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.     

Building brains for bodies

We describe a project to capitalize on newly available levels of computational resources in order to understand human cognition. We are building an integrated physical system including vision, sound input and output, and dextrous manipulation, all controlled by a continuously operating large scale parallel MIMD computer. The resulting system will learn to think by building on its bodily experiences to accomplish progressively more abstract tasks. Past experience suggests that in attempting to build such an integrated system we will have to fundamentally change the way artificial intelligence, cognitive science, linguistics, and philosophy think about the organization of intelligence. We expect to be able to better reconcile the theories that will be developed with current work in neuroscience.     

Detection and characterization of the electron paramagnetic resonance-silent glutathionyl-5,5-dimethyl-1-pyrroline N-oxide adduct derived from redox cycling of phenoxyl radicals in model systems and HL-60 cells

Rapidly growing knowledge about the nature and behaviour of breast cancer has led to many treatment modalities. Consequently, the possibilities of individualizing the treatment of breast cancer increase. The major tool for the determination of an optimal treatment plan is the estimation of the extent of the disease: in other words, staging. As a consequence, together with the expected result of the treatment, the stage of the disease gives information on the prognosis of the patient. Current staging systems insufficiently describe the clinically important features of breast cancer with respect to management and outcome: local and regional extent, invasiveness, aggressiveness, the state of dissemination, and the effectiveness of different treatment modalities. For staging of the local and regional extent, histology plays a prominent role and should be incorporated in future staging systems. Histological workup therefore needs standardisation. Histological parameters as tumour size, grade, nodal status, and vascular invasion are also the most important prognostic factors. Many so-called biological prognostic factors are related to the invasiveness and aggressiveness (metastatic potential) of the tumour, and therefore to the prognosis of the patient. However, these factors do not necessarily predict the effectiveness of certain systemic treatments. Only if the biological foundation of a prognostic factor is completely clarified can treatment be based on this knowledge, and the factor will become a predictor for the treatment effect. Many "biological" prognostic factors do not fulfil this main criterion and are therefore not useful for clinical decision making. A clinically useful staging system covers three primary aims: (1) to guide locoregional treatment, (2) to prognosticate the chance of survival, and (3) to indicate who needs what kind of adjuvant treatment. For the conception of a new staging system the following steps should be taken: standardization of all aspects of histology, identification of regional nodal involvement, and validation of prognostic factors with respect to their predictive value to treatment outcome.     

IT professional identity: needs,perceptions, and belonging

A theoretical model of professional identification is developed and empirically examined as a means to understanding information technology (IT) workers’ attachment to the IT profession. Professional identification represents oneness with or belonging to a profession and provides a unique means of investigating and evaluating the IT profession. Results from a survey of 305 IT workers indicate that professional identification is directly impacted by three factors: (1) the individual's need for professional identification; (2) the individual's perceived similarity to others in the IT profession; and (3) the individual's perceptions of the IT profession, signifying the importance of internalization to identification. Professional identification is also indirectly impacted by the public's perception of the IT profession.     

Interacting with team oriented plans in multi-robot systems

Team oriented plans have become a popular tool for operators to control teams of autonomous robots to pursue complex objectives in complex environments. Such plans allow an operator to specify high level directives and allow the team to autonomously determine how to implement such directives. However, the operators will often want to interrupt the activities of individual team members to deal with particular situations, such as a danger to a robot that the robot team cannot perceive. Previously, after such interrupts, the operator would usually need to restart the team plan to ensure its success. In this paper, we present an approach to encoding how interrupts can be smoothly handled within a team plan. Building on a team plan formalism that uses Colored Petri Nets, we describe a mechanism that allows a range of interrupts to be handled smoothly, allowing the team to efficiently continue with its task after the operator intervention. We validate the approach with an application of robotic watercraft and show improved overall efficiency. In particular, we consider a situation where several platforms should travel through a set of pre-specified locations, and we identify three specific cases that require the operator to interrupt the plan execution: (i) a boat must be pulled out; (ii) all boats should stop the plan and move to a pre-specified assembly position; (iii) a set of boats must synchronize to traverse a dangerous area one after the other. Our experiments show that the use of our interrupt mechanism decreases the time to complete the plan (up to 48 % reduction) and decreases the operator load (up to 80 % reduction in number of user actions). Moreover, we performed experiments with real robotic platforms to validate the applicability of our mechanism in the actual deployment of robotic watercraft.     

A biomechanical analysis of anterior load carriage

Front load carriage is a common occupational task in some industries (e.g. agriculture, construction), but, as compared to lifting tasks, relatively little research has been conducted on the biomechanical loading during these activities. The focus of this study was to explore the low back biomechanics during these activities and, specifically, to examine the effects of load height and walking speed on trunk muscle activity and trunk posture. Eleven male participants participated in two separate front load-carriage experiments. The first experiment called for carrying a barbell (with weight corresponding to 20% of elbow flexion strength) at three heights (knuckle height, elbow height and shoulder height) at a constant horizontal distance from the spine. The second experiment called for participants to carry a bucket of potatoes weighing 14 kg at the same three heights, but with no further restrictions in technique. In both experiments, the participants performed this task while either standing still or walking at a self-selected speed. As they performed these tasks, the activity levels of the right-side muscle of the rectus abdominis, external oblique, biceps brachii, anterior deltoid and three levels (T9, T12 and L3) of the erector spinae were sampled. Mid-sagittal plane trunk posture was also quantified using three magnetic field-based motion sensors at T9, T12 and L3. The results showed a significant effect of both walking speed and load height on trunk posture and trunk muscle activity levels in both the barbell and bucket experiments. In the barbell experiment, the walking trials generated 43% more trunk muscle activity than the standing trials. Trials at shoulder height produced 11% more muscle activity than trials at elbow height in the T9 erector spinae muscles and 71% more muscle activity in the anterior deltoid. In the bucket experiment, trunk muscle activity responded in a similar fashion, but the key result here was the quantification of the natural hyperextension posture of the spine used to balance the bucket of potatoes. These results provide insight into muscle activation patterns in dynamic settings, especially (load) carrying biomechanics, and have implications in industrial settings that require workers to carry loads in front of their bodies.     

The effect of leg fracture level and vehicle front-end geometry on pedestrian knee injury and response

In this study a MADYMO (mathematical dynamic modelling) model has been used to identify the influence of leg fracture on the injuries sustained by the pedestrian during front end impact with a vehicle. A factorial study of a MADYMO pedestrian and vehicle model are used to investigate the effect of different leg fracture tolerances, geometry, and vehicle compliance on the criteria measured in the European Enhanced Vehicle-safety Committee (EEVC) pedestrian safety tests. These criteria include knee bending, knee shear response, and lower leg bone (tibia) acceleration. The main study examines the spread of typical values of lower limb tolerance based on reported literature and contrasts the response of weaker, low-strength bones, normal tolerance, and limbs which do not fracture. Results show that knee bending angles and therefore ligament strains are significantly increased when fracture does not occur, and are decreased in bones exhibiting a low-strength response. Bone fracture tolerance is shown to be a significant parameter influencing knee bending. The parameters are compared to show that knee shear is significantly influenced by vehicle bumper compliance and that both criteria are heavily influenced by bumper height. Vehicles with more aggressive geometry, higher bumpers, and larger bumper lead were considered for comparative purposes.     

Image-based stained glass

We present a method of restyling an image so that it approximates the visual appearance of a work of stained glass. To this end, we develop a novel approach which involves image warping, segmentation, querying, and colorization along with texture synthesis. In our method, a given input image is first segmented. Each segment is subsequently transformed to match real segments of stained glass queried from a database of image exemplars. By using real sources of stained glass, our method produces high quality results in this nascent area of nonphotorealistic rendering. The generation of the stained glass requires only modest amounts of user interaction. This interaction is facilitated with a unique region-merging tool     

Frequency dependence of MR relaxation times. I. Paramagnetic ions

T1 and T2 of paramagnetic ions in free and chelated form were measured over the range of clinical magnetic resonance imaging field strengths (0.02-1.5 T). T1 values agreed with published data; however, to our knowledge, the field dependence of T2 has not been systematically studied before Mn2+, Cr3+, and Fe3+ all showed T2 reduction at high field strengths, although reduction due to Fe3+ was minimal. This is believed to be due to "contact" interactions, which have been previously noted for manganese. No such T2 reduction was seen in the chelates, except that dysprosium chelate (but not free ion) showed an anomalous decrease in T2 at high field strengths, which may possibly be explained by a dephasing effect caused by the large magnetic moment of Dy3+.