Molecular structures and conformational studies of triarylcyclopropyl and related nonsteroidal antiestrogens

Molecular structures and conformational characteristics of a series of 1,1-dichloro-2,2,3-triarylcyclopropanes (DTACs), which were reported previously to be distinctly antiestrogenic and inhibitors of the estrogen-receptor-positive MCF-7 human breast cancer cells in culture, are reported. In addition, structural and conformational features of the DTACs were compared to the first-known nonsteroidal antiestrogen, MER25, and the clinically useful antiestrogen Tamoxifen. The molecular structures of four DTAC compounds were determined by X-ray diffraction. Crystallographic structures show that the DTAC molecules have nearly the same relative conformation for the three aryl rings which is designated as a "nonpropeller" conformation in contrast to the observed "propeller" conformation for the three rings in all known triarylethylenes. Systematic conformational searches were performed to find the conformational preferences of DTACs, MER25, and Tamoxifen using idealized model compounds built from their respective crystal structure. Energy-minimization and conformational-search studies demonstrated that all DTAC molecules have a common, single global minimum energy conformer for their central core containing the dichlorotriarylcyclopropyl system, which is similar to that found in their crystal structures. Conformational search of MER25 showed that the molecule can assume a number of low-energy conformers of which two, one anti (A1) and one gauche (G1A), have about the same energy. The anti conformation is similar to the one observed in its crystal structure and resembles the estrogenic E-isomer of Tamoxifen, while the lowest energy gauche conformer of MER25 resembles more closely the antiestrogenic Z-isomer of Tamoxifen. NMR spectroscopic analysis of MER25 showed that the molecule exists predominantly in the anti conformation in solution. A comparative review of the structural features and bioactivities of Tamoxifen, DTACs, and MER25 provides a possible explanation for their low estrogen receptor binding affinity which is common to these compounds together with their antiestrogenic activity.     

The necessity of conducting to the end the activities of vector control in the onchocerciasis control program in west Africa: recall of the stakes and proposal of a minimum budget for the period 1998-2002

After a brief presentation of the Onchocerciasis Control Programme in West Africa (OCP), the authors realize the health and socioeconomic consequences that could follow a cessation of larvicide treatment before 2002 in the south-eastern and western extensions of the Programme. Taking into account that OCP activities are theoretically supported until 1997, but aware of financial constraints that will probably increase from now to 2002, this paper proposes an a minima estimation of the residual vector control activities for a "phasing out" spread out for five years (1998-2002). These estimations essentially concern the larvicide coverage, the insecticides used, the entomological surveillance, the logistical support and their financial aspects. As far as 48 U.S. $ million amount for 5 years are concerned, the budget allocated for vector control activities should not exceed the third of the global amount allocated to OCP for the actual fourth financial phase of the Programme (1992-1997).     

3D Motion recovery via affine Epipolar geometry

Algorithms to perform point-based motion estimation under orthographic and scaled orthographic projection abound in the literature. A key limitation of many existing algorithms is that they operate on the minimum amount of data required, often requiring the selection of a suitable minimal set from the available data to serve as a local coordinate frame. Such approaches are extremely sensitive to errors and noise in the minimal set, and forfeit the advantages of using the full data set. Furthermore, attention is seldom paid to the statistical performance of the algorithms.We present a new framework that allowsall available features to be used in the motion computations, without the need to select a frame explicitly. This theory is derived in the context of theaffine camera, which preserves parallelism and generalises the orthographic, scaled orthographic and para-perspective models. We define the affine epipolar geometry for two such cameras, giving the fundamental matrix in this case. The noise resistant computation of the epipolar geometry is discussed, and a statistical noise model constructed so that confidence in the results can be assessed.The rigid motion parameters are then determineddirectly from the epipolar geometry, using the novel rotation representation of Koenderink and van Doorn (1991). The two-view partial motion solution comprises the scale factor between views, the projection of the 3D axis of rotation and the cyclotorsion angle, while the addition of a third view allows the true 3D rotation axis to be computed (up to a Necker reversal). The computed uncertainties in these parameters permit optimal estimates to be obtained over time by means of a linear Kalman filter. Our theory extends work by Huang and Lee (1989), Harris (1990), and Koenderink and van Doorn (1991), and results are given on both simulated and real data.     

'98 Escherichia coli SWISS-2DPAGE database update

The combination of two-dimensional polyacrylamide gel electrophoresis (2-D PAGE), computer image analysis and several protein identification techniques allowed the Escherichia coli SWISS-2DPAGE database to be established. This is part of the ExPASy molecular biology server accessible through the WWW at the URL address http://www.expasy.ch/ch2d/ch2d-top.html . Here we report recent progress in the development of the E. coli SWISS-2DPAGE database. Proteins were separated with immobilized pH gradients in the first dimension and sodium dodecyl sulfate-polyacrylamide gel electrophoresis in the second dimension. To increase the resolution of the separation and thus the number of identified proteins, a variety of wide and narrow range immobilized pH gradients were used in the first dimension. Micropreparative gels were electroblotted onto polyvinylidene difluoride membranes and spots were visualized by amido black staining. Protein identification techniques such as amino acid composition analysis, gel comparison and microsequencing were used, as well as a recently described Edman "sequence tag" approach. Some of the above identification techniques were coupled with database searching tools. Currently 231 polypeptides are identified on the E. coli SWISS-2DPAGE map: 64 have been identified by N-terminal microsequencing, 39 by amino acid composition, and 82 by sequence tag. Of 153 proteins putatively identified by gel comparison, 65 have been confirmed. Many proteins have been identified using more than one technique. Faster progress in the E. coli proteome project will now be possible with advances in biochemical methodology and with the completion of the entire E. coli genome.     

Electrophysiological evidence for a postperceptual locus of suppression during the attentional blink

When an observer detects a target in a rapid stream of visual stimuli, there is a brief period of time during which the detection of subsequent targets is impaired. In this study, event-related potentials (ERPs) were recorded from normal adult observers to determine whether this "attentional blink" reflects a suppression of perceptual processes or an impairment in postperceptual processes. No suppression was observed during the attentional blink interval for ERP components corresponding to sensory processing (the P1 and N1 components) or semantic analysis (the N400 component). However, complete suppression was observed for an ERP component that has been hypothesized to reflect the updating of working memory (the P3 component). Results indicate that the attentional blink reflects an impairment in a postperceptual stage of processing.     

Longitudinal assessment of inpatient use and functioning of seriously mentally ill veterans with and without co-occurring substance use disorders

Within a fungal species, a subset of individuals may have more than the minimal complement of chromosomes. If the extra chromosomes are composed primarily of DNA not found in all representatives of the species, they are most appropriately referred to as supernumerary chromosomes. The patterns of repeated DNA sequences on certain supernumerary chromosomes suggest that they have a different evolutionary history from the essential chromosomes in the same genome. Supernumerary chromosomes can carry functional genes and, in at least two fungal species, genes on such chromosomes play important roles in host-pathogen interactions. Supernumerary chromosomes that confer an adaptive advantage in certain habitats, such as the ability to cause disease on a specific host, may be referred to as "conditionally dispensable" chromosomes in order to reflect their importance in some, but not all, growth conditions. In addition to describing the structural and functional characteristics of known supernumerary chromosomes in fungi, this review discusses the relative merits of the terms that have been used to describe them, and establishes experimental criteria for their identification.     

Colin Allen and Marc Bekoff,Species of Mind: The Philosophy and Biology of Cognitive Ethology

Minds and Machines -     

Goal Change in the Situation Calculus

Although there has been much discussion of belief change (e.g.[4, 21]), goal change has not received much attention. In thispaper, we propose a method for goal change in the frameworkof Reiter's; [12] theory of action in the situation calculus[8, 10], and investigate its properties. We extend the frameworkdeveloped by Shapiro et al. [17] and Shapiro and Lespérance[16], where goals and goal expansion were modelled, but goalcontraction was not.     

The prediction of the wild-type telomerase RNA pseudoknot structure and the pivotal role of the bulge in its formation

In this study, the three-dimensional structure of the wild-type human telomerase RNA pseudoknot was predicted via molecular modeling. The wild-type pseudoknot structure is then compared to the recent NMR solution structure of the telomerase pseudoknot, which does not contain the U177 bulge. The removal of the bulge from the pseudoknot structure results in higher stability and significant reduction of activity of telomerase. We show that the effect of the bulge on the structure results in a significant transformation of the pseudoknot junction region where the starting base pairs are disrupted and unique triple base pairs are formed. We found that the formation of the junction region is greatly influenced by interactions of the U177 bulge with loop residues and rotation of residue A174. Moreover, this is the first study to our knowledge where a structure as complex as the pseudoknot has been solved by purely theoretical methods.