Exact averages of central values of triple product L-functions

We obtain exact formulas for central values of triple product L-functions averaged over newforms of weight 2 and prime level. We apply these formulas to non-vanishing problems. This paper uses a period formula for the triple product L-function proved by Gross and Kudla

Structure of the Tetrahymena thermophila telomerase RNA helix II template boundary element

Telomere addition by telomerase requires an internal templating sequence located in the RNA subunit of telomerase. The correct boundary definition of this template sequence is essential for the proper addition of the nucleotide repeats. Incorporation of incorrect telomeric repeats onto the ends of chromosomes has been shown to induce chromosomal instability in ciliate, yeast and human cells. A 5′ template boundary defining element (TBE) has been identified in human, yeast and ciliate telomerase RNAs. Here, we report the solution structure of the TBE element (helix II) from Tetrahymena thermophila telomerase RNA. Our results indicate that helix II and its capping pentaloop form a well-defined structure including unpaired, stacked adenine nucleotides in the stem and an unusual syn adenine nucleotide in the loop. A comparison of the T.thermophila helix II pentaloop with a pentaloop of the same sequence found in the 23S rRNA of the Haloarcula marismortui ribosome suggests possible RNA and/or protein interactions for the helix II loop within the Tetrahymena telomerase holoenzyme

Different loop arrangements of intramolecular human telomeric (3+1) G-quadruplexes in K(+) solution

Intramolecular G-quadruplexes formed by the human telomeric G-rich strand are promising anticancer targets. Here we show that four-repeat human telomeric DNA sequences can adopt two different intramolecular G-quadruplex folds in K(+) solution. The two structures contain the (3+1) G-tetrad core, in which three G-tracts are oriented in one direction and the fourth in the opposite direction, with one double-chain-reversal and two edgewise loops, but involve different loop arrangements. This result indicates the robustness of the (3+1) core G-quadruplex topology, thereby suggesting it as an important platform for structure-based drug design. Our data also support the view that multiple human telomeric G-quadruplex conformations coexist in K(+) solution. Furthermore, even small changes to flanking sequences can perturb the equilibrium between different coexisting G-quadruplex forms

Crystallization and characterization of the thallium form of the Oxytricha nova G-quadruplex

The crystal structure of the Tl(+) form of the G-quadruplex formed from the Oxytricha nova telomere sequence, d(G(4)T(4)G(4)), has been solved to 1.55 Å. This G-quadruplex contains five Tl(+) ions, three of which are interspersed between adjacent G-quartet planes and one in each of the two thymine loops. The structure displays a high degree of similarity to the K(+) crystal structure [Haider et al. (2002), J. Mol. Biol., 320, 189–200], including the number and location of the monovalent cation binding sites. The highly isomorphic nature of the two structures, which contain such a large number of monovalent binding sites (relative to nucleic acid content), verifies the ability of Tl(+) to mimic K(+) in nucleic acids. Information from this report confirms and extends the assignment of (205)Tl resonances from a previous report [Gill et al. (2005), J. Am. Chem. Soc., 127, 16 723–16 732] where (205)Tl NMR was used to study monovalent cation binding to this G-quadruplex. The assignment of these resonances provides evidence for the occurrence of conformational dynamics in the thymine loop region that is in slow exchange on the (205)Tl timescale

Resolution and characterization of the structural polymorphism of a single quadruplex-forming sequence

The remarkable structural polymorphism of quadruplex-forming sequences has been a considerable impediment in the elucidation of quadruplex folds. Sequence modifications have commonly been used to perturb and purportedly select a particular form out of the ensemble of folds for nuclear magnetic resonance (NMR) or X-ray crystallographic analysis. Here we report a simple chromatographic technique that separates the individual folds without need for sequence modification. The sequence d(GGTGGTGGTGGTTGTGGTGGTGGTGG) forms a compact quadruplex according to a variety of common biophysical techniques. However, NMR and chromatography showed that this oligonucleotide produces at least eight monomeric quadruplex species that interconvert very slowly at room temperature. We have used a combination of spectroscopic, hydrodynamic and thermodynamic techniques to evaluate the physicochemical properties of the mixture and the individual species. These species have almost identical thermodynamic, hydrodynamic and electrophoretic properties, but significantly different NMR and circular dichroism (CD) spectra, as well as kinetic stability. These results demonstrate that simple standard low-resolution techniques cannot always be used for quadruplex fold determination or quality control purposes, and that simple thermodynamic analysis does not directly provide interpretable thermodynamic parameters

Stable Genetic Influence on Anxiety-Related Behaviours Across Middle Childhood

We examined the aetiology of anxiety symptoms in an unselected population at ages 7 and 9, a period during which anxiety disorders first begin to develop (mean age at onset is 11 years). Specifically, the aim of the study was to investigate genetic and environmental continuity and change in components of anxiety in middle childhood. Parents of over 3,500 twin pairs completed the Anxiety-Related Behaviours Questionnaire (ARBQ) when twins were 7 and 9 years old. Multivariate-longitudinal analyses were conducted to examine genetic and environmental influences on stability and change in four anxiety scales: Negative Cognition, Negative Affect, Fear and Social Anxiety. We found moderate temporal stability in all four scales from 7 to 9 years (correlations ranging from 0.45 to 0.54) and moderate heritability (average 54%). Both shared and non-shared environmental influences were modest (average 18%–28% respectively). Genetic factors (68%) explained most of the homotypic continuity in anxiety. We show that homotypic continuity of Anxiety-Related Behaviours (i.e. the continuation of one specific type of anxiety over time) was largely driven by genetic factors. In contrast, though more varied, heterotypic continuity between some traits (i.e. the change from one type of anxiety-related behaviour into another over time) was mainly due to shared-environmental factors

Characterization of the hydrogen bond network in guanosine quartets by internucleotide 3hJ(NC)' and 2hJ(NN) scalar couplings

Scalar coupling correlations across hydrogen bonds with carbonyl groups as acceptors have been observed in a variety of proteins, but not in nucleic acids. Here we present a pulse scheme that allows such an observation and quantification of trans-hydrogen bond 3hJ(NC)' correlations in nucleic acid base pairs, between the imino nitrogen 15N1 and the carbonyl 13C6 nuclei within the guanine quartets of the Oxy-1.5 DNA-quadruplex. Intra- and internucleotide N-H...O=C connectivities can be traced around each guanine quartet, allowing the hydrogen bonding partners to be unambiguously assigned. Absolute values of the 3hJ(NC)' couplings are approximately 0.2 Hz as quantified by a selective long-range H(N)CO experiment and are thus on average smaller than the analogous 3hJ(NC)' couplings observed in proteins. In addition, an improved version of the pseudo-heteronuclear H(N)N-COSY [Majumdar et al. (1999) J. Biomol. NMR, 14, 67-70] is presented which allows simultaneous detection of the 15N-donor and 15N-acceptor resonances connected by 2hJ(NN) couplings in hydrogen bonds involving amino groups. Using this experiment, values ranging between 6 and 8 Hz are determined for the 2hJNN couplings between 15N2 and 15N7 nuclei in the guanine quartet. These values are not strongly influenced by the presence of a significant amount of chemical exchange broadening due to amino group rotations