Generalized flows, intrinsic stochasticity, and turbulent transport

The study of passive scalar transport in a turbulent velocity field leads naturally to the notion of generalized flows, which are families of probability distributions on the space of solutions to the associated ordinary differential equations which no longer satisfy the uniqueness theorem for ordinary differential equations. Two most natural regularizations of this problem, namely the regularization via adding small molecular diffusion and the regularization via smoothing out the velocity field, are considered. White-in-time random velocity fields are used as an example to examine the variety of phenomena that take place when the velocity field is not spatially regular. Three different regimes, characterized by their degrees of compressibility, are isolated in the parameter space. In the regime of intermediate compressibility, the two different regularizations give rise to two different scaling behaviors for the structure functions of the passive scalar. Physically, this means that the scaling depends on Prandtl number. In the other two regimes, the two different regularizations give rise to the same generalized flows even though the sense of convergence can be very different. The “one force, one solution” principle is established for the scalar field in the weakly compressible regime, and for the difference of the scalar in the strongly compressible regime, which is the regime of inverse cascade. Existence and uniqueness of an invariant measure are also proved in these regimes when the transport equation is suitably forced. Finally incomplete self similarity in the sense of Barenblatt and Chorin is established.

Inverse radiation dose-rate effects on somatic and germ-line mutations and DNA damage rates

The mutagenic effect of low linear energy transfer ionizing radiation is reduced for a given dose as the dose rate (DR) is reduced to a low level, a phenomenon known as the direct DR effect. Our reanalysis of published data shows that for both somatic and germ-line mutations there is an opposite, inverse DR effect, with reduction from low to very low DR, the overall dependence of induced mutations being parabolically related to DR, with a minimum in the range of 0.1 to 1.0 cGy/min (rule 1). This general pattern can be attributed to an optimal induction of error-free DNA repair in a DR region of minimal mutability (MMDR region). The diminished activation of repair at very low DRs may reflect a low ratio of induced (“signal”) to spontaneous background DNA damage (“noise”). Because two common DNA lesions, 8-oxoguanine and thymine glycol, were already known to activate repair in irradiated mammalian cells, we estimated how their rates of production are altered upon radiation exposure in the MMDR region. For these and other abundant lesions (abasic sites and single-strand breaks), the DNA damage rate increment in the MMDR region is in the range of 10% to 100% (rule 2). These estimates suggest a genetically programmed optimatization of response to radiation in the MMDR region.

Generalized transduction in Streptomyces coelicolor

We report the isolation of generalized transducing phages for Streptomyces species able to transduce chromosomal markers or plasmids between derivatives of Streptomyces coelicolor, the principal genetic model system for this important bacterial genus. We describe four apparently distinct phages (DAH2, DAH4, DAH5, and DAH6) that are capable of transducing multiple chromosomal markers at frequencies ranging from 10−5 to 10−9 per plaque-forming unit. The phages contain DNA ranging in size from 93 to 121 kb and mediate linked transfer of genetic loci at neighboring chromosomal sites sufficiently close to be packaged within the same phage particle. The key to our ability to demonstrate transduction by these phages was the establishment of conditions expected to severely reduce superinfection killing during the selection of transductants. The host range of these phages, as measured by the ability to form plaques, extends to species as distantly related as Streptomyces avermitilis and Streptomyces verticillus, which are among the most commercially important species of this genus. Transduction of plasmid DNA between S. coelicolor and S. verticillus was observed at frequencies of ≈10−4 transductants per colony-forming unit.

Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors.

Histamine H2 receptors transfected in Chinese hamster ovary (CHO) cells are time- and dose-dependently upregulated upon exposure to the H2 antagonists cimetidine and ranitidine. This effect appears to be H2 receptor-mediated as no change in receptor density was observed after H1 or H3 antagonist treatment or after incubation with the structural analogue of cimetidine, VUF 8299, which has no H2 antagonistic effects. By using transfected CHO cells expressing different densities of wild-type H2 receptors or an uncoupled H2Leu124Ala receptor, the histamine H2 receptor was found to display considerable agonist-independent H2 receptor activity. Cimetidine and ranitidine, which both induce H2 receptor upregulation, actually functioned as inverse agonists in those cell lines displaying spontaneous agonist-independent H2 receptor activity. Burimamide, on the other hand, was shown to act as a neutral antagonist and did as expected not induce H2 receptor upregulation after long-term exposure. The displayed inverse agonism of H2 antagonists appears to be a mechanistic basis for the observed H2 antagonist-induced H2 receptor upregulation in transfected CHO cells. These observations shed new light on the pharmacological classification of the H2 antagonists and may offer a plausible explanation for the observed development of tolerance after prolonged clinical use.

Kinetics of self-assembling microtubules: an "inverse problem" in biochemistry.

Experimental time series for a nonequilibrium reaction may in some cases contain sufficient data to determine a unique kinetic model for the reaction by a systematic mathematical analysis. As an example, a kinetic model for the self-assembly of microtubules is derived here from turbidity time series for solutions in which microtubules assemble. The model may be seen as a generalization of Oosawa's classical nucleation-polymerization model. It reproduces the experimental data with a four-stage nucleation process and a critical nucleus of 15 monomers.

On the existence and implications of an inverse folding code in proteins.

The existence of a code relating the set of possible sequences at a given position in a protein backbone to the local structure at that location is investigated. It is shown that only 73% of 4-C alpha structure fragments in a sample of 114 protein structures exhibit a preference for a particular set of sequences. The remaining structures can accommodate essentially any sequence. The structures that encode specific sequence distributions include the classical "secondary" structures, with the notable exception of planar (beta) bends. It is suggested that this has implications as to the mechanism of folding in proteins with extensive sheet/barrel structure. The possible role of structures that do not encode specific sequences as mutation hot spots is noted.