A general synthetic route to 4-substituted-2,2′-bithiophenes

A new synthetic route to 4-substituted-2,2′-bithiophenes has been developed utilizing 4-bromo-2,2′-bithiophene ( 1 ). Formation of the bithienyllithium adduct via halogen-metal exchange was found to be problematic and resulted in complex mixtures of products. The Grignard reagent of 1 can be obtained easily via the “entrainment” method, allowing the production of 4-substituted-2,2′-bithiophenes (where sub-stituent = octyl, hydroxyethyl, hydroxymethyl, carboxy, carbomethoxy, acetoxyethyl, and acetoxymethyl).     

Anchor-based design of improved cholera toxin and E. coli heat-labile enterotoxin receptor binding antagonists that display multiple binding modes

The action of cholera toxin and E. coli heat-labile enterotoxin can be inhibited by blocking their binding to the cell-surface receptor GM1. We have used anchor-based design to create 15 receptor binding inhibitors that contain the previously characterized inhibitor MNPG as a substructure. In ELISA assays, all 15 compounds exhibited increased potency relative to MNPG. Binding affinities for two compounds, each containing a morpholine ring linked to MNPG via a hydrophobic tail, were characterized by pulsed ultrafiltration (PUF) and isothermal titration calorimetry (ITC). Crystal structures for these compounds bound to toxin B pentamer revealed a conserved binding mode for the MNPG moiety, with multiple binding modes adopted by the attached morpholine derivatives. The observed binding interactions can be exploited in the design of improved toxin binding inhibitors.     

A stochastic population projection system based on general age-dependent branching processes

"Algorithms for a stochastic population process, based on assumptions underlying general age-dependent branching processes in discrete time with time inhomogeneous laws of evolution, are developed through the use of a new representation of basic random functions involving birth cohorts and random sums of random variables. New algorithms provide a capability for computing the mean age structure of the process as well as variances and covariances, measuring variation about means. Four exploratory population projections, testing the implications of the algorithms for the case of time-homogeneous laws of evolution, are presented. Formulas extending mean and variance functions for unit population projections...are also presented. These formulas show that, in population processes with non-random laws of evolution, stochastic fluctuations about the mean function are negligible when initial population size is large. Further extensions of these formulas to the case of randomized laws of evolution suggest that stochastic fluctuations about the mean function can be significant even for large initial populations."     

Nonspanning bivalent ligands as improved surface receptor binding inhibitors of the cholera toxin B pentamer

A series of bivalent ligands of varying length were synthesized to inhibit the receptor-binding process of cholera toxin. Competitive surface receptor binding assays showed that significant potency gains relative to the constituent monovalent ligands were achieved independently from the ability of the extended bivalent ligands to span binding sites within the toxin pentamer. Several models that could account for the unexpected improvement in IC(50) values are examined, taking into account crystallographic analysis of each ligand in complex with the toxin pentamer. Evidence is presented that steric blocking at the receptor binding surface may play a role. The results of our study suggest that the use of relatively short, "nonspanning" bivalent ligands, or monovalent ligands of similar topology and bulk may be an effective way of blocking the interaction of multimeric proteins with their cell surface receptors.     

A PRAGMATIC MULTILEVEL APPROACH TO LARGE-SCALE RENEWABLE RESOURCE OPTIMIZATION: A TEST CASE

In recent years, public renewable resource management agencies have devoted substantial effort to local planning. This paper analyzes and evaluates a multilevel approach to utilizing these local planning analyses as an input in developing large–scale (national) resource management plans. This approach is evaluated in a test case with a two–level prototype model that is built from a global model that serves as a standard of comparison. The two–level prototype performs well at the highest level of analysis (involving aggregated variables) but is less reliable in terms of its implications for the lower level planning units.     

Computer-generated fMRI phantoms with motion-distortion interaction

As an extension of previous work on computer-generated phantoms, more accurate, realistic phantoms are generated by integrating image distortion and signal loss caused by susceptibility variations. With the addition of real motions and activations determined from actual functional MRI studies, these phantoms can be used by the fMRI community to assess with higher fidelity pre-processing algorithms such as motion correction, distortion correction and signal-loss compensation. These phantoms were validated by comparison to real echo-planar images. Specifically, studies have shown the effects of motion–distortion interactions on fMRI. We performed motion correction and activation analysis on these phantoms based on a block paradigm design using SPM2, and the results demonstrate that interactions between motion and distortion affect both motion correction and activation detection and thus represent a critical component of phantom generation.     

Evidence for the quantum birth of our universe

We present evidence for a nonsingular origin of the Universe with intial conditions determined by quantum physics and relativistic gravity. In particular, we establish that the present temperature of the microwave background and the present density of the Universe agree well with our predictions from these intial conditions, after evolution to the present age using the Einstein-Friedmann equation. Remarkably, the quantum origin for the Universe naturally allows its evolution at exactly the critical density. We also discuss the consequences of these results to some fundamental aspects of quantum physics in the early Universe.     

Use of chance-constrained programming to account for stochastic variation in theA-matrix of large-scale linear programs: A forestry application

Linear programming (LP) is widely used to select the manner in which forest lands are managed. Because of the nature of forestry, this application has several unique characteristics. For example, the models consider many different management actions that take place over many years, thus resulting in very large LP formulations with diverse data. In addition, almost none of the data are known with certainty. The most pervasive occurrence of stochastic information is in the production coefficients, which indicate the uncertain response of the managed forest ecosystem to various management options. A chance-constrained approach to handling this uncertainty would often be appropriate in forestry applications —managers and decision makers would like to specify a probability with which uncertain constraints are met. Unfortunately, chance-constrained procedures forA-matrix uncertainty produce nonlinear programming problems, which cannot currently be solved for large-scale forestry applications. This paper utilizes a Monte Carlo simulation approach (a linear program is repeatedly solved with randomly perturbedA-matrix coefficients) to describe the distribution of total output when the individual production coefficients are random. An iterative procedure for chance-constraining feasibility is developed and demonstrated with this sort of randomA-matrix. An iterative approach is required because the mean and variance of total output are unknown functions of the randomA-matrix coefficients and the level of output required. This approach may have applications in other fields as well.     

Solution- and solid-phase syntheses of guanidine-bridged, water-soluble linkers for multivalent ligand design

[reaction: see text] Efficient syntheses of guanidine-bridged poly(ethylene glycol) linkers of various lengths in fully protected form are reported for both solution- and solid-phase protocols. The application of such linkers in the construction of water-soluble and high-affinity multivalent ligands against cholera toxin is demonstrated. Synthetic intermediates for multivalent ligands as large as 20 kDa in molecular weight have been assembled using presynthesized linkers. The final ligands are highly water-soluble, thus enabling proper biophysical characterization.