Investigations into the molecular effects of single nucleotide polymorphism

Objectives: DNA sequences are very rich in short repeats and their pattern can be altered by point mutations. We wanted to investigate the effect of single nucleotide polymorphism (SNP) on the pattern of short DNA repeats and its biological consequences. Methods: Analysis of the pattern of short DNA repeats of the Thy-1 sequence with and without SNP. Searching for DNA-binding factors in any region of significance. Results: Comparing the pattern of short repeats in the Thy-1 gene sequences of Turkish patients with ataxia telangiectasia (AT) with the `wild type' sequence from the DNA database, we identified a missing 8-bp repeat element due to an SNP in position 1271 (intron II) in AT-DNA sequences. Only the mutated sequence had the potential for the formation of a stem loop in DNA or pre-mRNA. In super-shift experiments we found that DNA oligomers covering the area of this SNP formed a complex with proteins amongst which we identified the proliferating cell nuclear antigen (PCNA) protein. Conclusion: SNPs have the potential to alter DNA or pre-mRNA conformation. Although no SNP-depeding formation of the DNA-protein complex was evident, future investigations could reveal differential molecular mechanisms of cellular regulation. Copyright (C) 2001 S. Karger AG, Basel

A non-hyponormal operator generating Stieltjes moment sequences

A linear operator $S$ in a complex Hilbert space \hh for which the set \dzn{S} of its $C^\infty$-vectors is dense in \hh and $\{\|S^n f\|^2\}_{n=0}^\infty$ is a Stieltjes moment sequence for every f \in \dzn{S} is said to generate Stieltjes moment sequences. It is shown that there exists a closed non-hyponormal operator $S$ which generates Stieltjes moment sequences. What is more, \dzn{S} is a core of any power $S^n$ of $S$. This is established with the help of a weighted shift on a directed tree with one branching vertex. The main tool in the construction comes from the theory of indeterminate Stieltjes moment sequences. As a consequence, it is shown that there exists a non-hyponormal composition operator in an $L^2$-space (over a $\sigma$-finite measure space) which is injective, paranormal and which generates Stieltjes moment sequences. In contrast to the case of abstract Hilbert space operators, composition operators which are formally normal and which generate Stieltjes moment sequences are always subnormal (in fact normal). The independence assertion of Barry Simon's theorem which parameterizes von Neumann extensions of a closed real symmetric operator with deficiency indices $(1,1)$ is shown to be false

How training and testing histories affect generalization: a test of simple neural networks

We show that a simple network model of associative learning can\ud reproduce three findings that arise from particular training and\ud testing procedures in generalization experiments: the effect of 1)\ud ``errorless learning'' and 2) extinction testing on peak shift, and\ud 3) the central tendency effect. These findings provide a true test\ud of the network model, which was developed to account for other\ud penhomena, and highlight the potential of neural networks to study\ud phenomena that depend on sequences of experiences with many stimuli.\ud Our results suggest that at least some such phenomena, e.g.,\ud stimulus range effects, may derive from basic mechanisms of\ud associative memory rather than from more complex memory processes

Methods of calculating ionization energies of multielectron (five or more) isoelectronic atomic ions

We have previously used simple empirical equations to reproduce the literature values of the ionization energies of isoelectronic sequences of up to four electrons which gave very good agreement. We reproduce here a kinetic energy expression with corrections for relativity and Lamb shift effects which give excellent agreement with the literature values. These equations become more complex as the number of electrons in the system increases. Alternative simple quadratic expressions for calculating ionization energies of multielectron ions are discussed. A set of coefficients when substituted into a simple expression produces very good agreement with the literature values. Our work shows that Slater's rules are not appropriate for predicting trends or screening constants. This work provides very strong evidence that ionization energies are not functions of complete squares, and when calculating ionization energies electron transition/relaxation has to be taken into account. We demonstrate clearly that for particular isoelectronic sequences, the ionizing electrons may occupy different orbitals and in such cases more than one set of constants are needed to calculate the ionization energies

Symbolic Dynamics, Modular Curves, and Bianchi IX Cosmologies

It is well known that the so called Bianchi IX spacetimes with SO(3)-symmetry in a neighbourhood of the Big Bang exhibit a chaotic behaviour of typical trajectories in the backward movement of time. This behaviour (Mixmaster Model of the Universe) can be encoded by the shift of two-sided continued fractions. Exactly the same shift encodes the sequences of intersections of hyperbolic geodesics with purely imaginary axis in the upper complex half-plane, that is geodesic flow on an appropriate modular surface. A physical interpretation of this coincidence was suggested in arXiv:1402.2158: namely, that Mixmaster chaos is an approximate description of the passage from a hot quantum Universe at the Big Bang moment to the cooling classical Universe. Here we discuss and elaborate this suggestion, looking at the Mixmaster Model from the perspective of the second class of Bianchi IX spacetimes: those with SU(2)-symmetry (self-dual Einstein metrics). We also extend it to the more general context related to Painleve' VI equations.Comment: 26 pages, Te

Targeting the Ets Binding Site of the HER2/neu Promoter with Pyrrole-Imidazole Polyamides

Three DNA binding polyamides (1-3) were synthesized that bind with high affinity (Ka = 8.7·10^9 M^-1 to 1.4·10^10 M^-1) to two 7-base pair sequences overlapping the Ets DNA binding site (EBS; GAGGAA) within the regulatory region of the HER2/neu proximal promoter. As measured by electrophoretic mobility shift assay, polyamides binding to flanking elements upstream (1) or downstream (2 and 3) of the EBS were one to two orders of magnitude more effective than the natural product distamycin at inhibiting formation of complexes between the purified EBS protein, epithelial restricted with serine box (ESX), and the HER2/neu promoter probe. One polyamide, 2, completely blocked Ets-DNA complex formation at 10 nM ligand concentration, whereas formation of activator protein-2-DNA complexes was unaffected at the activator protein-2 binding site immediately upstream of the HER2/neu EBS, even at 100 nM ligand concentration. At equilibrium, polyamide 1 was equally effective at inhibiting Ets/DNA binding when added before or after in vitro formation of protein-promoter complexes, demonstrating its utility to disrupt endogenous Ets-mediated HER2/neu preinitiation complexes. Polyamide 2, the most potent inhibitor of Ets-DNA complex formation by electrophoretic mobility shift assay, was also the most effective inhibitor of HER2/neu promoter-driven transcription measured in a cell-free system using nuclear extract from an ESX- and HER2/neu-overexpressing human breast cancer cell line, SKBR-3

Defect Particle Kinematics in One-Dimensional Cellular Automata

Let A^Z be the Cantor space of bi-infinite sequences in a finite alphabet A, and let sigma be the shift map on A^Z. A `cellular automaton' is a continuous, sigma-commuting self-map Phi of A^Z, and a `Phi-invariant subshift' is a closed, (Phi,sigma)-invariant subset X of A^Z. Suppose x is a sequence in A^Z which is X-admissible everywhere except for some small region we call a `defect'. It has been empirically observed that such defects persist under iteration of Phi, and often propagate like `particles'. We characterize the motion of these particles, and show that it falls into several regimes, ranging from simple deterministic motion, to generalized random walks, to complex motion emulating Turing machines or pushdown automata. One consequence is that some questions about defect behaviour are formally undecidable.Comment: 37 pages, 9 figures, 3 table