Role of adenine functional groups in the recognition of the 3′-splice-site AG during the second step of pre-mRNA splicing

The AG dinucleotide at the 3′ splice sites of metazoan nuclear pre-mRNAs plays a critical role in catalytic step II of the splicing reaction. Previous studies have shown that replacement of the guanine by adenine in the AG (AG → GG) inhibits this step. We find that the second step was even more severely inhibited by cytosine (AG → CG) or uracil (AG → UG) substitutions at this position. By contrast, a relatively moderate inhibition was observed with a hypoxanthine substitution (AG → HG). When adenine was replaced by a purine base (AG → PG) or by 7-deazaadenine (AG → c7AG), little effect on the second step was observed, suggesting that the 6-NH2 and N7 groups do not play a critical role in adenine recognition. Finally, replacement of adenine by 2-aminopurine (AG → 2-APG) had no effect on the second step. Taken together, our results suggest that the N1 group of adenine functions as an essential determinant in adenine recognition during the second step of pre-mRNA splicing.

Yeast mutations in multiple complementation groups inhibit brome mosaic virus RNA replication and transcription and perturb regulated expression of the viral polymerase-like gene

Brome mosaic virus (BMV), a member of the alphavirus-like superfamily of positive-strand RNA viruses, encodes two proteins, 1a and 2a, that interact with each other, with unidentified host proteins, and with host membranes to form the viral RNA replication complex. Yeast expressing 1a and 2a support replication and subgenomic mRNA synthesis by BMV RNA3 derivatives. Using a multistep selection and screening process, we have isolated yeast mutants in multiple complementation groups that inhibit BMV-directed gene expression. Three complementation groups, represented by mutants mab1–1, mab2–1, and mab3–1 (for maintenance of BMV functions), were selected for initial study. Each of these mutants has a single, recessive, chromosomal mutation that inhibits accumulation of positive- and negative-strand RNA3 and subgenomic mRNA. BMV-directed gene expression was inhibited when the RNA replication template was introduced by in vivo transcription from DNA or by transfection of yeast with in vitro transcripts, confirming that cytoplasmic RNA replication steps were defective. mab1–1, mab2–1, and mab3–1 slowed yeast growth to varying degrees and were temperature-sensitive, showing that the affected genes contribute to normal cell growth. In wild-type yeast, expression of the helicase-like 1a protein increased the accumulation of 2a mRNA and the polymerase-like 2a protein, revealing a new level of viral regulation. In association with their other effects, mab1–1 and mab2–1 blocked the ability of 1a to stimulate 2a mRNA and protein accumulation, whereas mab3–1 had elevated 2a protein accumulation. Together, these results show that BMV RNA replication in yeast depends on multiple host genes, some of which directly or indirectly affect the regulated expression and accumulation of 2a.

Evaluation of total purchasing pilots in England and Scotland and implications for primary care groups in England: personal interviews and analysis of routine data

Objectives: To evaluate the reported achievements of the 52 first wave total purchasing pilot schemes in 1996-7 and the factors associated with these; and to consider the implications of these findings for the development of the proposed primary care groups.

Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups

Induction of phase 2 enzymes and elevations of glutathione are major and sufficient strategies for protecting mammals and their cells against the toxic and carcinogenic effects of electrophiles and reactive forms of oxygen. Inducers belong to nine chemical classes and have few common properties except for their ability to modify sulfhydryl groups by oxidation, reduction, or alkylation. Much evidence suggests that the cellular “sensor” molecule that recognizes the inducers and signals the enhanced transcription of phase 2 genes does so by virtue of unique and highly reactive sulfhydryl functions that recognize and covalently react with the inducers. Benzylidene-alkanones and -cycloalkanones are Michael reaction acceptors whose inducer potency is profoundly increased by the presence of ortho- (but not other) hydroxyl substituent(s) on the aromatic ring(s). This enhancement correlates with more rapid reactivity of the ortho-hydroxylated derivatives with model sulfhydryl compounds. Proton NMR spectroscopy provides no evidence for increased electrophilicity of the β-vinyl carbons (the presumed site of nucleophilic attack) on the hydroxylated inducers. Surprisingly, these ortho-hydroxyl groups display a propensity for extensive intermolecular hydrogen bond formation, which may raise the reactivity and facilitate addition of mercaptans, thereby raising inducer potencies.

Quantum groups with invariant integrals

Quantum groups have been studied intensively for the last two decades from various points of view. The underlying mathematical structure is that of an algebra with a coproduct. Compact quantum groups admit Haar measures. However, if we want to have a Haar measure also in the noncompact case, we are forced to work with algebras without identity, and the notion of a coproduct has to be adapted. These considerations lead to the theory of multiplier Hopf algebras, which provides the mathematical tool for studying noncompact quantum groups with Haar measures. I will concentrate on the *-algebra case and assume positivity of the invariant integral. Doing so, I create an algebraic framework that serves as a model for the operator algebra approach to quantum groups. Indeed, the theory of locally compact quantum groups can be seen as the topological version of the theory of quantum groups as they are developed here in a purely algebraic context.

The operator algebra approach to quantum groups

A relatively simple definition of a locally compact quantum group in the C*-algebra setting will be explained as it was recently obtained by the authors. At the same time, we put this definition in the historical and mathematical context of locally compact groups, compact quantum groups, Kac algebras, multiplicative unitaries, and duality theory.

X-ray emission from clusters and groups of galaxies

Recent major advances in x-ray imaging and spectroscopy of clusters have allowed the determination of their mass and mass profile out to ≈1/2 the virial radius. In rich clusters, most of the baryonic mass is in the gas phase, and the ratio of mass in gas/stars varies by a factor of 2–4. The baryonic fractions vary by a factor of ≈3 from cluster to cluster and almost always exceed 0.09 h50−[3/2] and thus are in fundamental conflict with the assumption of Ω = 1 and the results of big bang nucleosynthesis. The derived Fe abundances are 0.2–0.45 solar, and the abundances of O and Si for low redshift systems are 0.6–1.0 solar. This distribution is consistent with an origin in pure type II supernova. The amount of light and energy produced by these supernovae is very large, indicating their importance in influencing the formation of clusters and galaxies. The lack of evolution of Fe to a redshift of z ≈ 0.4 argues for very early enrichment of the cluster gas. Groups show a wide range of abundances, 0.1–0.5 solar. The results of an x-ray survey indicate that the contribution of groups to the mass density of the universe is likely to be larger than 0.1 h50−2. Many of the very poor groups have large x-ray halos and are filled with small galaxies whose velocity dispersion is a good match to the x-ray temperatures.

Adjoint modular Galois representations and their Selmer groups

In the last 15 years, many class number formulas and main conjectures have been proven. Here, we discuss such formulas on the Selmer groups of the three-dimensional adjoint representation ad(φ) of a two-dimensional modular Galois representation φ. We start with the p-adic Galois representation φ0 of a modular elliptic curve E and present a formula expressing in terms of L(1, ad(φ0)) the intersection number of the elliptic curve E and the complementary abelian variety inside the Jacobian of the modular curve. Then we explain how one can deduce a formula for the order of the Selmer group Sel(ad(φ0)) from the proof of Wiles of the Shimura–Taniyama conjecture. After that, we generalize the formula in an Iwasawa theoretic setting of one and two variables. Here the first variable, T, is the weight variable of the universal p-ordinary Hecke algebra, and the second variable is the cyclotomic variable S. In the one-variable case, we let φ denote the p-ordinary Galois representation with values in GL2(Zp[[T]]) lifting φ0, and the characteristic power series of the Selmer group Sel(ad(φ)) is given by a p-adic L-function interpolating L(1, ad(φk)) for weight k + 2 specialization φk of φ. In the two-variable case, we state a main conjecture on the characteristic power series in Zp[[T, S]] of Sel(ad(φ) ⊗ ν−1), where ν is the universal cyclotomic character with values in Zp[[S]]. Finally, we describe our recent results toward the proof of the conjecture and a possible strategy of proving the main conjecture using p-adic Siegel modular forms.

The structure of Selmer groups

The purpose of this article is to describe certain results and conjectures concerning the structure of Galois cohomology groups and Selmer groups, especially for abelian varieties. These results are analogues of a classical theorem of Iwasawa. We formulate a very general version of the Weak Leopoldt Conjecture. One consequence of this conjecture is the nonexistence of proper Λ-submodules of finite index in a certain Galois cohomology group. Under certain hypotheses, one can prove the nonexistence of proper Λ-submodules of finite index in Selmer groups. An example shows that some hypotheses are needed.

Zeta functions and Eisenstein series on classical groups

We construct an Euler product from the Hecke eigenvalues of an automorphic form on a classical group and prove its analytic continuation to the whole complex plane when the group is a unitary group over a CM field and the eigenform is holomorphic. We also prove analytic continuation of an Eisenstein series on another unitary group, containing the group just mentioned defined with such an eigenform. As an application of our methods, we prove an explicit class number formula for a totally definite hermitian form over a CM field.