Candidate Elements Research Articles

It's not junk!

The human genome is approximately 3 billion basepairs long. An estimated 2--3% of DNA codes for genes; the remaining 97--98% is noncoding DNA [11]. Although the noncoding regions in DNA were once called "junk DNA" (with the assumption that these regions were not serving a purpose) it is now understood that within noncoding DNA are functional regions that affect the expression of genes [34]. However, we are still far from understanding the breadth of function in the noncoding regions, and identification of functional elements is a complex problem, difficult to study in vitro because of the enormous number of possibilities. In this project, we are searching in silico for candidate functional elements in noncoding DNA. These candidates will then be studied at the bench to assess function. Our guiding principle is that regions of noncoding DNA that have been conserved across evolutionary time are good candidates as functional elements; we use a genetic algorithms approach to search for these candidate elements, called motifs. Our system is thus called GAMI, Genetic Algorithms for Motif Inference. GAMI has been demonstrated to be a successful approach to this task, as will be described below.

Reinforcement Learning with Orthonormal Basis Adaptation Based on Activity-Oriented Index Allocation

An orthonormal basis adaptation method for function approximation was developed and applied to reinforcement learning with multi-dimensional continuous state space. First, a basis used for linear function approximation of a control function is set to an orthonormal basis. Next, basis elements with small activities are replaced with other candidate elements as learning progresses. As this replacement is repeated, the number of basis elements with large activities increases. Example chaos control problems for multiple logistic maps were solved, demonstrating that the method for adapting an orthonormal basis can modify a basis while holding the orthonormality in accordance with changes in the environment to improve the performance of reinforcement learning and to eliminate the adverse effects of redundant noisy states.

A New Approach for Understanding Lead Transfer in Agricultural Soil

Surface water is frequently contaminated by the trace metals, in particular lead and zinc, produced by mining activities. The infiltration of this water is likely to pollute surface soils and ground water. The study of the transfer of trace elements, especially lead, under real conditions is difficult to carry out due to the physicochemical and hydrodynamic complexity of real soil (preferential flows, conditions of unsaturation...), of the presence of colloids and of many candidate elements. The objective of the present study was to gain a better understanding of the parameters influencing the migration processes of trace elements in simplified systems; it was based on the study of Pb transfer in laboratory columns filled with soil. The results showed that retention of lead in soil is strongly dependent on feed flow rate, particulate bed tortuosity, bed height, water–soil surface contact and volume of water. Increase in bed height, water–soil surface contact and particulate bed tortuosity leads to higher contact time thus higher lead retention by soil, whereas increase in feed flow rate and volume of water leads to lower contact time thus lower lead retention by soil.

Induction of Hsp22 (HspB8) by estrogen and the metalloestrogen cadmium in estrogen receptor– positive breast cancer cells

Estrogen (E2) plays a critical role in the etiology and progression of human breast cancer. The estrogenic response is complex and not completely understood, including in terms of the involved responsive genes. Here we show that Hsp22 (synonyms: HspB8, E2lG1, H11), a member of the small heat shock protein (sHSP) superfamily, was induced by E2 in estrogen receptor-positive MCF-7 breast cancer cells, resulting in an elevated Hsp22 protein level, whereas it was not induced in estrogen receptor-negative MDA-MB-231 cells. This induction was prevented by the pure anti-estrogen ICI182780 (faslodex, fulvestrant), whereas tamoxifen, a substance with mixed estrogenic and antiestrogenic properties, had no major inhibitory effect on this induction, nor did it induce Hsp22 on its own. Cadmium (Cd) is an environmental pollutant with estrogenic properties (metalloestrogen) that has been implicated in breast cancer. Treatment of MCF-7 cells with Cd also resulted in induction of Hsp22, and this induction was also inhibited by ICI182780. In live MCF-7 cells, Hsp22 interacted at the level of dimers with Hsp27, a related sHSP, as was shown by quantitative fluorescence resonance energy transfer measurements. In cytosolic extracts of MCF-7 cells, most of the E2- and Cd-induced Hsp22 was incorporated into high-molecular mass complexes. In part, Hsp22 and Hsp27 were components of distinct populations of these complexes. Finally, candidate elements in the Hsp22 promoter were identified by sequence analysis that could account for the induction of Hsp22 by E2 and Cd. Taken together, Hsp22 induction represents a new aspect of the estrogenic response with potential significance for the biology of estrogen receptor-positive breast cancer cells.

Scattering of Planetesimals by a Planet: Formation of Comet Cloud Candidates

We have investigated the first dynamical stage of comet cloud formation, the scattering of planetesimals by a planet. The orbits of planetesimals were calculated using circular restricted three-body formalism. We obtained the probabilities of the following results of scattering as functions of the orbital parameters of the planets and planetesimals: (1) collision with the planet, (2) escape from the planetary system, and (3) candidacy as a member of the comet cloud (planetesimals with large semimajor axes). We also derived simple empirical formulae for these probabilities that are accurate enough for order-of-magnitude estimation. We found that a planetesimal with an initial eccentricity of e ≳ 0.4 can escape from the planetary system or be a candidate for an element of the comet cloud due to scattering by a planet. As the energy range of the comet cloud is narrow, the probability of any planet producing escapers is always much higher than that of producing candidates. Using the probabilities and assuming a distribution of planetesimals, we obtained the efficiencies of collision, escape, and candidacy for a given planet. We applied the results to the solar system and found that, among the four giant planets, Jupiter is the planet most responsible for producing candidate elements of the Oort Cloud, as long as the inclination of planetesimals is constant or proportional to the reduced Hill radius of each planet.

Determining Colors for Traffic Control Devices at Transponder-Controlled Tollbooth Lanes with a Sign Simulator

The number of toll roads is increasing in the United States, and drivers face signing practices that vary greatly across jurisdictions. In addition to the increase in toll roads, there is an increase in the use of electronic toll collection (ETC) transponders. The present study was undertaken to develop standard signing practices—specifically for background color, legend color, underlay color (i.e., the background color for the pictographs), and pictograph—for ETC-supported toll road signs. The study reviewed selected ETC toll road signs in the United States to help select candidate elements and options to be used in a laboratory experiment. On the basis of that review, 120 signs depicted on 35-mm slides were developed with a standard sign-design software package. The signs were presented to 60 participants (equally divided by sex and age group) in the recently updated Turner-Fairbank Highway Research Center's sign simulator. The signs were shown to participants starting at a simulated distance of approxi...

Determining Colors for Traffic Control Devices at Transponder-Controlled Tollbooth Lanes with a Sign Simulator

The number of toll roads is increasing in the United States, and drivers face signing practices that vary greatly across jurisdictions. In addition to the increase in toll roads, there is an increase in the use of electronic toll collection (ETC) transponders. The present study was undertaken to develop standard signing practices—specifically for background color, legend color, underlay color (i.e., the background color for the pictographs), and pictograph—for ETC-supported toll road signs. The study reviewed selected ETC toll road signs in the United States to help select candidate elements and options to be used in a laboratory experiment. On the basis of that review, 120 signs depicted on 35-mm slides were developed with a standard sign-design software package. The signs were presented to 60 participants (equally divided by sex and age group) in the recently updated Turner–Fairbank Highway Research Center's sign simulator. The signs were shown to participants starting at a simulated distance of approximately 1,125 ft (343 m), and then the image was zoomed toward the participants at a constant speed controlled by the laboratory's computer. Each participant's detection distance, guidance legibility distance, and pictograph legibility distance were recorded. The results showed that, overall, green as a background color obtained the longest guidance information legibility distance. Also, fonts that provided the highest contrast to the background color (such as white on black) were the most effective for legibility. Underlay colors that showed the highest contrast to the pictographs were the most effective and included all of the lighter colors tested (white, yellow, and blue).

Two-level scheme for selection of primary degrees of freedom and semi-analytic sensitivity based on the reduced system

A number of approximate techniques have been developed to calculate the eigenvalues in a reduced manner. These schemes approximate the lower eigenvalues that represent the global behavior of the structures. The present study proposes a two-level condensation scheme (TLCS). This scheme consists of two-steps. In the first step, the candidate elements are selected for constructing the reduced system by energy estimation. In the second step, primary degrees of freedom are selected by sequential elimination from the candidate degrees of freedom linked to the selected elements through the first step. The proposed method saves computational cost effectively and recovers eigenvalues of the full system with high accuracy from the lowest to the truncated range of frequency. Moreover, besides the accuracies of the eigenvalue, well-constructed reduced system assures the accuracy of sensitivity of the eigenvalue compared to full system. In this paper, the semi-analytic design sensitivity of eigenvalues is obtained by the rigid body separation technique in reduced system. For the sensitivity calculation, the eigenvectors obtained from the reduced system are transformed into global system field. Numerical examples demonstrate the reliability of the eigenvalue and its sensitivity obtained by the reduced system through the comparison with conventional sensitivity schemes.

Complex regulation of somatic hypermutation by cis-acting sequences in the endogenous IgH gene in hybridoma cells.

To create high-affinity antibodies, B cells target a high rate of somatic hypermutation (SHM) to the Ig variable-region genes that encode the antigen-binding site. This mutational process requires transcription and is triggered by activation-induced cytidine deaminase (AID), which converts deoxycytidine to deoxyuridine. Mistargeting of AID to non-Ig genes is thought to result in the malignant transformation of B cells, but the mechanism responsible for targeting SHM to certain DNA regions and not to others is largely unknown. Cis-acting elements have been proposed to play a role in directing the hypermutation machinery, but the motifs required for targeting SHM have been difficult to identify because many of the candidate elements, such as promoters or enhancers, are also required for transcription of Ig genes. Here we describe a system in cultured hybridoma cells in which transcription of the endogenous heavy-chain Ig gene continues in the absence of the core intronic enhancer (Emu) and its flanking matrix attachment regions (MARs). When AID is expressed in these cells, SHM occurred at the WT frequency even when Emu and the MARs were absent together. Interestingly, SHM occurred at less than the WT frequency when Emu or the MARs were individually absent. Our results suggest that these intronic regulatory elements can exert a complex influence on SHM that is separable from their role in regulating transcription.

Using matrix effects as a probe for the study of the charge-transfer mechanism in inductively coupled plasma-atomic emission spectrometry

A novel method is presented for using matrix effects as a probe for the charge-transfer reaction between analyte atoms and argon ions in inductively coupled plasma-atomic emission spectrometry (ICP-AES). The method is based on the fact that the matrix effect caused by Ca or Ba depends on whether the studied analyte spectral line is from an ion or a neutral atom. Because the charge transfer reaction directly links atomic and high-energy ionic levels of the analyte, ionic spectral lines excited by charge transfer behave more like neutral-atom emission. As a result, quasi-resonant ionic emission lines exhibit a unique matrix effect character and can be easily identified. A commercial simultaneous full UV–Vis wavelength-coverage ICP spectrometer was used to study the responses of a large pool of spectral lines from a total of 22 elements in the presence of Na, Ca and Ba matrices. Candidate elements with charge-transfer character were thereby identified. The results match closely with those reported in the literature. The technique was further used to study charge-transfer reactions exhibited by the fourth-row metals from Sr to Sb. With the exception of Cd, Sr and Mo, all the other studied fourth-row metals showed positive evidence of excitation and ionization by charge-transfer from argon ion. While Sr showed negative results, the charge transfer-character of Cd and Mo could not be confirmed. It was also found that charge transfer can originate from other low-lying atomic analyte levels, in addition to the atomic ground state, and that charge-transfer reactions can occur at an appreciable rate even with a negative energy defect (i.e. negative ΔE) up to −1.6 eV.

Structural Damage Detection and Assessment from Modal Response

This paper presents a global damage detection and assessment algorithm based on a parameter estimation method using a finite-element model and the measured modal response of a structure. Damage is characterized as a reduction of the member constitutive parameter from a known baseline value. An optimization scheme is proposed to localize damaged parts of the structure. The algorithm accounts for the possibility of multiple solutions to the parameter estimation problem that arises from using spatially sparse measurements. Errors in parameter estimates caused by sensitivity to measurement noise are reduced by selecting a near-optimal measurement set from the data at each stage of the localization algorithm. Damage probability functions are computed upon completion of the localization process for candidate elements. Monte Carlo methods are used to compute the required probabilities based on the statistical distributions of the parameters for the damaged and the associated baseline structure. The algorithm is tested in a numerical simulation environment using a planar bridge truss as a model problem.

Transcriptional Activation of the MUC2 Gene by p53

MUC2 is one of the major components of mucins that provide a protective barrier between epithelial surfaces and the gut lumen. We investigated possible alterations of MUC2 gene expression by p53 and p21(Sdi1/Waf1/Cip1) in a human colon cancer cell line, DLD-1, establishing subclones in which a tetracycline-regulatable promoter controls exogenous p53 and p21 expression. MUC2 mRNA more significantly increased in response to p53 than to p21. Unexpectedly, MUC2 expression was also induced in human osteosarcoma cells, U-2OS and Saos-2, by exogenous p53. We next performed a reporter assay to test the direct regulation of MUC2 gene expression by p53. Deletion and mutagenesis of the MUC2 promoter region showed that it contains two sites for transactivation by p53. Furthermore, an electrophoretic mobility shift assay indicated that p53 binds to those elements. We analyzed MUC2 expression in other cell types possessing a functional p53 after exposure to various forms of stress. In MCF7 breast cancer and A427 lung cancer cells, MUC2 expression was increased along with the endogenous p53 level by actinomycin D, UVC, and x-ray, but not in RERF-LC-MS lung cancer cells carrying a mutated p53. These results suggest that p53 directly activates the MUC2 gene in many cell types.

Structural Damage Detection by Genetic Algorithms

A two-stage procedure utilizing incomplete measurements to assess the location and extent of structural damage is presented. In the first stage, candidate damaged elements are identified using the residual force method. Based on a priori knowledge from the first stage, the damage extent is determined from candidate elements using a proposed optimization scheme based on the method of simulated evolution.

Investigation of Additive Effects on Zn Diffusion in Hot-Dip Galvanizing by DFT Calculations

The DFT calculations of M-Zn12 clusters, which model the associates of Zn with 26 additive elements M in hot-dip galvanizing, have been carried out to investigate the additive effects on controlling coating thickness. A discrimination function, consisting of the calculated binding energy of clusters and the chemical shift of zinc 2p energy, is obtained which can predict the effects of additives. It has been further confirmed that an effective additive may intensely attract electronic charge from zinc and greatly grasp zinc atoms to form an associate. The zinc diffusion coefficients in the systems of various additives are estimated, by assuming that the binding energy is proportional to the diffusion activation energy and further the chemical shift is inversely proportional to the pre-exponent factor in the Arrhenius equation. The additive behaviors of six candidate elements are predicted by using the calculated diffusion coefficients. This study may assist in the design of binary and ternary additives sin...

Elements of a unifying theory of biology.

To discover a unifying theory of biology, it is necessary first to believe in its existence and second to seek its elements. Such a theory would explain the regulation of the cell cycle, differentiation and the origin of life. Some elements of the theory may be obtained by considering both eukaryotic and prokaryotic cell cycles. These elements include cytoskeletal proteins, calcium, cyclins, protein kinase C, phosphorylation, transcriptional sensing, autocatalytic gene expression and the physical properties of lipids. Other more exotic candidate elements include the dynamic enzoskeleton, ATP generation, mechanotransduction, the piezoelectric effect and resonance. Bringing these disparate elements together--and discovering others--will require extensive collaborations between specialists from different sciences. This can only be achieved within the context of an integrated approach to biology.

Segmentation of multidimensional cardiac images

One of the initial steps in the analysis of three-dimensional (3D)/four-dimensional (4D) images is Segmentation, which entails partitioning the images into relevant subsets such as object and background. In this paper, we present a multidimensional segmentation algorithm to extract object surfaces from Multidimensional Cardiac Computed Tomography (CT) scans. We propose the Generalized Morphological operators for segmentation in multidimensions. A priori knowledge of the approximate location of the object surface is communicated to the algorithm via the definition of the Search Space. The algorithm uses this definition of the Search Space to obtain the Surface Candidate elements. The search space specification reduces the computational cost and increases the reliability of the detected features.

Novel sorting network-based architectures for rank order filters

This paper presents two novel sorting network-based architectures for computing high sample rate nonrecursive rank order filters. The proposed architectures consist of significantly fewer comparators than existing sorting network-based architectures that are based on bubble-sort and Batcher's odd-even merge sort. The reduction in the number of comparators is obtained by sorting the columns of the window only once, and by merging the sorted columns in a way such that the number of candidate elements for the output is very small. The number of comparators per output is reduced even further by processing a block of outputs at a time. Block processing procedures that exploit the computational overlap between consecutive windows are developed for both the proposed networks.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

Structural and functional characterization of the mouse hepatocyte growth factor gene promoter.

To understand the molecular mechanisms underlying the regulation of hepatocyte growth factor (HGF) gene expression and to define the DNA sequences essential for its cell-type specific and inducible expression, we have isolated and characterized the 5'-flanking region of the HGF gene. A genomic clone containing 2.8 kilobases of the 5'-flanking region of the HGF gene has been isolated from a mouse liver genomic library. Sequence analysis showed that the promoter region of the mouse HGF gene contains a noncanonical TATA box (ATAAA). Further analysis of the 5'-flanking region revealed a number of putative regulatory elements, such as four interleukin-6 response elements (IL-6 RE), two potential binding sites for NF-IL6, a TGF-beta inhibitory element (TIE), a cAMP response element (CRE), two estrogen response elements (ERE) including one located in the first intron, a potential vitamin D response element (VDRE) which overlaps a chicken ovalbumin upstream promoter (COUP) transcription factor binding element, two liver-specific transcription factor (C/EBP) binding sites, and a B cell- and macrophage-specific transcriptional factor binding site (PU.1/ETS). To determine the location of sites that may be critical for the function of the HGF promoter, we constructed a series of chimeric genes containing variable regions of the 5'-flanking sequence of HGF gene and the coding region for chloramphenicol acetyltransferase (CAT). Transient transfection of chimeric plasmids demonstrated that the mouse HGF gene promoter containing 70 base pairs of the 5'-flanking sequences were active in mouse fibroblast NIH 3T3 cells and in human endometrial carcinoma RL95-2 cells. This basal transcription activity of the HGF promoter was modulated in NIH 3T3 and RL95-2 cells by multiple upstream elements. Three positive elements were identified at positions -2848 to -2674, -1386 to -1231, and -699 to -274, and three negative candidate elements were mapped to positions -1652 to -1386, -964 to -699, and -274 to -70, respectively. By the combination of a series of 5'-end deletion and internal deletion, a cell type-specific negative regulatory element in RL95-2 cells was localized to the nucleotide position -964 to -699. Moreover, the reporter plasmid containing interleukin 6 (IL-6) response element was responsive to IL-6 stimulation in stably transfected NIH 3T3 cells. Our findings revealed a complex pattern of transcriptional regulation of the mouse HGF gene expression.

Mechanisms controlling the direct solid sampling of silicon from gold samples by atomic absorption spectrometry with electrothermal atomization. Part 1. Analyte migration to the solid surface

The results of electrothermal atomic absorption spectrometry (ETAAS) investigations of Si vaporization from solid gold samples indicate that Si is released only after melting of the gold matrix, and the migration of Si to the surface is assisted by the formation of convection cells in the melt. This convection is driven by the thermal gradients in the sample. Diffusion alone, in either the solid or the melt, is too slow to account for the relatively short time for total Si release before a significant portion of the gold matrix is depleted. Silicon that is carried by the induced convection to the surface is readily vaporized. It is shown that the liquidus lines of the binary phase diagrams associated with a gold solvent can be used to predict the existence of analyte carryover in the gold. Consequently, these diagrams offer a means of identifying, a priori, candidate elements that may be determined by solid sampling ETAAS in gold, via aqueous solution calibration.

Analysis of a fushi tarazu autoregulatory element: multiple sequence elements contribute to enhancer activity.

Regulatory sequences or factors involved in the regulation of target genes of Drosophila homeodomain proteins are largely unknown. Here, we identify sequence elements that are involved in the function of the fushi tarazu (ftz) autoregulatory element AE, a direct in vivo target of the homeodomain protein ftz. A systematic deletion analysis of AE in transgenic embryos defines multiple elements that are redundantly involved in enhancer activity. Sequences juxtaposed to ftz binding sites are not strictly required for enhancer function. Several sequence motifs are conserved in other developmentally regulated genes of Drosophila melanogaster and in the AE homologue of Drosophila virilis. The D. virilis AE is functional in D. melanogaster. The sequence motifs identified here are candidate elements contributing to the target specificity of the homeodomain protein ftz.