mammalian brain is best understood as a multi-scale hierarchical neural system, in the sense that connection and function occur on multiple scales from micro to macro. Modern genomic-scale expression profiling can provide insight into methodologies that elucidate this architecture. We present a methodology for understanding the relationship of gene expression and neuroanatomy based on correlation between gene expression profiles across tissue samples. A resulting tool, NeuroBlast, can identify networks of genes co-expressed within or across neuroanatomic structures. The method applies to any data modality that can be mapped with sufficient spatial resolution, and provides a computation technique to elucidate neuroanatomy via patterns of gene expression on spatial and temporal scales. In addition, from the perspective of spatial location, we discuss a complementary technique that identifies gene classes that contribute to defining anatomic patterns.

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    Menon Lab
    11/01/11 | Frozen tissue can provide reproducible proteomic results of subcellular fractionation.
    Lim J, Menon V, Bitzer M, Miller LM, Madrid-Aliste C, Weiss LM, Fiser A, Angeletti RH
    Analytical biochemistry. 2011 Nov 1;418(1):78-84. doi: 10.1016/j.ab.2011.06.045

    Differential detergent fractionation (DDF) is frequently used to partition fresh cells and tissues into distinct compartments. We have tested whether DDF can reproducibly extract and fractionate cellular protein components from frozen tissues. Frozen kidneys were sequentially extracted with three different buffer systems. Analysis of the three fractions with liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified 1693 proteins, some of which were common to all fractions and others of which were unique to specific fractions. Normalized spectral index (SI(N)) values obtained from these data were compared to evaluate both the reproducibility of the method and the efficiency of enrichment. SI(N) values between replicate fractions demonstrated a high correlation, confirming the reproducibility of the method. Correlation coefficients across the three fractions were significantly lower than those for the replicates, supporting the capability of DDF to differentially fractionate proteins into separate compartments. Subcellular annotation of the proteins identified in each fraction demonstrated a significant enrichment of cytoplasmic, cell membrane, and nuclear proteins in the three respective buffer system fractions. We conclude that DDF can be applied to frozen tissue to generate reproducible proteome coverage discriminating subcellular compartments. This demonstrates the feasibility of analyzing cellular compartment-specific proteins in archived tissue samples with the simple DDF method.

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    Menon Lab
    04/01/11 | Hallmarks of molecular action of microtubule stabilizing agents: effects of epothilone B, ixabepilone, peloruside A, and laulimalide on microtubule conformation.
    Khrapunovich-Baine M, Menon V, Yang CH, Northcote PT, Miller JH, Angeletti RH, Fiser A, Horwitz SB, Xiao H
    The Journal of biological chemistry. 2011 Apr 1;286(13):11765-78. doi: 10.1074/jbc.M110.162214

    Microtubule stabilizing agents (MSAs) comprise a class of drugs that bind to microtubule (MT) polymers and stabilize them against disassembly. Several of these agents are currently in clinical use as anticancer drugs, whereas others are in various stages of development. Nonetheless, there is insufficient knowledge about the molecular modes of their action. Recent studies from our laboratory utilizing hydrogen-deuterium exchange in combination with mass spectrometry (MS) provide new information on the conformational effects of Taxol and discodermolide on microtubules isolated from chicken erythrocytes (CET). We report here a comprehensive analysis of the effects of epothilone B, ixabepilone (IXEMPRA(TM)), laulimalide, and peloruside A on CET conformation. The results of our comparative hydrogen-deuterium exchange MS studies indicate that all MSAs have significant conformational effects on the C-terminal H12 helix of α-tubulin, which is a likely molecular mechanism for the previously observed modulations of MT interactions with microtubule-associated and motor proteins. More importantly, the major mode of MT stabilization by MSAs is the tightening of the longitudinal interactions between two adjacent αβ-tubulin heterodimers at the interdimer interface. In contrast to previous observations reported with bovine brain tubulin, the lateral interactions between the adjacent protofilaments in CET are particularly strongly stabilized by peloruside A and laulimalide, drugs that bind outside the taxane site. This not only highlights the significance of tubulin isotype composition in modulating drug effects on MT conformation and stability but also provides a potential explanation for the synergy observed when combinations of taxane and alternative site binding drugs are used.

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    Menon Lab
    12/15/09 | Distinct pose of discodermolide in taxol binding pocket drives a complementary mode of microtubule stabilization.
    Khrapunovich-Baine M, Menon V, Verdier-Pinard P, Smith AB, Angeletti RH, Fiser A, Horwitz SB, Xiao H
    Biochemistry. 2009 Dec 15;48(49):11664-77. doi: 10.1021/bi901351q

    The microtubule cytoskeleton has proven to be an effective target for cancer therapeutics. One class of drugs, known as microtubule stabilizing agents (MSAs), binds to microtubule polymers and stabilizes them against depolymerization. The prototype of this group of drugs, Taxol, is an effective chemotherapeutic agent used extensively in the treatment of human ovarian, breast, and lung carcinomas. Although electron crystallography and photoaffinity labeling experiments determined that the binding site for Taxol is in a hydrophobic pocket in beta-tubulin, little was known about the effects of this drug on the conformation of the entire microtubule. A recent study from our laboratory utilizing hydrogen-deuterium exchange (HDX) in concert with various mass spectrometry (MS) techniques has provided new information on the structure of microtubules upon Taxol binding. In the current study we apply this technique to determine the binding mode and the conformational effects on chicken erythrocyte tubulin (CET) of another MSA, discodermolide, whose synthetic analogues may have potential use in the clinic. We confirmed that, like Taxol, discodermolide binds to the taxane binding pocket in beta-tubulin. However, as opposed to Taxol, which has major interactions with the M-loop, discodermolide orients itself away from this loop and toward the N-terminal H1-S2 loop. Additionally, discodermolide stabilizes microtubules mainly via its effects on interdimer contacts, specifically on the alpha-tubulin side, and to a lesser extent on interprotofilament contacts between adjacent beta-tubulin subunits. Also, our results indicate complementary stabilizing effects of Taxol and discodermolide on the microtubules, which may explain the synergy observed between the two drugs in vivo.

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    Spruston LabMenon Lab
    09/29/09 | A state-mutating genetic algorithm to design ion-channel models.
    Menon V, Spruston N, Kath WL
    Proceedings of the National Academy of Sciences of the United States of America. 2009 Sep 29;106(39):16829-34. doi: 10.1073/pnas.0903766106

    Realistic computational models of single neurons require component ion channels that reproduce experimental findings. Here, a topology-mutating genetic algorithm that searches for the best state diagram and transition-rate parameters to model macroscopic ion-channel behavior is described. Important features of the algorithm include a topology-altering strategy, automatic satisfaction of equilibrium constraints (microscopic reversibility), and multiple-protocol fitting using sequential goal programming rather than explicit weighting. Application of this genetic algorithm to design a sodium-channel model exhibiting both fast and prolonged inactivation yields a six-state model that produces realistic activity-dependent attenuation of action-potential backpropagation in current-clamp simulations of a CA1 pyramidal neuron.

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    Spruston LabMenon Lab
    07/30/09 | Synapse distribution suggests a two-stage model of dendritic integration in CA1 pyramidal neurons.
    Katz Y, Menon V, Nicholson DA, Geinisman Y, Kath WL, Spruston N
    Neuron. 2009 Jul 30;63(2):171-7. doi: 10.1016/j.neuron.2009.06.023

    Competing models have been proposed to explain how neurons integrate the thousands of inputs distributed throughout their dendritic trees. In a simple global integration model, inputs from all locations sum in the axon. In a two-stage integration model, inputs contribute directly to dendritic spikes, and outputs from multiple branches sum in the axon. These two models yield opposite predictions of how synapses at different dendritic locations should be scaled if they are to contribute equally to neuronal output. We used serial-section electron microscopy to reconstruct individual apical oblique dendritic branches of CA1 pyramidal neurons and observe a synapse distribution consistent with the two-stage integration model. Computational modeling suggests that the observed synapse distribution enhances the contribution of each dendritic branch to neuronal output.

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