Read-Across of 90-day Rat Oral Repeated-Dose Toxicity: A Case Study for Selected n-Alkanols

n-Alkanols provide an excellent example where a category-approach to read-across may be used to estimate the repeated-dose endpoint for a number of untested derivatives (target chemicals) using experimental data for tested derivatives (source chemicals). n-Alkanols are non-reactive and exhibit the unspecific, reversible simple anaesthesia or non-polar narcosis mode of toxic action in that the metabolic products of the parent alcohols do not contribute to the toxic endpoint evaluated. In this case study, the chemical category is limited to the readily bioavailable (C5 to C13) analogues. The toxicokinetic premise includes rapid absorption via the gastrointestinal tract, distribution in the circulatory system, and first-pass metabolism in the liver resulting in metabolism via oxidation to CO2 and with minor elimination of oxidative intermediate as glucuronides. Two analogues have experimental 90-day oral repeated-dose toxicity data which exhibit qualitative and quantitative consistency. Typical findings include decreased body weight, slightly increased liver weight which, in some cases, is accompanied by clinical chemical and haematological changes but generally without concurrent histopathological effects at the Lowest Observed Effect Level (LOEL). Chemical similarity between the analogues is readily defined by a variety of structure-related properties; data uncertainty associated with toxicokinetic and toxicodynamic similarities is low. Uncertainty associated with mechanistic relevance and completeness of the read-across is reduced by the concordance of in vivo and in vitro results, as well as high throughput and in silico methods data. As shown in detail, the 90-day oral repeated-dose toxicity No Observed Effect Level (NOEL) value of 1000 mg/kg bw/d for 1-pentanol and 1-hexanol based on LOEL of very low systemic toxicity can be read across to fill the data gaps of the untested analogues in this category with acceptable uncertainty

Local Structure and Dynamics of Trans-polyisoprene oligomers

Mono- and poly-disperse melts of oligomers (average length 10 monomers) of trans-1,4-polyisoprene are simulated in full atomistic detail. The force-field is developed by means of a mixture of ab initio quantum-chemistry and an automatic generation of empirical parameters. Comparisons to NMR and scattering experiments validate the model. The local reorientation dynamics shows that for C$-$H vectors there is a two-stage process consisting of an initial decay and a late-stage decorrelation originating from overall reorientation. The atomistic model can be successfully mapped onto a simple model including only beads for the monomers with bond springs and bond angle potentials. End-bridging Monte Carlo as an equilibration stage and molecular dynamics as the subsequent simulation method together prove to be a useful method for polymer simulations.Comment: 25 pages, 15 figures, accepted by Macromolecule

The element of uncertainty in the interpretation of feeding experiments / 165

Cover title.Bibliography: p. 578-579

Quasi-uniformity of Minimal Weighted Energy Points on Compact Metric Spaces

For a closed subset $K$ of a compact metric space $A$ possessing an $\alpha$-regular measure $\mu$ with $\mu(K)>0$, we prove that whenever $s>\alpha$, any sequence of weighted minimal Riesz $s$-energy configurations $\omega_N=\{x_{i,N}^{(s)}\}_{i=1}^N$ on $K$ (for `nice' weights) is quasi-uniform in the sense that the ratios of its mesh norm to separation distance remain bounded as $N$ grows large. Furthermore, if $K$ is an $\alpha$-rectifiable compact subset of Euclidean space ($\alpha$ an integer) with positive and finite $\alpha$-dimensional Hausdorff measure, it is possible to generate such a quasi-uniform sequence of configurations that also has (as $N\to \infty$) a prescribed positive continuous limit distribution with respect to $\alpha$-dimensional Hausdorff measure. As a consequence of our energy related results for the unweighted case, we deduce that if $A$ is a compact $C^1$ manifold without boundary, then there exists a sequence of $N$-point best-packing configurations on $A$ whose mesh-separation ratios have limit superior (as $N\to \infty$) at most 2

Symmetric Shannon capacity is the independence number minus 1

A symmetric variant of Shannon capacity is defined and computed.Comment: 4 pages, submitted to Electronic Journal of Combinatoric

On the complete weight enumerators of some linear codes with a few weights

Linear codes with a few weights have important applications in authentication codes, secret sharing, consumer electronics, etc.. The determination of the parameters such as Hamming weight distributions and complete weight enumerators of linear codes are important research topics. In this paper, we consider some classes of linear codes with a few weights and determine the complete weight enumerators from which the corresponding Hamming weight distributions are derived with help of some sums involving Legendre symbol

Sparse halves in dense triangle-free graphs

Erd\H{o}s conjectured that every triangle-free graph $G$ on $n$ vertices contains a set of $\lfloor n/2 \rfloor$ vertices that spans at most $n^2 /50$ edges. Krivelevich proved the conjecture for graphs with minimum degree at least $\frac{2}{5}n$. Keevash and Sudakov improved this result to graphs with average degree at least $\frac{2}{5}n$. We strengthen these results by showing that the conjecture holds for graphs with minimum degree at least $\frac{5}{14}n$ and for graphs with average degree at least $(\frac{2}{5} - \varepsilon)n$ for some absolute $\varepsilon >0$. Moreover, we show that the conjecture is true for graphs which are close to the Petersen graph in edit distance.Comment: 23 page

Multi-objective optimal designs in comparative clinical trials with covariates: The reinforced doubly adaptive biased coin design

The present paper deals with the problem of allocating patients to two competing treatments in the presence of covariates or prognostic factors in order to achieve a good trade-off among ethical concerns, inferential precision and randomness in the treatment allocations. In particular we suggest a multipurpose design methodology that combines efficiency and ethical gain when the linear homoscedastic model with both treatment/covariate interactions and interactions among covariates is adopted. The ensuing compound optimal allocations of the treatments depend on the covariates and their distribution on the population of interest, as well as on the unknown parameters of the model. Therefore, we introduce the reinforced doubly adaptive biased coin design, namely a general class of covariate-adjusted response-adaptive procedures that includes both continuous and discontinuous randomization functions, aimed to target any desired allocation proportion. The properties of this proposal are described both theoretically and through simulations.Comment: Published in at http://dx.doi.org/10.1214/12-AOS1007 the Annals of Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical Statistics (http://www.imstat.org