Bio-logic: gene expression and the laws of combinatorial logic

Original article can be found at: http://www.mitpressjournals.org/ Copyright MIT Press DOI: 10.1162/artl.2008.14.1.121At the heart of the development of fertilized eggs into fully formed organisms and the adaptation of cells to changed conditions are genetic regulatory networks (GRNs). In higher multi-cellular organisms, signal selection and multiplexing is performed at the cis-regulatory domains of genes, where combinations of transcription factors (TFs) regulate the rates at which the genes are transcribed into mRNA. To be able to act as activators or repressors of gene transcription, TFs must first bind to target sequences on the regulatory domains. Two TFs that act in concert may bind entirely independently of each other, but more often binding of the first one will alter the affinity of the other for its binding site. This paper presents a systematic investigation into the effect of TF binding dependencies on the predicted regulatory function of this “bio-logic”. Four extreme scenarios, commonly used to classify enzyme activation and inhibition patterns, for the binding of two TFs were explored: independent (the TFs bind without affecting each other’s affinities), competitive (the TFs compete for the same binding site), ordered (the TFs bind in a compulsory order), and joint binding (the TFs either bind as a preformed complex, or binding of one is virtually impossible in the absence of the other). The conclusions are: 1) the laws of combinatorial logic hold only for systems with independently binding TFs; 2) systems formed according to the other scenarios can mimic the functions of their Boolean logical counterparts, but cannot be combined or decomposed in the same way; and 3) the continuously scaled output of systems consisting of competitively binding activators and repressors can be more robustly controlled than that of single TF or (quasi-) logical multi-TF systems. Keywords: Transcription regulation, Genetic regulatory networks, Enzyme kinetics, Combinatorial logic, Non-Boolean continuous logic, Modelling.Peer reviewe

An Enhanced Nonlinear Critical Gradient for Electron Turbulent Transport due to Reversed Magnetic Shear

The first nonlinear gyrokinetic simulations of electron internal transport barriers (e-ITBs) in the National Spherical Torus Experiment show that reversed magnetic shear can suppress thermal transport by increasing the nonlinear critical gradient for electron-temperature-gradient-driven turbulence to three times its linear critical value. An interesting feature of this turbulence is nonlinearly driven off-midplane radial streamers. This work reinforces the experimental observation that magnetic shear is likely an effective way of triggering and sustaining e-ITBs in magnetic fusion devices.Comment: 4 pages, 5 figure

An Enhanced Nonlinear Critical Gradient for Electron Turbulent Transport due to Reversed Magnetic Shear

The first nonlinear gyrokinetic simulations of electron internal transport barriers (e-ITBs) in the National Spherical Torus Experiment show that reversed magnetic shear can suppress thermal transport by increasing the nonlinear critical gradient for electron-temperature-gradient-driven turbulence to three times its linear critical value. An interesting feature of this turbulence is nonlinearly driven off-midplane radial streamers. This work reinforces the experimental observation that magnetic shear is likely an effective way of triggering and sustaining e-ITBs in magnetic fusion devices.Comment: 4 pages, 5 figure

Angle-resolved photoemission study of insulating and metallic Cu-O chains in PrBa2_2Cu3_3O7_7 and PrBa2_2Cu4_4O8_8

We compare the angle-resolved photoemission spectra of the hole-doped Cu-O chains in PrBa$_2$Cu$_3$O$_7$ (Pr123) and in PrBa$_2$Cu$_4$O$_8$ (Pr124). While, in Pr123, a dispersive feature from the chain takes a band maximum at $k_b$ (momentum along the chain) $\sim$ $\pi/4$ and loses its spectral weight around the Fermi level, it reaches the Fermi level at $k_b$ $\sim$ $\pi/4$ in Pr124. Although the chains in Pr123 and Pr124 are approximately 1/4-filled, they show contrasting behaviors: While the chains in Pr123 have an instability to charge ordering, those in Pr124 avoid it and show an interesting spectral feature of a metallic coupled-chain system.Comment: 4 pages, 5 figures, to be published in PR

Patchy Interspecific Sequence Similarities Efficiently Identify Positive cis-Regulatory Elements in the Sea Urchin

We demonstrate that interspecific sequence conservation can provide a systematic guide to the identification of functional cis-regulatory elements within a large expanse of genomic DNA. The test was carried out on the otx gene of Strongylocentrotus purpuratus. This gene plays a major role in the gene regulatory network that underlies endomesoderm specification in the embryo. The cis-regulatory organization of the otx gene is expected to be complex, because the gene has three different start sites (X. Li, C.-K. Chuang, C.-A. Mao, L. M. Angerer, and W. H. Klein, 1997, Dev. Biol. 187, 253–266), and it is expressed in many different spatial domains of the embryo. BAC recombinants containing the otx gene were isolated from Strongylocentrotus purpuratus and Lytechinus variegatus libraries, and the ordered sequence of these BACs was obtained and annotated. Sixty kilobases of DNA flanking the gene, and included in the BAC sequence from both species, were scanned computationally for short conserved sequence elements. For this purpose, we used a newly constructed software package assembled in our laboratory, “FamilyRelations.” This tool allows detection of sequence similarities above a chosen criterion within sliding windows set at 20–50 bp. Seventeen partially conserved regions, most a few hundred base pairs long, were amplified from the S. purpuratus BAC DNA by PCR, inserted in an expression vector driving a CAT reporter, and tested for cis-regulatory activity by injection into fertilized S. purpuratus eggs. The regulatory activity of these constructs was assessed by whole-mount in situ hybridization (WMISH) using a probe against CAT mRNA. Of the 17 constructs, 11 constructs displayed spatially restricted regulatory activity, and 6 were inactive in this test. The domains within which the cis-regulatory constructs were expressed are approximately consistent with results from a WMISH study on otx expression in the embryo, in which we used probes specific for the mRNAs generated from each of the three transcription start sites. Four separate cis-regulatory elements that specifically produce endomesodermal expression were identified, as well as ubiquitously active elements, and ectoderm-specific elements. We confirm predictions from other work with respect to target sites for specific transcription factors within the elements that express in the endoderm

Prostate Cancer Incidence and Mortality in Barbados, West Indies

We describe prostate cancer incidence and mortality in Barbados, West Indies. We ascertained all histologically confirmed cases of prostate cancer during the period July 2002 to December 2008 and reviewed each death registration citing prostate cancer over a 14-year period commencing January 1995. There were 1101 new cases for an incidence rate of 160.4 (95% Confidence Interval: 151.0–170.2) per 100,000 standardized to the US population. Comparable rates in African-American and White American men were 248.2 (95% CI: 246.0–250.5) and 158.0 (95% CI: 157.5–158.6) per 100,000, respectively. Prostate cancer mortality rates in Barbados ranged from 63.2 to 101.6 per 100,000, compared to 51.1 to 78.8 per 100,000 among African Americans. Prostate cancer risks are lower in Caribbean-origin populations than previously believed, while mortality rates appeared to be higher than reported in African-American men. Studies in Caribbean populations may assist understanding of disparities among African-origin populations with shared heredity

Pressure-induced phase transition of Bi2Te3 into the bcc structure

The pressure-induced phase transition of bismuth telluride, Bi2Te3, has been studied by synchrotron x-ray diffraction measurements at room temperature using a diamond-anvil cell (DAC) with loading pressures up to 29.8 GPa. We found a high-pressure body-centered cubic (bcc) phase in Bi2Te3 at 25.2 GPa, which is denoted as phase IV, and this phase apperars above 14.5 GPa. Upon releasing the pressure from 29.8 GPa, the diffraction pattern changes with pressure hysteresis. The original rhombohedral phase is recovered at 2.43 GPa. The bcc structure can explain the phase IV peaks. We assumed that the structural model of phase IV is analogous to a substitutional binary alloy; the Bi and Te atoms are distributed in the bcc-lattice sites with space group Im-3m. The results of Rietveld analysis based on this model agree well with both the experimental data and calculated results. Therefore, the structure of phase IV in Bi2Te3 can be explained by a solid solution with a bcc lattice in the Bi-Te (60 atomic% tellurium) binary system.Comment: 12 pages, 5 figure

Collective and independent-particle motion in two-electron artificial atoms

Investigations of the exactly solvable excitation spectra of two-electron quantum dots with a parabolic confinement, for different values of the parameter R_W expressing the relative magnitudes of the interelectron repulsion and the zero-point kinetic energy of the confined electrons, reveal for large R_W a remarkably well-developed ro-vibrational spectrum associated with formation of a linear trimeric rigid molecule composed of the two electrons and the infinitely heavy confining dot. This spectrum transforms to one characteristic of a "floppy" molecule for smaller values of R_W. The conditional probability distribution calculated for the exact two-electron wave functions allows for the identification of the ro-vibrational excitations as rotations and stretching/bending vibrations, and provides direct evidence pertaining to the formation of such molecules.Comment: Published version. Latex/Revtex, 5 pages with 2 postscript figures embedded in the text. For related papers, see http://www.prism.gatech.edu/~ph274c

The alloy undercooling experiment on the Columbia STA 61-C space shuttle mission

An Alloy Undercooling experiment was performed in an electromagnetic levitator during the Columbia STS 61-C mission in January 1986. One eutectic nickel-tin alloy specimen was partially processed before an equipment failure terminated the experiment. Examination of the specimen showed evidence of undercooling and some unusual microstructural features

Gene regulatory network subcircuit controlling a dynamic spatial pattern of signaling in the sea urchin embryo

We dissect the transcriptional regulatory relationships coordinating the dynamic expression patterns of two signaling genes, wnt8 and delta, which are central to specification of the sea urchin embryo endomesoderm. cis-Regulatory analysis shows that transcription of the gene encoding the Notch ligand Delta is activated by the widely expressed Runx transcription factor, but spatially restricted by HesC-mediated repression through a site in the delta 5′UTR. Spatial transcription of the hesC gene, however, is controlled by Blimp1 repression. Blimp1 thus represses the repressor of delta, thereby permitting its transcription. The blimp1 gene is itself linked into a feedback circuit that includes the wnt8 signaling ligand gene, and we showed earlier that this circuit generates an expanding torus of blimp1 and wnt8 expression. The finding that delta expression is also controlled at the cis-regulatory level by the blimp1-wnt8 torus-generating subcircuit now explains the progression of Notch signaling from the mesoderm to the endoderm of the developing embryo. Thus the specific cis-regulatory linkages of the gene regulatory network encode the coordinated spatial expression of Wnt and Notch signaling as they sweep outward across the vegetal plate of the embryo