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Sodium channel
Voltage-gated sodium channels are responsible for action potential initiation and propagation in excitable cells, including nerve, muscle, and neuroendocrine cell types. They are also expressed at low levels in nonexcitable cells, where their physiological role is unclear. Sodium channels are the founding members of the ion channel superfamily in terms of their discovery as a protein and determination of their amino acid sequence. [817]
Sodium channels were the first members of the ion channel superfamily to be discovered; the superfamily also includes voltage-gated K+ channels, voltage-gated Ca2+ channels, Trp-related channels (a diverse family permeable to various cations) and cyclic-nucleotide-gated channels (Hille B: Ion Channels of Excitable Membranes. Sunderland, MA: Sinauer Associates Inc; 2001. ). But in evolution, the sodium channel family is the most recent of the voltage-gated ion channels to have arisen, having evolved from similarly structured Ca2+ channels that contain four homologous domains. Ca2+ channels, in turn, probably arose by two rounds of gene duplication from the ancestors of K+ and cyclic-nucleotide-gated channels, which form functional channels as tetramers of single-domain subunits. The appearance of four-domain sodium channels coincided with evolution of metazoans that had specialized neurons [821]. Although 'classical' four-domain sodium channels have not been identified from prokaryotes, a recent report has identified a bacterial sodium channel (Figure 1c in [820]) in the salt-loving bacterium Bacillus halodurans [822]. This single-domain voltage-dependent sodium channel, which also has sequence and pharmacological characteristics resembling those of Ca2+ channels, opens up the intriguing possibility that it is similar to the ancestral single-domain channel from which the Ca2+ and Na+ channels have arisen. (Whole paragraph from Yu [820].) For more detailed information about the adaptive evolution of voltage-gated sodium channels see Zakon (2012) [1366].
In mammals nine functionally expressed voltage-gated sodium channel (Nav1.1-Nav1.9, VGSC) are encoded by 11 genes (SCN1A-SCN11A) [834]. VGSC consist in: i) Alfa-subunits organized into four homologous domains (DI-DIV) composed of six transmembrane segments: segments 1-4 form the voltage sensor while segments 5-6 and the linker P-loop compose the pore region ii) Beta-subunits that act as regulatory molecules. The SCN7A/Nax gene encodes an atypical sodium channel, named 'Nax' that is considered to be a descendant of the voltage-gated sodium channel, although it is not regulated by the membrane's voltage as in the other channels of the sodium channel family [879]. Four sodium channel isoforms (Nav1.1, Nav1.2, Nav1.3 and Nav1.6) are highly expressed in the central nervous system. Two isoforms are abundant in muscle: Nav1.4 in adult skeletal muscle and Nav1.5 in embryonic and denervated skeletal muscle and heart muscle. Finally, Nav1.7, Nav1.8 and Nav1.9, are expressed primarily in the peripheral nervous system [834].
For a phylogenetic tree and nomenclature/classification, see Catterall [817].
: Sodium channel
According to the convention of the International Union of Pharmacologists, the nomenclature of sodium channels (for example, Nav1.1) consists of the chemical symbol of the principal permeating ion (Na) and the principal physiological regulator (voltage, subscript) followed by a number indicating the gene subfamily and a decimal that separates the number assigned to specific channel isoforms [817].
From Catterall [817]: All of the pharmacological agents that act on sodium channels have receptor sites on the alpha subunits. At least six distinct receptor sites for neurotoxins and one receptor site for local anesthetics and related drugs have been identified [815]; Table 1 in [817]. Neurotoxin receptor site 1 binds the nonpeptide pore blockers tetrodotoxin and saxitoxin and the peptide pore blocker mu-conotoxin [818], [819], [815].
The two muscle sodium channel isoforms can easily be distinguished from each other and from the CNS isoforms on the basis of toxin sensitivity [834]:
The receptor sites for these toxins are formed by amino acid residues in the pore loops and immediately on the extracellular side of the pore loops at the outer end of the pore. Neurotoxin receptor site 2 binds a family of lipid-soluble toxins, including batrachotoxin, veratridine, aconitine, and grayanotoxin, which enhance activation of sodium channels. Photoaffinity labeling and mutagenesis studies implicate transmembrane segments IS6 and IVS6 in the receptor site for batrachotoxin [815]. Neurotoxin receptor site 3 binds the alpha-scorpion toxins and sea anemone toxins, which slow the coupling of sodium channel activation to inactivation. These peptide toxins bind to a complex receptor site that includes the S3-S4 loop at the outer end of the S4 segment in domain IV [815]. Neurotoxin receptor site 4 binds the beta-scorpion toxins, which enhance activation of the channels. The receptor site for the beta-scorpion toxins includes the S3-S4 loop at the extracellular end of the voltage-sensing S4 segments in domain II (Cestele and Catterall, 2000). Neurotoxin receptor site 5 binds the complex polyether toxins brevetoxin and ciguatoxin, which are made by dinoflagellates and cause toxic red tides in warm ocean waters [815]. Transmembrane segments IS6 and IVS5 are implicated in brevetoxin binding from photoaffinity labeling studies [815].
Neurotoxin receptor site 6 binds delta-conotoxins, which slow the rate of inactivation like the alpha-scorpion toxins. The location of neurotoxin receptor site 6 is unknown. Finally, the local anesthetics and related antiepileptic and antiarrhythmic drugs bind to overlapping receptor sites located in the inner cavity of the pore of the sodium channel [815]. Amino acid residues in the S6 segments from at least three of the four domains contribute to this complex drug receptor site, with the IVS6 segment playing the dominant role. Tables 2 through 10 in [817] summarize the major molecular, physiological, and pharmacological properties for each of the nine sodium channels that have been functionally expressed. Quantitative data are included for voltage dependence of activation and inactivation, single-channel conductance, and binding of drugs and neurotoxins, focusing on those agents that are widely used and diagnostic of channel identity and function.
The gene expression of Nav channels present in the DRG are regulated by 17β-Estradiol and this may be an important mechanism of pain regulation [1447].
For a structural overview image see Yu [820] and Catterall [1367].
Sodium channels consist of a large α subunit that associates with other proteins, such as β subunits. An α subunit forms the core of the channel and is functional on its own. When the α subunit protein is expressed by a cell, it is able to form channels that conduct Na+ in a voltage-gated way, even if β subunits or other known modulating proteins are not expressed. When accessory proteins assemble with α subunits, the resulting complex can display altered voltage dependence and cellular localization.
Alfa-subuntit [834].
The α-subunit has four repeat domains, labeled I through IV, each containing six membrane-spanning regions, labeled S1 through S6. The highly conserved S4 region acts as the channel's voltage sensor. The voltage sensitivity of this channel is due to positive amino acids located at every third position. When stimulated by a change in transmembrane voltage, this region moves toward the extracellular side of the cell membrane, allowing the channel to become permeable to ions. The ions are conducted through a pore, which can be broken into two regions. The more external (i.e., more extracellular) portion of the pore is formed by the "P-loops" (the region between S5 and S6) of the four domains. This region is the most narrow part of the pore and is responsible for its ion selectivity. The inner portion (i.e., more cytoplasmic) of the pore is formed by the combined S5 and S6 regions of the four domains. The region linking domains III and IV is also important for channel function. This region plugs the channel after prolonged activation, inactivating it.
Beta-subuntit [834].
Many of the mammalian sodium channel alfa-subunits are associated with accessory beta-subunits in vivo. The beta-1 subunit is noncovalently attached to the alfa-subunit, and the beta-2 subunit is covalently linked to the alfa-subunit by disulfide bonds. Channels in the adult CNS are associated with both beta-1 and beta-2 subunits, and channels in adult skeletal muscle are associated with just beta-1. In addition, cDNA clones encoding a beta-3 subunit have been isolated. The sequences of the three beta-subunits are not homologous, but they are all clearly related based on the phylogenetic tree. Each of the beta subunit sequences predicts a protein with an amino-terminal signal sequence and single membrane-spanning region, indicative of an extracellular amino terminus. All three beta-subunits contain immunoglobulin-like folds similar to those found in neural cell adhesion molecules. Co-expression of the beta-1 subunit with many of the alfa-subunits in Xenopus oocytes modulates the electrophysiological properties of the channel, including accelerating inactivation and shifting the voltage-dependence of steady-state inactivation in the negative direction. Co-expression of the beta-3 subunit modulates gating of the alfa-subunit sodium channels to a lesser extent than does co-expression of beta-1, and co-expression of the beta-2 subunit modulates alfa-subunit gating the least of the beta-subunits. The beta-subunits are also important for sodium channel interactions with cellular proteins. The beta-2 subunit significantly increases membrane capacitance, which may indicate that it is involved in insertion of the channels into the cellular membrane. Both beta-1 and beta-2 interact with the extracellular matrix proteins tenascin-C and tenascin-R, suggesting that the proteins may function as cellular adhesion molecules. Consistent with this hypothesis, both beta-1 and beta-2 subunits recruit ankyrin to sites of cell-cell contact, and this recruitment requires the cytoplasmic domains of the subunits.
The pore of sodium channels contains a selectivity filter made of negatively charged amino acid residues, which attract the positive Na+ ion and keep out negatively charged ions such as chloride. The cations flow into a more constricted part of the pore that is 0.3 by 0.5 nm wide, which is just large enough to allow a single Na+ ion with a water molecule associated to pass through. The larger K+ ion cannot fit through this area. Differently sized ions also cannot interact as well with the negatively charged glutamic acid residues that line the pore.
The density of Na+ channels in the AIS of cortical layer 5 pyramidal neurons is high (on average 50-fold higher than the density at the soma and proximal dendrites). A high AIS Na+ channel density (2,500 pS per square micro meter) is required to account for experimental observations on the rate of rise of axonal action potentials, as well as on action potential initiation and backpropagation. [287].
Central Nervous System Channels [834]
Nav1.1, Nav1.2, Nav1.3, and Nav1.6 are expressed abundantly in the CNS. Nav1.5 was not originally detected in brain, but more sensitive approaches have demonstrated expression in the piriform cortex and subcortical limbic nuclei, which may explain the observation of sodium currents in the entorhinal cortex, with properties similar to those in cardiac muscle. Specifically, Nav1.1 was detected at high levels in the cell bodies within the hippocampus, cerebellum, spinal cord, brainstem, cortex, substantia nigra, and caudate. In the cerebellum, Nav1.1 is detectable in Purkinje cells but not in granule cells. Nav1.2 was observed at high levels in the axons within the globus pallidus, hippocampus, and thalamus. There is no rostral-caudal gradient of Nav1.6 mRNA, but it is present in a somato-dendritic distribution in output neurons of the cerebellum, cerebral cortex, and hippocampus, as well as in Purkinje cells in the cerebellar granule cell layer. Nav1.1, Nav1.2, Nav1.3, and Nav1.6 are present in neurons and glia, although the function of the channels in glial cells is not well understood. The isoforms in the CNS are present at different times in development, which has been studied most extensively in the rat. Nav1.1, Nav1.2, and Nav1.6 are present at significant levels in the adult CNS. Nav1.1 expression increases during the third postnatal week and peaks at the end of the first postnatal month, after which levels decrease by about 50% in the adult. Nav1.2 expression also increases during the third postnatal week, but then continues to increase until reaching maximal levels during adulthood. Nav1.6 is the most abundantly expressed isoform in the CNS during adulthood but it was detected during the embryonic period in brain, and levels increased shortly after birth and peaked by 2-weeks of age. Levels of Nav1.3 peak at birth but remain detectable at a lower level in adulthood.
Skeletal and Heart Muscle Channels [834]
Nav1.4 and Nav1.5 are expressed at significant levels in skeletal or cardiac muscle. Nav1.4 is expressed at high levels in adult skeletal muscle, at low levels in neonatal skeletal muscle, and not at all in brain or heart. Nav1.5 is present at high levels in heart, but not in liver, kidney, or uterus. Nav1.5 is not observed in adult skeletal muscle, but it is detectable in neonatal skeletal muscle and after denervation of adult muscle. Although both isoforms are present in denervated skeletal muscle, the increase in the level of sodium channel mRNA following denervation results from an induction of Nav1.5 expression.
Peripheral Nervous System Channels [834]
Nav1.7, Nav1.8, and Nav1.9 are expressed primarily in the PNS. The Nav1.1 isoform has been shown to be expressed at high levels in the PNS whereas the levels of Nav1.2 and Nav1.3 are significantly higher in the CNS than in the PNS. Nav1.6 is the most abundantly expressed channel in the CNS, and it can also be detected in both gray and white matter in the spinal cord and in all diameter cells in the DRG, including both motor and primary sensory neurons. This channel is also present at the nodes of Ranvier in the sciatic nerve, spinal cord, and optic nerve, locations at which the other isoforms were not detected. Nav1.7 is widespread in the PNS, present in all types of DRG neurons, in Schwann cells, and in neuroendocrine cells. The expression of Nav1.8 is more localized and found primarily in small diameter sensory neurons of the DRG and trigeminal ganglion, in which the channel has been observed during both neonatal and adult periods. The Nav1.9 channel is expressed in small fibers (sensory neurons) of the DRG and trigeminal ganglion, and the level of expression is down-regulated after axotomy.
The current density and gating properties of VGSC can also be modulated by the differential expression of channel "partners" or ChiPs:
For further information see Table 3 (VGSC protein partners) in [1376]
Channelopathies [1385]
Mutations in any of the genes encoding the alfa-subunits (SCN1A–SCN11A) and beta-subunits (SCN1B–SCN4B) can alter the structure of the channel and, thus, its biophysical properties leading to the development of "channelopathies". Channelopathies are associated with autosomal dominant inheritance and de novo mutations and they can be classified in four groups depending on the predominant organ involved:
When the cell membrane is depolarized by a few millivolts, sodium channels activate and inactivate within milliseconds. Influx of sodium ions through the integral membrane proteins comprising the channel depolarizes the membrane further and initiates the rising phase of the action potential. [820]
There are significant differences among the three isoforms with respect to persistent current:
[1] HHNa (Model ID = 2)
[2] McCormick Na (Model ID = 34)
[3] Na (Model ID = 35)
[4] Na_S (Model ID = 36)
[5] NaP (Model ID = 37)
[6] Nap_Et2 (Model ID = 51)
[7] NaTa_t (Model ID = 52)
[8] NaTs2_t (Model ID = 53)
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Contributors : Rajnish Ranjan, Michael Schartner, Erika Borcel
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You Again
When a young woman realizes her brother is about to marry the girl who bullied her in high school, she sets out to expose the fiancée's true colors.
You Again stars Kristen Bell as a young woman who goes home to find her brother is engaged to marry her high school nemesis. The great Victor Garber plays her father. Jamie Lee Curtis plays her mother, and the evil fiancee's only living relative is played by Sigourney Weaver. It then turns out that Sigourney and Jamie were high school rivals as well. Then we have Betty White. I mean, I love Betty White, but she has to stop playing the same role over and over again which is a horny oldster with white hair and red lipstick and sleazy comments. This movie actually has some legitimacy to it. It tackles the idea that high school could be really tough on kids and there things that people don't necessarily get over very easily. But the only character that really had any resonance was the fiancee's ex-fiance who shows up at the rehearsal dinner to give this rather poignant statement of loss. But the rest of it, the only thing I can do is blame the director, I suppose. He trid to get people too hyper. It's a good cast, but it is has all of this forced gaiety, and it just makes you uncomfortable after awhile. It's a legitimate topic but trying too hard for laughs I think. I mean, Kristen Bell is a talented comedian and especially a physical comedian, but the movie tried too hard with a sensitive subject that could have been handled with a much lighter hand. So, I give it two stars.


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Top 50 Glaziers 2016: The Market
June 6, 2016
A Decade of Sales Fluctuations
This chart depicts the percentage of Top 50 Glaziers experiencing year-over-year sales increases and decreases from 2005 to 2015. (Only companies that provided exact sales figures are included). The percentage of companies reporting gains in 2015 expanded slightly from 2014, from 71 percent to 77 percent, continuing the market's growth trend. Glaziers have performed much better than during the 2009 to 2011 downturn, reporting four consecutive years of stronger growth. The percentage of companies reporting an increase in 2015, however, remains below the peak years of 2006 and 2007 when 82 percent and 91 percent of companies, respectively, reported y-o-y gains.
|Change in sales for each company between 2014 and 2015
Of the companies reporting y-o-y sales increases, seven reported sales increases of 50 percent or more (indicated in white in the chart at right). Of those, three companies— Egan Company/ InterClad, Graboyes Commercial Window Co. and Palm Beach Glass Specialties Inc.—reported sales increases of 100 percent or more. Nine companies reported sales increases of 25 to 50 percent, and 19 companies saw sales increase 0 to 25 percent.
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|How did bid levels in 2015 compare to the previous year?
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|How did profit margins in 2015 compare to the previous year?
Profit margins were also on the rise—56 percent of companies reported higher margins, with only 8 percent reporting lower margins.
|Which geographic markets offer the most growth potential in the coming year?
Survey respondents were asked to mark all regions that offered the most potential for growth. However, responses were mixed. A small plurality of respondents—29 percent—forecast the most growth in three regions, all along the coasts—in the Northeast, East Coast and West Coast. A slightly smaller number of respondents—24 percent—said the South offered the most growth potential, with 20 percent indicating the Southeast and the West. The regions with the fewest votes were the Midwest (13 percent), the Northwest (11 percent) and the Southwest (9 percent).
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Contract glaziers continue to face a labor shortage. More than half of Top 50 Glaziers reported increased difficulty in finding workers in 2015 compared to 2014, with another 25 percent reporting that they had the same difficulty finding workers compared to the previous year. While Top 50 Glaziers reported challenges filling a range of positions, the most difficult position to fill was glazier (50 percent), followed by project manager (26 percent).
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Now that Eden Sassoon has revealed she's done with RHOBH, she's doing press and really going hard on Bravo, Andy and her co-stars. In her most recent interview, Eden alleges that Lisa Vanderpump's charitable contributions come with strings attached and has a lot to say about her experience being on the show.
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Eden also told
Eden told The Tomorrow Show with Keven Undergaro, that she wants no part of Andy Cohen's ass kissing. "I'm not someone who's going to make my way to you and try to get attention — I'm not that person. If we naturally come together and we have a rapport and we start a conversation, great, but he [Andy] is like the animals attack, literally attack, and even at one of our parties my girlfriend was like 'go talk to him' and I was like 'no why' and then I ended up talking to you know the exec of Bravo all night and we were having an amazing fascinating conversation."
And despite what played out this season, Eden says she'll be rooting for Rinna in the future. "Rinna and I were texting yesterday… it was beautiful. I thanked Rinna for the journey that we had together and how you know impactful she was on my life and to take me to the next level and we're all on different stages and I said you know on the DL not anymore, Rinna I'll be your biggest fan next season, get it you know."
What are her thoughts about the social media hate she's received? "I talk to the people that talk to me. I think if people are actually taking the time to reach out to you, there's a reason. You don't ignore that. I actually reach out and I speak back to them and we start a conversation, and there's, it's a lot. And I, it's part of who I am, so I don't ignore it."
Photo Credit: Bravo


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text: Jean-Paul Rodrigue/Wikimedia Commons All Tech Considered Another Tech Bubble? Maybe Not April 16, 2012 With Instagram sold to Facebook for $1 billion and Facebook itself expected to be valued at up to $100 billion in its initial public offering, some feel they're reliving the last tech bubble. But some analysts say this time is different. The new generation of tech entrepreneurs tends to reinvest its winnings in even more ideas. Another Tech Bubble? Maybe Not Listen · 7:49 7:49 Toggle more options Download Embed Embed <iframe src="https://www.npr.org/player/embed/150740985/150745371" width="100%" height="290" frameborder="0" scrolling="no" title="NPR embedded audio player"> Transcript


text:
by Perry Meisel
Renee and I had settled into our seats at Avery Fisher Hall with lots of expectations that hot night last July. Here was a chance to see Boz Scaggs up close and find out whether he could deliver the elegance and heartbreak of Silk Degrees in front of real people. After all, his newly cultivated persona was bound up body and soul (if such terms still had meaning here) with the air-conditioned isolation and faintly android world-view of the Sun Belt studio. Until a few listenings had revealed how astonishingly moving and melodic Silk Degrees really was, its slicko production could easily be taken for a rocker's version of Lou Rawls in Philadelphia, or maybe George Benson in Vegas. Besides, there was something musically troubling, too. Even on TV, he usually looked strained, a little black under the eyes, and we'd seen him hang out at Mikell's, not quite sure what to do with his hands.
We didn't get a chance to find out much of anything that July night, since three tunes into the concert suddenly the lights, the sound, everything went out and Boz's story slipped into darkness once again. The music was at the mercy of the machine more than Boz perhaps had wished. With his new album - Down Two Then Left, on Columbia - the presence of the machine seems to have diminished, although its futuristic title and jacket conjure up a Boz of the studios even more forbidding than the suspected technocrat of Silk Degrees.
To be sure, the title's assumption of a (probably nonorganic) grid or puzzle on which we locate ourselves (or is it seats at a concert, or the way to the men's room?) is a wonderfully subtle way of suggesting how the album positions its tunes and its vocal manners across a wide variety of cultural and musical combinations or styles. Boz runs a wider musical gamut here than ever before, stretching from throaty stomps like "Hollywood," to falsetto r&b ("Then She Walked Away") and the Cab Calloway nuances of "Gimme the Goods." Culturally, meanwhile, Scaggs's distinctly Bozoid compeers on the album's silvery cover (sources? selves? servants?) may even define his present identity as a series of personations, perhaps an attempt to account for the self-conscious minstrelsy on which his ambience has depended since "Can Somebody Spare Me a Dime?" Is he outdoing Leon Redbone? Or is he simply replaying the Pips without the pedigree?
But don't let the album's neurology fool you. Like Silk Degrees, this one needs to be listened to five, maybe 10 times before it starts turning up in your head in the middle of a movie. It has the same insinuating melodic power as Silk Degrees, with even more of the passion on the run that gave the earlier record so real and powerful a charge of longing and regret. Here Boz is once again battered by forces beyond his control and even beyond his ken. His triumph is to achieve so superb a sense of balance, whether the forces that rock him are to be read in a sociopolitcal way (preppie whiteboy from Dallas actually pays his dues) or in the global and vaguely apocalyptic context of "1993."
Boz's poise is moral, however, only in terms of what the new album finally tells us about his growing sense of craft. Here technique itself becomes an ethical category, as if the only agreeable relation to black culture possible for a white musician is to learn from it singular lessons of restraint and artistic rigor. Thus, the breakthrough of Silk Degrees itself, with its sure sense of limits in singing and songwriting alike. The tunes were exemplary for their shrewd lyricism and the singing for its knowledge of where to stop the phrase and where to crack the voice without letting a lack of natural genius betray itself in mediocrity or, more likely, in plain old mistakes. Down Two Then Left follows the same pattern, only with stronger chops, which allow him to be an even more ambitious writer and singer and to hit more grooves and more inflections without risking his credibility at all.
So the striving that relieves and transforms the regret here is the product of a joyful sense of knowing just how to do it and just where to stop. That this brand of sublimation is perfectly in accord with the super-'70s sensibility at work in Boz's sleek, glistening persona helps to relieve it of its mechanistic, technocratic, and just-plain-plastic scariness. Boz is Disco Redeemed, the guy who shows us how much we lost by not taking this new tone and manner as a genuine musical possibility. With honorable melodies, serious soloing (even a trumpet on "We're Waiting," besides a number of guitar rides peppered throughout the album), and a lot of heart, this stuff really is the knockout we always thought it couldn't be. Take heart, world - Graham Parker is not alone.
Originally published in The Village Voice, January 2, 1978


text:
- Proceedings
- Open Access
Inferring transcription factor collaborations in gene regulatory networks
- Sherine Awad1 and
- Jin Chen1, 2Email author
© Awad and Chen; licensee BioMed Central Ltd. 2014
- Published: 24 January 2014
Living cells are realized by complex gene expression programs that are moderated by regulatory proteins called transcription factors (TFs). The TFs control the differential expression of target genes in the context of transcriptional regulatory networks (TRNs), either individually or in groups. Deciphering the mechanisms of how the TFs control the expression of target genes is a challenging task, especially when multiple TFs collaboratively participate in the transcriptional regulation.
We model the underlying regulatory interactions in terms of the directions (activation or repression) and their logical roles (necessary and/or sufficient) with a modified association rule mining approach, called mTRIM. The experiment on Yeast discovered 670 regulatory interactions, in which multiple TFs express their functions on common target genes collaboratively. The evaluation on yeast genetic interactions, TF knockouts and a synthetic dataset shows that our algorithm is significantly better than the existing ones.
mTRIM is a novel method to infer TF collaborations in transcriptional regulation networks. mTRIM is available at http://www.msu.edu/~jinchen/mTRIM.
- Regulatory Interaction
- Area Under Curve
- Association Rule Mining
- Transcriptional Regulatory Network
- Time Series Gene Expression
Considering the prohibitive costs and the tremendous number of possible combinations of higher-order gene knockouts, it is currently impossible for researchers to examine all of possible gene knockout combinations experimentally. One solution to this problem is to select only the TF groups that are most likely to bring about the phenotypic change. In order to accomplish this, we need to understand the interactions employed by multiple TFs (called regulatory interactions) to regulate their common target genes. However, this is a difficult task, because when multiple TFs simultaneously or sequentially control their target genes, a single gene responds to merged inputs, resulting in complex gene expression patterns [17, 18]. The exhaustive approach requires enumerating all TF combinations, which, given the high complexity of combinatorial, is simply impractical at the whole genome level.
In our previous research [19], a Hidden Markov model was developed to relate gene expression patterns to regulatory interactions, in order to solve a relatively simpler sub-problem that considers only two TFs. To predict regulatory interactions for all possible collaborative TFs, we propose an algorithm called "mTRIM" (m ultiple T ranscriptional R egulatory I nteraction M echanism) in this paper. By uncovering the regulatory interactions in terms of their directions (activation or repression) and corresponding logical roles (necessary and/or sufficient) from gene expression and TF-DNA binding data, mTRIM identifies TF groups that are collaboratively responsible for target gene expressions. Such inferences may provide high-quality candidate sets for further experimentally detecting the collaborative functions of gene regulations that are largely unknown [18]. Yeang and Jaakkola [3] attempted to characterize the combinatorial regulation of multiple-TF regulatory interactions using a heuristic approach to measure how well a regulatory module fits the associated binding and gene expression data with a log-likelihood function. The regulatory module's likelihood is maximized with a greedy approach by incrementally adding genes to the module and monitoring the predictions of the regulatory interactions for optimality. However, this incremental approach does not study the functions of the TFs simultaneously because of the scalability issue introduced by the greedy search. This method also uses a probability-based approach to calculate the significance of the combinatorial property of TFs, determined by the gap of likelihood scores between their model and a model built on randomized data in the entire time frame. However, as stated in [4], a TF usually functions at specific "activation time points" instead of throughout the entire time course, meaning that the identification of regulatory interaction modules should be focused on activation time-points rather than the entire time frame.
To derive dynamic regulatory networks that associate TFs with target genes at their activation time-points, an algorithm called DREM was proposed [4]. DREM integrates time-series gene expression data and protein-DNA binding data to build a global temporal map, in order to uncover transcriptional regulatory events leading to the observed temporal expression patterns and the underlying factors that control these events during a cell's response to stimuli. The method mainly works by identifying bifurcation time-points where the expression of a subset of genes diverges from the rest of the genes. The bifurcation points are then annotated with the TFs regulating these transitions, which result in a unified temporal map. The method can therefore facilitate the determination of the time when TFs are exerting their influence, and assigns genes to paths in the map based on their expression profiles and the TFs that control them. Unlike the method by Yeang and Jaakkola [3], DREM's ability to derive dynamic maps that associate TFs with the genes they regulate and their activation time-points has indeed led to better insights for the regulatory module being studied. However, DREM does not infer the logical roles of the TFs (i.e., whether a specific TF is necessary or sufficient for regulating a set of target genes). Such knowledge is extremely useful for designing high-order genetic variation experiments to understand the complex regulatory mechanisms of biological processes.
TRIM is an HMM based model which was developed to infer the collaboration of at most two TFs that regulate the same target genes. In the HMM, the functions of a TF are hidden states. The model starts with random priors, and then is iteratively trained using EM till convergence. Since each possible function of a TF is a node in the HMM, there are four nodes (AS, AN, RS, and RN) for each TF. With the design of HMM (and the limited training data), the number of TFs TRIM can handle is limited.
The enumeration of all TF combinations is clearly a NP problem. Therefore, we focused on the most important biological problem (i.e., 2-TF combination) and therefore "hardcoded the problem in TRIM. In this paper, we solve the efficiency problem by developing an association rule mining algorithm which is capable to handle a large amount of data with high-level combinations.
In this paper, we propose a new model mTRIM for inferring regulatory interactions for multiple TFs with an EM-based Bayesian inference approach [20, 21] and a modified bottom-up association rule mining method. Experimental results evaluated with yeast genetic interactions, TF knockouts and a synthetic dataset shows that our algorithm is significantly better than the existing ones.
mTRIM is developed to efficiently infer regulatory interactions for all possible collaborative TFs in a TRN. The feasibility is achieved in two steps. First, an EM-based Bayesian inference approach is developed to identify all the significant individual TF regulatory interactions, meaning that individual TFs that can regulate the target genes independent to the existence of other TFs. For the TFs which require collaborations with other TFs to drive the target genes, or are actually non-deterministic (meaning lack of clear evidence of regulation), their p-values are insignificant. They are considered as the inputs of the second step.
Second, in order to identify the collaboration of k TFs (k ≥ 2), i.e., k-TF regulatory interaction, a bottom-up association rule mining approach is developed. While the significant TF groups are reported to the users, the insignificant ones are joined with each other to mine (k + 1)-TF regulatory interactions. It should be noted that unlike the conventional association rule mining which seeks the longest possible patterns, mTRIM outputs the shortest significant results, in that the goal of mTRIM is to discover the smallest group of TFs that can regulate the target genes, so that biological experiments with high-order genetic variations can be subsequently carried out for the understanding of the behavior of TRNs. In terms of time complexity, consider a candidate k-TF regulatory interaction . The algorithm computes AfnScore and p-values of all of the subsets, I - {tf j } (∀j = 1, 2, ..., k). If one of them is significant, I is immediately pruned. Hence the time complexity is O(k) for each candidate k-TFs regulatory interaction. Every merging operation requires at most k - 2 equality comparisons. In the best-case scenario, it produces a viable candidate k-TF interaction. In the worst case, the algorithm merges every pair of infrequent (k - 1)-TF candidates. Therefore, the overall cost of merging candidates is between , where P k is the candidate set of k-TF regulatory interactions. To improve the algorithm efficiency, a hash tree is constructed for the storage and quick access to all of the candidates. Because the maximum depth of the hash tree is k, the cost for populating the hash tree of candidates is . During candidate pruning, it is required to verify whether the k - 1 subsets of every candidate k-TF regulatory interactions are significant. Since the cost for looking up an item in a hash tree is O(k), the time complex of candidate pruning step is .
A TRN can be represented as a directed graph in which each node is a TF or a gene, and each edge pointing from a TF to a gene represents a regulation relationship between them. In many organisms, in-depth transcriptome analysis has revealed the modular architecture of gene expression [22]. A regulatory module is a self-consistent regulatory unit R(TF, G, I) representing a set of co-expressed genes G = {g1, g2, ..., g n } regulated in concert by a group of TFs in TF = {tf1, tf2, ..., tf m } that govern the target genes' behaviors via regulatory interaction I [5]. An example of the regulatory module is shown in Figure 1b.
A regulatory interaction (which is the final output of mTRIM) is defined as a set of TFs {tf1, ..., tf m } co-regulating a set of genes {g1, ..., g n }, where is the behavior of TF i; h g is the behavior of all the target genes in R, and h x ∈ {↑, ↓, -}, meaning up-express, down-express and no change respectively. For example, if tf1 ↑ and tf2 ↓ always cause the target genes g1 and g2 to be up-regulated, the regulatory interaction is <tf1 ↑, tf2 ↓> ⇒ g ↑. For individual regulatory interactions, I ∈ {AN, AS, RN, RS, ANS, RNS}. In this work, we assume that a regulatory interaction is consistent in the context of transcriptional control as long as the experimental conditions are unchanged. Note that binaries gene expression values are used in mTRIM, since TF activity is not always proportional to its mRNA abundance [23].
mTRIM Step 1. Inferring individual regulatory interactions
To solve a relatively easier problem of inferring the regulatory interactions for each individual TF and to prepare input for multi-TF regulatory interaction inference, an EM-based Bayesian inference algorithm has been developed [20, 21].
To define the probabilities in Eq. 2 and Eq. 3, we followed the definitions in [20]. Eq 2 represents the prior probability of the interaction model I m , and Eq 3 represents the probability of gene expression correlation between TFs and targets given the interaction model I m . In the Bayesian model, the training dataset is a matrix that contains gene expression levels of TFs and their targets, from which Γ(I m ) is estimated using Eq 4. And then, the likelihood is calculated using Eq 3. The prior probabilities are randomly assigned initially. In each iteration, the posterior probabilities and the frequency of I m are updated. The iteration will continue till the posterior probabilities converge.
where Pri(I m ) is the prior probability of regulatory interaction I m (defined in Eq 2) and the likelihood Lk(tf m , R k , I m ) is defined in Eq 3.
where fre(I m ) is the frequency of regulatory interaction I m in all of the regulatory modules, |R| is the number of the regulatory modules, |TF| is the number of TFs, and I m ∈ {AS, RS, AN, RN}.
An expectation-maximization (EM) algorithm is adopted to maximize the posterior probabilities Pos(tf m , R k , I m ). The EM model is initialized with each TF assigned a random regulatory interaction. In the expectation step, we compute the likelihood of each TF to be a specific interaction using Eq 3. Consequently, the posterior probabilities of interactions for every TF is updated with Eq 1. As a result, each TF is assigned with the regulatory interaction with the highest posterior probability. In the maximization step, we maximize the scoring function for each regulatory module R k , which measures how the interaction of each TF in R k matches the target gene expression changes. Note that in the iteration the priors are updated but the likelihoods are constant.
Finally, in order to determine whether I m is "necessary and sufficient" (ANS and RNS) or "no decision", the following strategy is adopted: if none of the posterior probabilities are significant, the output is "no decision"; if the probabilities of both N and S states are significant, and there is no significant difference between them, the output is ANS or RNS depending on the target gene expression direction; otherwise the output is the regulatory interaction with the highest posterior probability.
Illustrative example of time-series gene expression data for the genes in Figure 1b.
t 0
t 1
t 2
t 3
t 4
t 5
t 6
t 7
t 8
t 9
t 10
t 11
tf 1
tf 2
tf 3
g 1
g 2
Illustrative example of regulatory interaction identification on the TRN in Figure 1b.
Regulatory Interaction
<tf1 ↓>⇒ g ↓
<tf1 ↑, tf2 ↑>⇒ g ↑
<tf2 ↑, tf3 ↓>⇒ g ↑
<tf1 ↑, tf3 ↓>⇒ g ↑
<tf1 ↑, tf2 ↑, tf3 ↓>⇒ g ↑
mTRIM Step 2. Mining multiple-TF regulatory interactions
where P(x) is the number of times that x appears in the given time series gene expression dataset divided by the product of the total number of time points and the total number of target genes. The p-value of each candidate regulatory interaction is computed by considering the distribution of AfnScore for the regulatory interactions with the same number of TFs. Only the candidate interactions with p-values smaller than 0.05 are reported to the user. Specifically, if all the TFs in I are up-regulated, the TFs are "sufficient"; if they are all down-regulated, the TFs are "necessary"; otherwise, each TF acts differently to drive the target genes to the same direction.
For an illustrative example, there are 40 possible multiple-TF regulatory interactions in the regulatory module shown in Figure 1b. Using the time-series gene expression data in Table 1 all the 2-TF regulatory interaction candidates are screened and their p-values are computed (see Table 2 row 2-4). Since none of the 2-TF regulatory interaction candidates is significant, a 3-TF interaction I4 =<tf1 ↑, tf2 ↑, tf3 ↓>=>g ↑ is generated by merging I2 and I3. The AfnScore of I4 is ((10/24) * (10/24))/(12/24)) = 0.347 and its p-value is 0.04 (see Table 2 row 5). Based on I0 and I4, we conclude that the target genes g1 and g2 are induced by the up-expression of tf1 and tf2 and the down-expression of tf3, and the same target genes are repressed by the down-expression of tf1.
Experimental results
mTRIM was applied on two independently-constructed yeast transcriptional regulatory networks (the Harbison dataset [15] and the Reimand dataset [12]) to identify regulatory interactions. For performance comparison, DREM v3.0 [17] and TRIM [19] were both applied on the same datasets. We did not compare mTRIM with Yeang's method [3] because the latter's objective is to build a reliable TRN instead of predicting regulatory interactions. We evaluated these methods systematically with three independent sources: single TF knockouts [16] for individual regulatory interactions, genetic interactions (GI) [25] for 2-TF regulatory interactions and synthetic data for high-order regulatory interactions.
The number and type of the regulatory interactions for individual TFs predicted by mTRIM.
Necessary & Sufficient
No Decision
Number of the multiple-TF regulatory interactions identified by mTRIM.
Data preparation
Yeast ChlP-chip binding data [15] was downloaded from http://younglab.wi.mit.edu/regulatory_code, and a p-value cutoff of 0.001 was applied (the same threshold used in [4]) to obtain the Harbison dataset. It contains 169 TFs, 2,864 target genes and 6,253 TF-DNA bindings. Next we applied the same statistical approach as in [12] to filter the union of the yeast ChlP-chip binding data [26] and the binding-site predictions [27, 28] to generate the Reimand dataset with 2,230 TF-DNA binding relationships between 268 TFs and 1,509 target genes. To obtain the regulatory modules in the TRNs, all the target genes were clustered based on their gene expression values with Cluster 3.0 (specifically, k-means), which uses Pearson correlation coefficient for gene similarity metric [29], resulting in 50 clusters. The clusters are then evaluated with Gene Ontology enrichment analysis using Bingo [30], and unenriched clusters are discarded. To construct regulatory modules from the clustering results, the target genes that are regulated by the same TFs were partitioned if they are not in the same cluster. Finally, 2,172 and 1,031 regulatory modules were obtained in the Harbison and Reimand networks respectively. The distribution of genes and regulatory modules (Figure SI and Table S2 in Additional file 1) reveal that many genes are bound by multiple TFs.
To identify the individual and collaborative regulatory interactions in the above datasets, three widely used time-series microarray datasets (alpha, CDC28 and elu) from yeast cell cycle studies were collected [31] as training data. These datasets contain 49 time points in total. In these experiments, yeast cells were first synchronized to the same cell cycle stage, released from synchronization, and then the total RNA samples were taken at even intervals for a period of time (Table SI in Additional file 1). In order to decide whether a gene is significantly up or down regulated, a gene expression change cutoff of 0.35 was applied (the same threshold used in [19]).
To evaluate the individual regulatory relations, single-TF knockout microarray data were collected [16], and a p-value cut-off of 0.05 (as used in [16]) was applied to determine whether a gene is significantly affected by a TF knockout. To evaluate the 2-TF regulatory interactions, we downloaded the SGA genetic interaction dataset [25], which is composed of 1,711 queries crossed to 3,885 array strains. Of the 1,711 queries, 1,377 are deletion mutants of non-essential genes and 334 are essential gene alleles. The SGA dataset contains 762,146 genetic interactions. Two genes are genetically interacted if mutations in both of them produce a phenotype that is significantly different to each mutation's individual effects. In a 2-TF regulatory interaction, if TFs collaboratively regulate the same target genes, the down-regulation of both TFs should have a significantly different phenotype as the down regulation of each individual TF. Therefore, such TF pairs should have a significant p-value in the GI dataset. To evaluate the high-order multiple-TF regulatory interactions, a synthetic binding network were built, which contains 11 TFs, 17 target genes and 58 regulation/binding relationships. The network also contains two feed forward loops. Corresponding time-series gene expression data containing 500 time-points were randomly generated with 10% or 40% noise rate.
Evaluation 1. Single TF knock-outs
We used the single TF knockout microarray data to evaluate the performance of mTRIM on individual TF regulatory interaction predictions in terms of the identification of "necessary" TFs (i.e., if the expression values of the target genes are significantly changed when the TF is knocked out). For the Harbison dataset, the prediction precision of mTRIM is 94.44%, higher than the results of TRIM (82.50%). Using the Reimand dataset, mTRIM has a precision of 91.94%, significantly higher than the results of TRIM (61.54%). DREM is not compared since it does not predict "necessary" TFs.
Evaluation 2. Genetic interaction
Evaluation 3. Synthetic transcriptional regulatory networks
Case studies
Revealing the mechanisms of the transcriptional regulatory programs in TRNs is essential for understanding the complex control by which genes are expressed in living cells. The inference of collaborative protein-DNA functions helps paving the critical path for new drug development. In this work, we identify the regulatory interactions between TFs and target genes with mTRIM, an integration of an EM-based Bayesian inference and a new association rule mining approach built on a set of basic constraints that relate gene expression patterns to regulatory interactions. mTRIM is not limited by the number of TFs. The experimental results show that mTRIM is clearly better than the existing algorithms. Since it is difficult to obtain the ground truth for algorithm performance evaluation on real data, we generated two sets of synthetic data and used them to validate the results of our algorithm. In our future work, we will use third-party biological evidences including multiple TF knockouts, metabolic pathways, protein-protein interactions, etc., for biological validation. In our future work, we would like to extend this work by including extra data in addition to wild-type gene expression datasets. For example, since miRNA can degrade the genes induced by certain TFs [32], we will consider miRNA-target bindings and miRNA expressions, aiming to understand how miRNAs and TFs collaborate to regulate target gene expressions.
This project has been funded by the Egyptian Government GM 845.
The publication costs for this article were funded by the corresponding author's institution.
This article has been published as part of BMC Systems Biology Volume 8 Supplement 1, 2014: Selected articles from the Twelfth Asia Pacific Bioinformatics Conference (APBC 2014): Systems Biology. The full contents of the supplement are available online at http://www.biomedcentral.com/bmcsystbiol/supplements/8/S1.
Authors' Affiliations
- Qiu P: Recent advances in computational promoter analysis in understanding the transcriptional regulatory network. Biochem Bioph Res Co. 2003, 309: 495-501. 10.1016/j.bbrc.2003.08.052.View ArticleGoogle Scholar
- Maienschein-Cline M, Zhou J, White K, Sciammas R, Dinner A: Discovering Transcription Factor Regulatory Targets Using Gene Expression and Binding Data. Bioinformatics. 2011, 28: 206-213.PubMed CentralView ArticlePubMedGoogle Scholar
- Yeang H, Jaakkola T: Modeling the combinatorial functions of multiple transcription factors. J Comput Biol. 2006, 13: 463-480. 10.1089/cmb.2006.13.463.View ArticlePubMedGoogle Scholar
- Ernst J, Vainas O, Harbison C, Simon I, Bax-Joseph Z: Reconstructing dynamic regulatory maps. Mol Syst Biol. 2007, 3 (74): 1-13.Google Scholar
- Segal E, Shapira M, Regev A, Pe'er D, Botstein D, Koller D, Friedman N: Module networks: identifying regulatory modules and their condition-specific regulators from gene expression data. Nat Genet. 2003, 34: 166-167. 10.1038/ng1165.View ArticlePubMedGoogle Scholar
- Hagen D, McCaffrey G, Sprague G: Pheromone Response Elements Are Necessary and Sufficient for Basal and Pheromone-Induced Transcription of the FUS1 Gene of Saccharomyces cerevisiae. Method Mol Cell Biol. 1991, 11 (6): 2952-2961.View ArticleGoogle Scholar
- Babur O, Demir E, Gonen M, Sander C, Dogrusoz U: Discovering modulators of gene expression. Nucleic Acids Res. 2010, 38: 5648-5656. 10.1093/nar/gkq287.PubMed CentralView ArticlePubMedGoogle Scholar
- Park P: ChlPseq: advantages and challenges of a maturing technology. Nat Rev Genet. 2009, 10 (10): 669-680. 10.1038/nrg2641.PubMed CentralView ArticlePubMedGoogle Scholar
- Deplancke B, Dupuy D, Vidal M, Walhout A: A gateway-compatible yeast one-hybrid system. Genome Res. 2004, 14 (10b): 2093-2101. 10.1101/gr.2445504.PubMed CentralView ArticlePubMedGoogle Scholar
- Deplancke B, Mukhopadhyay A, Ao W, et al: A gene-centered C. elegans protein-DNA interaction network. Cell. 2006, 125: 1193-1205. 10.1016/j.cell.2006.04.038.View ArticlePubMedGoogle Scholar
- Ren B, Robert F, Wyrick J, et al: Genome-wide location and function of DNA binding proteins. Science. 2000, 290: 2306-2309. 10.1126/science.290.5500.2306.View ArticlePubMedGoogle Scholar
- Reimand J, Vaquerizas J, Todd A, Vilo J, Luscombe N: Comprehensive reanalysis of transcription factor knockout expression data in Saccharomyces cerevisiae reveals many new targets. Nucleic Acids Res. 2010, 38: 4768-4777. 10.1093/nar/gkq232.PubMed CentralView ArticlePubMedGoogle Scholar
- Hoth S, Morgante M, Sanchez J, et al: Genome-wide gene expression profiling in Arabidopsis thaliana reveals new targets of abscisic acid and largely impaired gene regulation in the abil-1 mutant. J Cell Sci. 2006, 115: 4891-4900.View ArticleGoogle Scholar
- Tong A, Boone C: Synthetic genetic array analysis in Saccharomyces cerevisiae. Meth Mol Biol. 2006, 313: 171-191.Google Scholar
- Harbison C , B G, Lee T, et al: Transcriptional regulatory code of a eukaryotic genome. Nature. 2004, 431: 99-104. 10.1038/nature02800.PubMed CentralView ArticlePubMedGoogle Scholar
- Hu Z, Killion P, Iyer V: Genetic reconstruction of a functional transcriptional regulatory network. Nat Genet. 2007, 39: 683-687. 10.1038/ng2012.View ArticlePubMedGoogle Scholar
- Bar-Joseph Z, Gerber G, Lee T, et al: Computational discovery of gene modules and regulatory networks. Nat Biotechnol. 2003, 21: 1337-1342. 10.1038/nbt890.View ArticlePubMedGoogle Scholar
- Balaji S, Babu M, Iyer M, Luscombe M, Aravind L: Comprehensive analysis of combinatorial regulation using the transcriptional regulatory network of yeast. Mol Biol. 2001, 360: 213-227.View ArticleGoogle Scholar
- Awad S, Panchy N, Ng S, Chen J: Inferring the regulatory interaction types of transcription factors in transcriptional regulatory networks. J Bioinfo Comp Bio. 2012, 10 (5): 1250012-10.1142/S0219720012500126.View ArticleGoogle Scholar
- Duda R, Hart P, Stork D: Pattern Classification. 2001, John Wiley and Sonss, 2Google Scholar
- Thorne T, Stumpf M: Inference of temporally varying Bayesian Networks. Bioinformatics. 2012, 28 (24): 3298-3305. 10.1093/bioinformatics/bts614.PubMed CentralView ArticlePubMedGoogle Scholar
- Ihmels J, Friedlander G, et al: Revealing modular organization in the yeast transcriptional network. Nat Genet. 2002, 31: 370-377.PubMedGoogle Scholar
- Gygi S, Rochon Y, Franza B, Aebersold R: Correlation between protein and mRNA abundance in yeast. Molecular and cellular biology. 1999, 19 (3): 1720-1730.PubMed CentralView ArticlePubMedGoogle Scholar
- Agrawal R, Srikant R: Fast algorithms for mining association rules. Proc of VLDB. 1994, 487-499.Google Scholar
- Costanzo M, Baryshnikova A, Bellay J, et al: The Genetic Landscape of a Cell. Science. 2010, 327: 425-431. 10.1126/science.1180823.View ArticlePubMedGoogle Scholar
- Lee T, Rinaldi N, Robert F, et al: Transcriptional Regulatory Networks in Saccharomyces cerevisiae. Science. 2002, 298: 799-804. 10.1126/science.1075090.View ArticlePubMedGoogle Scholar
- Erb I, Nimwegen E: Statistical features of yeast's transcriptional regulatory code. Proc of ISCB. 2006, 1: 111-118.Google Scholar
- Maclsaac K, Wang T, Gordon B, Gifford D, Stormo G, Fraenkel E: An improved map of conserved regulatory sites for Saccharomyces cerevisiae. BMC Bioinformatics. 2006, 7: 113-10.1186/1471-2105-7-113.View ArticleGoogle Scholar
- Eisen M, Spellman P, Brown P, Botstein D: Cluster analysis and display of genome-wide expression patterns. P Natl Acad Sci USA. 1998, 95: 14863-14868. 10.1073/pnas.95.25.14863.View ArticleGoogle Scholar
- Maere S, Heymans K, Kuiper M: BiNGO a Cytoscape plugin to assess overrepresentation of Gene Ontology categories in Biological Networks. Bioninformatics. 2005, 21: 3448-3449. 10.1093/bioinformatics/bti551.View ArticleGoogle Scholar
- Spellman P, Sherlock G, Zhang M, et al: Comprehensive Identification of Cell Cycle-regulated Genes of the Yeast Saccharomyces cerevisiae by Microarray Hybridization. Mol Biol Cell. 1998, 9: 3273-3297. 10.1091/mbc.9.12.3273.PubMed CentralView ArticlePubMedGoogle Scholar
- Joung J, Hwang K, et al: Discovery of microRNA-mRNA modules via population-based probabilistic learning. Bioinformatics. 2007, 23: 1141-1147. 10.1093/bioinformatics/btm045.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.


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Its been years since a kid walking into a game store could look at the shelf and find a new Sega console. In fact, since early 2000, the Dreamcast fluttered away with the emergence of Sony's juggernaut of a system, the Playstation 2.
But this hasn't diminished Sega's 128 bit processing machine in the minds of retro gamers. Still today, hardcore collectors flock to flea markets, ebay, and independent video game stores to find the very best that the Dreamcast had to offer such as Marvel vs Capcom, Sonic Adventure, Jet Set Radio, and most importantly, the RPG masterpiece Skies of Aracadia. With Nintendo preparing for its launch of the Gamecube during that time, Sega focused more on serious-minded games, software ip's that would buck the trend common to other companies. Shenmue was the perfect example of this with its day and night weather system, hyper realism, and voice over dialogue that pervaded its breathtaking atmosphere. This was a title only a company like Sega could release at the time. Everything was in place for a full comeback from the parent company of Sonic, but reality came crashing down on all this initial success.
Dreamcast inferior to Playstation
Even with a built-in internet modem, four player outputs for controllers, fantastic titles, and a virtual memory unit card that felt like having a portable console at your disposal, the Sega Dreamcast couldn't keep up with Sony's brilliant marketing campaign. At the time, the Playstation 2 had two things which determined its superiority over any of the competing consoles at its launch: the cheaper production costs of its software, and most importantly, its dvd drive.
At the time, Sega had amplified its intended dominance on the market with its reported 80 million dollar release of Shenmue, but this proved to be its first of a continual decline on its gaming home base. Shenmue failed to live up to its hype, having sold only half a million units worldwide and staggering on the domestic video game market.
A critical masterpiece, but a tremendous commercial flop, Shenmue had nearly bankrupted Sega's software development team.
The second, and most important nail in the Dreamcast's coffin was its lack of a dvd player along with backwards compatibility in its mainframe. Sony at the point had been brilliant in waiting for its turn to up the ante on the next gen market, allowing the Sega Dreamcast to have almost a full year before it unleashed the beast the was the PS2. Upon release, the PS2 immediately grabbed a foothold on Sega's sales, having within a few months a launch line up that included Unreal Tournament, Madden 2001, and Summoner.
Not only did it have titles that could push it past Sega's meager earnings, but it also created a brilliant marketing campaign that usurped the DVD revolution that was beginning to spread on the mass market audience.
Significance in gaming history
Consumers were flocking to a console that could not only play its older games from the original Playstation, but could also watch movies right in the convenience of their living rooms. What else could an adolescent ask for?
A console that could play its older Playstation games, movies, and cd's, all on one technology. But even with all this, the years haven't washed away Sega's last stance. With the rise of homebrew and independent gaming, the Dreamcast is still alive and well, producing an array of shoot em ups, rpgs, and adventure titles that are as relevant to gamers as the latest Madden title. The Dreamcast shouldn't be perceived as a failure but a bright spot in video game history. It was the last of a line of consoles that produced within a short lifespan a series of games that were as unique and undeniably rich in charm than any other competing console of its day. The Dreamcast keeps dreaming, and fans can still dust off their old VMU sets, and boot up a copy of Sonic Adventure with the same gleam in their eyes as they did on September 9th, 1999.


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EXCLUSIVE: GERMANY - DaimlerChrysler yield on capital: - approximately minus 12 billion dollars per year
Dieter Zetsche, who DaimlerChrysler has just appointed as chief executive of Chrysler last week, is not giving interviews just yet, but we are in line for one. As he considers the problems facing his emergency rescue team, he must be thinking: how did my boss get into this mess? While we wait for the interview, we'll tell you how it happened.
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They say they need to review the Lois Lerner emails to make sure there are no duplicates. They are just helping us out. Really?
I would say that the shamelessness is unbelievable, but it is all too believable. The IRS has no reason to fear Congress. They come up with pathetic, transparently false excuses to refuse to allow Congress to find any evidence of wrongdoing. And they know that no one is going to do anything to make them comply.
Fox Business reports, "IRS Finds 6,400 Lois Lerner Emails But Won't Hand Em Over."
The Internal Revenue Service may have found 6,400 emails from Lois Lerner, who oversaw the tax agency's Exempt Organizations Unit, but the government agency has no plans to share.
Attorneys from the Department of Justice representing the IRS say the emails won't be shared because the service is making sure that none of them are duplicates. Lerner is at the center of a scandal in which the tax agency denied special tax status to conservative groups. Her emails have been sought by members of Congress and conservative groups alike.
One of those groups, Judicial Watch, has been seeking emails as part of a Freedom of Information Act (FOIA) request filed two years ago. Originally, the IRS said the email trail was permanently lost because the computer drive that contained it crashed. However, the Treasury Department's Inspector General for Tax Administration or TIGTA, was able to retrieve 6,400 emails which it has subsequently sent to the agency. It is these emails that the IRS wants to check for duplicates.
As I have pointed out before, the Freedom Of Information Act is more like a suggestion than a law. There are obviously no consequences for Federal agencies to disregard the requirements of the law. Without enforceable penalties, the law is useless.


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"Golden Sun Marketing reaches far and wide across the produce
industry with connections and relationships that are invaluable to
a company like FirstFruits Marketing. They provide insight and
knowledge into current industry trends and help us leverage that
information to create opportunities within our own business model.
Not only did Golden Sun Marketing take the time to understand our
culture and mission, they brought it to life with our high-impact
'Take a Bite Out of Hunger' program where we were able to build
stronger relationships with our customers while working toward our
mission of helping the underserved."
"We've achieved a lot working with Golden Sun Marketing over the
past few seasons. Don and his team have helped us with strategic
planning as well as the development and execution of detailed
marketing programs from start to finish, including our highly
successful Heritage Reserve Navel Orange program. Don enhanced our
understanding of how to leverage that program to establish new
business, and our distribution has expanded because of connections
established, or re-established, due to Don's industry
"Rouses Markets was introduced to Golden Sun Marketing in the
spring of 2011, when GSM assisted Rouses in developing a marketing
strategy for promoting and selling both unique and exclusive fresh
produce commodities in our stores. The support we have received
from GSM on every project we have worked on has been incredible;
the success of our combined planned promotions has been very
satisfying. From in-store signage, social and print media, and even
personal appearances from growers in our stores, the entire package
has been a win-win. Additionally, the new relationships we have
developed with shippers have allowed our company to maintain a
level of differentiation from our competitors."
"I had numerous shippers come up to me afterwards and tell me
how much they enjoyed this talk, and just how relevant it was.
Don's experience brought a very real perspective to the overall
produce arena and to potatoes specifically. Our industry typically
says 'I have great potatoes and I can get them to you on time and
at a good price," rather than a story that will get them past a
supplier relationship. While we have said it to the industry,
hearing from Don now made it a real and believable
"Don is an articulate spokesperson with key relationships. His
extensive experience in meeting the needs of grocery retailers
allows him to identify appropriate new seed varieties for growers
to produce while developing marketing avenues for retail that meet
consumer expectations for food quality and unique attributes. Don
is to be respected for his revolutionary food marketing concepts
and programs which interest seed companies, growers, shippers,
retailers and consumers."
"The professional development programs we offer at Purdue
University are attended by upper level managers and executives who
have high expectations of speakers and instructors. Don Goodwin
delivers his message in an articulate way and brings insight to
many topics including brand management, joint venture agreements,
and food distribution systems. He stimulates the thinking of
participants and sets the stage for meaningful discussion. I highly
recommend Don."


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Whate'er the theme, the Maiden sang As if her song could have no ending; I saw her singing at her work And o'er the sickle bending;— I listened, motionless and still; And as I mounted up the hill, The music in my heart I bore, Long after it was heard no more.Trilling says the Romantics were preoccupied "with children, women, peasants, savages, because their mental life, it is felt, is less overlaid than that of the educated adult male by the proprieties of social habit." (Trilling, The Liberal Imagination, p. 184) That is well-meaning, I guess, if patronizing. Wordsworth was terribly well-meaning, socially progressive, and had a revolutionary and salutary effect on English literature. He didn't have a particularly easy life either, being orphaned by age 13. But he misrepresents and sentimentalizes the hard work of reaping grain in a way that rings particularly false. He is selling himself the fantasy that peasant girls sing because they live simple lives, free of modern problems. But even a horse has been known to object to manual labor, and I've never seen a bucket list with the line item, before I die, I must reap some grain. What is unfortunately irritating about Wordsworth's poem is that it's an extreme sort of fantasy that does not seem to take hardly any account of reality. I will speculate that his mother's death when he was 7 caused him to wish to idealize suffering women in his poetry and to want to make their suffering disappear in visions of imperturbable beauty and unstained, unstainable virtue. If we could see the ground of real suffering out of which this keening hallucination sprang—that is, if the fantasy poem took some slight account of the difficult realities underpinning it, it would be more artistically successful. As such, it's too insubstantial for me to swallow. The irony is that the associations and etymology of the very word peasant completely undermine the airy, patronizing, Wordsworthian fantasy of the carefree singing Solitary Reaper. Peasant comes from paysanne in French, which comes from pays, meaning land. WW has tried to fill his peasant girl with helium and untether her from the hard material ground that gave peasants their earthy name. Gustave Flaubert, who effected a rebellion against the excesses of literary romance, by contrast weighs his peasants down with crude, unflattering reality. To juxtapose "The Solitary Reaper" and this passage from Madame Bovary about a naïve peasant woman being honored at the Yonville Agricultural Show is to puncture the Wordsworthian fantasy in a comic way:
Then to the platform came a frightened-looking little old lady who seemed shrunken in her shabby garments. On her feet were heavy wooden clogs and around her hips a large blue apron. Her scrawny face, framed by a borderless cap, was more wrinkled than a shriveled apple, and bony knuckles dangled from the sleeves of her red bodice. They were so encrusted, roughened, and gnarled from barn dust, soapsuds and grease from sheep's wool that they seemed dirty even though they had been washed in clean water. They remained half bent from having worked so long, humble witnesses of so much suffering. The expression on her face was of an almost nunlike inflexibility. Having lived in the company of animals, she had acquired their muteness and placidity. This was the first time that she found herself in the midst of such a numerous group, and inwardly frightened by the flags and drums, by the gentlemen in frock coats, and by the counselor's Cross of Honor, she remained stock-still, not knowing whether to move forward or run off, nor why the people were pushing her and the examiners smiling. There, before these expansive townspeople, stood this half-century of servitude. "Come forth, venerable Catherine-Nicaise-Elizabeth Leroux!" said the counselor, who had taken the list of winners from the president's hands. "Come up, come up," he repeated in a paternal tone, alternately looking at the sheet of paper and the old woman. "Are you deaf?" said Tuvache, hopping up from his chair. He began to shout in her ear: "Fifty-four years of service! A silver medal. Twenty-five francs. For you." Madame Bovary, Signet Classics trans., pp. 153-154Flaubert's hilarious description of the peasant lady crushed and compacted by a lifetime of menial labor is a far cry from the fairy-creature singing in that Scottish field with her magic sickle. The counselor figure in the above passage seems to satirize Wordsworth in his unseeing fantasy. It's funny; but in the pairing you can also see a tectonic movement in literary history. There is Romanticism—and in particular Wordsworth's denial of death mixed with Rousseau's rebellion against the starched aristocratic order—giving way to a later generation's rebellion in the form of a radical modern realism.


text: Aritco Lift, Sweden A special 3-beam solution with an additional beam to support the heavy pallet means that the load is distributed evenly. At the same time back mesh has been mounted on the upper locations in order to prevent that the pallet is pushed inadvertently from the pallet rack. Boots Plc, UK Boots are the UK's leading health & beauty retailer. They decided to consolidate their supply chain for fast moving goods. Chr. Hansen, Denmark Constructor has delivered deepstore and pushback racking for the warehouses at Chr. Hansen ECO-Boråstapeter, Sweden ECO-Boråstapeter invested in a Push Back installation and pallet racking P90 from Constructor. Hansa Print, Finland Hansaprint is the largest magazine printing house in Finland, they decided to store their paper in P90 Last in First Out (LIFO) - and First In First Out (FIFO) pallet racking. Huhtamäki, Finland Huhtamäki, a global packaging company, has a logistics centre in Hämeenlinna. We supplied their Drive-in pallet racking and Pallet Flow racking.


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|Dave & John Curtis
|Great Falls, Montana, USA
The Rite by Curtis tractor brand was created by Dave & John Curtis of Montana, USA. The brothers were in the farm implememt business and started selling Wagner tractors in 1954. But the Wagner tractors were designed originally for Industrial applications, and various problems arose that the brothers fixed. One of there customers then asked for them to build a 425 hp (317 kW) tractor for him, so based on their experience with the Wagner's faults, they designed a new transmission layout to cope with field work.
The brothers contracted a local engineering company Great Falls Iron Works Co. to build the tractors, and they badged them as Madson for some reason. They were recalled and renamed and sprayed as the color was not the same shade of yellow as used on earlier tractors.
By 2009, 38 Rite tractors had been built with a variety of engines from Cummins, Caterpillar and Detroit Diesel to suit each customers preference, and it was quoted in 2013 that tractors could still be ordered.[1]
Model rangeEdit
As the tractors are custom built specs vary but several models evolved other the years.
|Year(s) Produced
|Engine Type
|Misc Notes
|Rite 303
|300 hp (220 kW)
|Rite 404
|404 hp (301 kW)
|Rite 470
|470 hp (350 kW)
|Detroit Diesel
|Rite 505
|500 hp (370 kW)
|Rite 606
|600 hp (450 kW)
|Rite 707
|700 hp (520 kW)
|Detroit Diesel
|Rite 750
|750 hp (560 kW)
|Detroit Diesel
|Rite 750 Earthquake
|re-tuned to 850 hp (630 kW)
|Detroit Diesel
|Rite 2460
|450 hp (340 kW)
|Detroit Diesel
See alsoEdit
References / sourcesEdit
External linksEdit
|Add any external links that directly relate to this articles subject and have more info or have related images. Other general external links can be added to the web Site Links list.


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Installation Examples
Glass Mosaic at Seattle Children's Hospital
Wallpaper Wrap on Opposite Walls at Adventist Medical Center
Traditional Wall Artwork at Tacoma General Hospital
Triptych at Trios Southridge Hospital
Triptych at Trios Southridge Hospital
Research References and Links
We are grateful for the work of all the healthcare professionals, architects, designers, organizations, and researchers who continually strive to improve healthcare. You have built a bridge for those who come after you. Thank you.
Are you interested in learning more about evidence-based design, fractals and/or stress? We hope you will find these references helpful. We recommend two excellent documentaries: Hunting the Hidden Dimension (about fractals) from NOVA, and Stress: Portrait of a Killer from National Geographic, both are free to watch online and are linked below. Your recommendations regarding useful links are welcome. If we have forgotten someone we should acknowledge, please let us know. Thank you.
In nature we never see anything isolated, but everything in connection with something else which is before it, beside it, under it and over it.—Goethe
American Institute of Stress (AIS). http://www.stress.org/
Briggs, John & Peat, David F. (1999). Seven life lessons of chaos: Spiritual wisdom from the science of change. New York:
HarperCollins Publ.
Center for Health Design (CHD). http://www.healthdesign.org
Center for Studying Health System Change www.hschange.org
Domke, Henry. (2009). Picture of health: Handbook for healthcare art. New Bloomfield, MO: Henry Domke Fine Art Publisher. Pdf available at henrydomke.com
Environmental Design Research Association (EDRA). http://www.edra.org/
Eisen, S. L., Nanda, U., & Zanah, R. (2010). Effect of art on patient anxiety in a psychiatric holding unit and implications for the business case.
The Journal of Psychiatric and Mental Health Nursing, Leeds, England.
Frampton, Gilpin, & Charmel, Editors. (2003). Putting patients first: Designing and practicing patient-centered care. San Francisco, CA: Jossey-Bass
Louv, Richard. (2011). The nature principle: Human restoration and the end of nature-deficit disorder. Chapel Hill, NC, Algonquin Books Publishers
Malkin, Jain. (2008). A visual reference for eveidence-based design.
The Center for Healthcare Design, Concord, CA.
Matthews, Robert. (2011). Finding the fractal solution. Retrieved July 25, 2011 from http://cmtk3.webring.org/l/rd?ring=astr0317;id=1;url=http%3A%2F%2Fwebspace%2Ewebring%2Ecom%2Fpeople%2Fu0%2FOmegaman_uk%2Ffractal%2Ehtml
Nanda, U., Eisen, S. L., & Baladandayuthapani, V. (2008). Undertaking an art
survey to compare patients vs. design student art preferences,
Environment & Behavior, New York.
Nanda, Upali (2010). Visual art in healthcare: Is the jury still out?
Research Design Connections, Dec. 2010, Issue #4
NOVA. Hunting the Hidden Dimension: How mysteriously beautiful fractals
are shaking up the world of mathematics and deepening our under standing of nature. Watch free video on YouTube.
Robert Wood Johnson Foundation (RWJF). http://www.rwjf.org/
Selye, Hans. The nature of stress. International Institute of Stress. Retrieved August 06, 2012 from http://www.icnr.com/articles/the-nature-of-stress.html
Schiller, Jakob (2011). Really? $4.3 Million for that photo? Wired Magazine. Retrieved November 12, 2011, from http://www.wired.com/rawfile/2011/11/really-4-4-million-for-that-photo/
Sternberg, Esther M. (2009). Healing spaces: The science of place and
well-being. First Harvard University Press.
Sternberg, Esther, M. (2000). The balance within: The science of connecting health and emotions. W.H. Freeman and Company New York.
Stress: Portrait of a Killer. National Geographic documentary featuring neuroscientist Robert Sapolsky. Retrieved Mar 10, 2012 from http://www.youtube.com/watch?v=oNtQQsEJ-gE&feature=plcp
Society for the Arts in Healthcare. http://www.thesah.org The Society for the Arts in Healthcare is about to become the Global Alliance for Arts & Health.
Therapeutic Landscapes Network. http://www.healinglandscapes.org
Ulrich, R.S., Zimring, C.A., Zhu, X., Dubose, J., Seo, H, Choi, Y., Joseph, A. (2008). A review of the research literature on Evidence-based Design.
Health Environments Research & Design Journal, 1(3), 61-125
Williams, Roy. (2002). Exponential little bits: The magic of the ELBS. Retrieved Sept., 21, 2011, http://www.mondaymorningmemo.com/newsletters/read/1407
Wilson, E.O. (1984). Biophilia. by the President and Fellows of Harvard College. ISBN 0-674-0744-2.
Everyone must believe in something. I believe I will go canoeing.—Henry David Thoreau
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