Stereoselective total syntheses and reassignment of stereochemistry of the freshwater cyanobacterial hepatotoxins cylindrospermopsin and 7-epicylindrospermopsin

A stereoselective total synthesis of the structure 1 proposed for the freshwater cyanobacterial heptatotoxin cylindrospermopsin has been accomplished in approximately 30 operations starting from commercially available 4-methoxypyridine. Utilizing methodology developed by Comins, the tetrasubstituted piperidine A-ring unit of the hepatotoxin was efficiently constructed. The two remaining stereocenters in the natural product were then set by a stereospecific intramolecular N-sulfinylurea Diels-Alder cyclization/Grignard ring opening/allylic sulfoxide [2,3]-sigmatropic rearrangement sequence previously developed in these laboratories, leading to key intermediate 29. The stereochemical assignment of alcohol 29, which contains all six of the stereogenic centers of the natural product, was confirmed by an X-ray crystal structure determination of a derivative. Installation of the D-ring uracil moiety was effected by using our new methodology developed for this purpose, and construction of the C-ring guanidine completed the total synthesis of racemic structure 1. However, the (1)H NMR data for this compound do not match that of cylindrospermopsin, but instead agree with the data reported for 7-epicylindrospermopsin, a minor toxic metabolite that co-occurs with cylindrospermopsin. Therefore, we propose a revision of the stereochemical assignments of these natural products such that cylindrospermopsin is now represented as structure 2 and 7-epicylindrospermopsin is 1. This reassignment was further confirmed by Mitsunobu inversion of the C-7 alcohol 51 to epimer 52, and conversion of this compound to tetracyclic diol 57, which has previously been transformed to cylindrospermopsin (2).     

Kinetically locked-in colloidal transport in an array of optical tweezers

We describe measurements of colloidal transport through arrays of micrometer-scale potential wells created with holographic optical tweezers. Varying the orientation of the trap array relative to the external driving force results in a hierarchy of lock-in transitions analogous to symmetry-selecting processes in a wide variety of systems. Focusing on colloid as a model system provides the first opportunity to observe the microscopic mechanisms of kinetic lock-in transitions and reveals a new class of statistically locked-in states. This particular realization also has immediate applications for continuously fractionating particles, biological cells, and macromolecules.     

Differential inhibition of postnatal brain,spinal cord and body growth by a growth hormone antagonist

Background  

Growth hormone (GH) plays an incompletely understood role in the development of the central nervous system (CNS). In this study, we use transgenic mice expressing a growth hormone antagonist (GHA) to explore the role of GH in regulating postnatal brain, spinal cord and body growth into adulthood. The GHA transgene encodes a protein that inhibits the binding of GH to its receptor, specifically antagonizing the trophic effects of endogenous GH.     

Structure of optical vortices

Helical modes of light can be focused into toroidal optical traps known as optical vortices, which are capable of localizing and applying torques to small volumes of matter. Measurements of optical vortices created with the dynamic holographic optical tweezer technique reveal an unsuspected dependence of their structure and angular momentum flux on their helicity. These measurements also provide evidence for a novel optical ratchet potential in practical optical vortices.     

Measuring a colloidal particle's interaction with a flat surface under nonequilibrium conditions

A new and general approach is proposed to analyze the dynamics of a colloidal particle interacting with a nearby wall. This analysis can be used to determine the acting forces even when the system is non-stationary. As an illustration, we use total internal reflection microscopy to investigate the forces acting on a polystyrene sulfate latex particle as it is receding from a charged glass surface. Received 10 October 2002 Published online: 16 April 2003 RID="a" ID="a"Present address: Department of Polymer Physics, BASF Aktiengesellschaft, 67056 Ludwigshafen, Germany RID="b" ID="b"Present address: Arryx. Inc., Chicago, IL 60601, USA     

Test-Based Variable Selection via Cross-Validation

Abstract

Test-based variable selection algorithms in regression often are based on sequential comparison of test statistics to cutoff values. A predetermined a level typically is used to determine the cutoffs based on an assumed probability distribution for the test statistic. For example, backward elimination or forward stepwise involve comparisons of test statistics to prespecified t or F cutoffs in Gaussian linear regression, while a likelihood ratio. Wald, or score statistic, is typically used with standard normal or chi square cutoffs in nonlinear settings. Although such algorithms enjoy widespread use, their statistical properties are not well understood, either theoretically or empirically. Two inherent problems with these methods are that (1) as in classical hypothesis testing, the value of α is arbitrary, while (2) unlike hypothesis testing, there is no simple analog of type I error rate corresponding to application of the entire algorithm to a data set. In this article we propose a new method, backward elimination via cross-validation (BECV), for test-based variable selection in regression. It is implemented by first finding the empirical p value α*, which minimizes a cross-validation estimate of squared prediction error, then selecting the model by running backward elimination on the entire data set using α* as the nominal p value for each test. We present results of an extensive computer simulation to evaluate BECV and compare its performance to standard backward elimination and forward stepwise selection.     

Influence of nonconservative optical forces on the dynamics of optically trapped colloidal spheres: the fountain of probability

We demonstrate both experimentally and theoretically that a colloidal sphere trapped in a static optical tweezer does not come to equilibrium, but rather reaches a steady state in which its probability flux traces out a toroidal vortex. This nonequilibrium behavior can be ascribed to a subtle bias of thermal fluctuations by nonconservative optical forces. The circulating sphere therefore acts as a Brownian motor. We briefly discuss ramifications of this effect for studies in which optical tweezers have been treated as potential energy wells.     

Transfer measurements for the Ti+Ni systems at near barrier energies

Large enhancements have been observed in the sub-barrier fusion cross sections for Ti+Ni systems in our previous studies. Coupled channel calculations incorporating couplings to 2⁺ and 3⁻ states failed to explain these enhancements completely. A possibilty of transfer channels contributing to the residual enhancements had been suggested. In order to investigate the role of relevant transfer channels, measurements of one- and two-nucleon transfer were carried out for ^46,48Ti+⁶¹Ni systems. The present paper gives the results of these studies.