Protein phosphorylation and signal transduction modulation: chemistry perspectives for small-molecule drug discovery.

Protein phosphorylation has been exploited by Nature in profound ways to control various aspects of cell proliferation, differentiation, metabolism, survival, motility and gene transcription. Cellular signal transduction pathways involve protein kinases, protein phosphatases, and phosphoprotein-interacting domain (e.g., SH2, PTB, WW, FHA, 14-3-3) containing cellular proteins to provide multidimensional, dynamic and reversible regulation of many biological activities. Knowledge of cellular signal transduction pathways has led to the identification of promising therapeutic targets amongst these superfamilies of enzymes and adapter proteins which have been linked to various cancers as well as inflammatory, immune, metabolic and bone diseases. This review focuses on protein kinase, protein phosphatase and phosphoprotein-interacting cellular protein therapeutic targets with an emphasis on small-molecule drug discovery from a chemistry perspective. Noteworthy studies related to molecular genetics, signal transduction pathways, structural biology, and drug design for several of these therapeutic targets are highlighted. Some exemplary proof-of-concept lead compounds, clinical candidates and/or breakthrough medicines are further detailed to illustrate achievements as well as challenges in the generation, optimization and development of small-molecule inhibitors of protein kinases, protein phosphatases or phosphoprotein-interacting domain containing cellular proteins.

Semiquantitative determination of off-notes in mint oils by solid-phase microextraction.

Mint essential oils are produced by the steam distillation of dried or partially dried harvested plant material. In the United States, harvesting is done mechanically so that any weeds found in the field are concomitantly harvested. Steam distillation of contaminated plant material leads to off-notes in the oil, which are currently determined by a sensory panel. Furthermore, nonoptimized distillation conditions can lead to the thermal degradation of carbohydrates and proteins resulting also in the formation of very volatile off top-notes. As a result, the use of a nonequilibrated solid-phase microextraction (SPME) procedure to determine the off-notes is evaluated. The results of this evaluation include a combination of semiquantitative data, odor threshold data, and mathematical data manipulation to ascertain the capabilities of a SPME approach. The results are correlated with sensory panel data to yield a relatively rapid analytical methodology that can be used either in place of or in support of sensory analyses. The main advantage of the technique described is to provide some semiquantitative data in support of the odor-panel screening of mint oils for off-notes. Based on the data presented in this report, it is believed that this has been successfully demonstrated.

The effects of eye and limb movements on working memory.

Three experiments examined the role of eye and limb movements in the maintenance of information in spatial working memory. In Experiment 1, reflexive saccades interfered with memory span for spatial locations but did not interfere with memory span for letters. In Experiment 2, three different types of eye movements (reflexive saccades, pro-saccades, and anti-saccades) interfered with working memory to the same extent. In all three cases, spatial working memory was much more affected than verbal working memory. The results of these two experiments suggest that eye movements interfere with spatial working memory primarily by disrupting processes localised in the visuospatial sketchpad. In Experiment 3, limb movements performed while maintaining fixation produced as much interference with spatial working memory as reflexive saccades. These results suggest that the interference produced by eye movements is not the result of their visual consequences. Rather, all spatially directed movements appear to have similar effects on visuospatial working memory.

Continuous assessment of back stress (CABS): a new method to quantify low-back stress in jobs with variable biomechanical demands.

Jobs with a high degree of variability in manual materials handling requirements expose limitations in current low-back injury risk assessment tools and emphasize the need for a probabilistic representation of the biomechanical stress in order to quantify both acute and cumulative trauma risk. We developed a hybrid assessment methodology that employs established assessment tools and then represents their evaluations in a way that emphasizes the distributions of biomechanical stress. Construction work activities in the home building industry were evaluated because of the high degree of variability in the manual material handling requirements. Each task was evaluated using the Revised NIOSH Lifting Equation, The University of Michigan Three-Dimensional Static Strength Prediction Program, and the Ohio State University Lumbar Motion Monitor Model. The output from each model was presented as time-weighted histograms of low-back stress, and the assessments were compared. The results showed considerable differences in what were considered high-risk activities, indicating that these 3 assessment tools consider the risk of low-back injury from different perspectives. The time-weighted distribution aspect of this methodology also contributed vital information toward the identification of high-risk activities. These results illustrate the necessity for more advanced low-back injury risk assessment techniques for jobs with highly variable manual materials handling requirements.

User assessment of manual wheelchair ride comfort and ergonomics.

OBJECTIVE: To examine wheelchair-user perceived ride comfort during propulsion and to compare the ride comfort of ultralight and lightweight manual wheelchairs. An ultralight wheelchair is defined as having a high degree of adjustability, whereas a lightweight wheelchair has minimal adjustability. DESIGN AND PARTICIPANTS: Repeated measures design of a sample of 30 community-dwelling manual wheelchair users evaluating 7 different manual wheelchairs over an activities of daily living course. SETTING: A rehabilitation engineering center. MAIN OUTCOME MEASURES: Subject ratings of perceived ride comfort and basic ergonomics while propelling over the activities of daily living course. Ratings were recorded for each wheelchair on individual tasks and for the course overall. RESULTS: The Invacare Action XT wheelchair was ranked best for both ride comfort and basic ergonomics. The ride-comfort scores (p < .05) and wheelchair ergonomics ratings (p < .05) for the ultralight wheelchair group were significantly different from those for lightweight wheelchair group. CONCLUSION: There are differences in perceived ride comfort and basic ergonomics between the designs of the wheelchairs (lightweight vs ultralight). Subjects perceived that ultralight wheelchairs were more comfortable and had better basic ergonomics than lightweight wheelchairs.

Examination of the enantiomeric distribution of certain monoterpene hydrocarbons in selected essential oils by automated solid-phase microextraction-chiral gas chromatography-mass selective detection.

A viable approach for the determination of sources of essential oils based on automatic injection solid-phase microextraction-chiral-gas chromatography-mass selective detection is demonstrated. With no sample preparation, it is shown that the source of essential oils such as peppermint, spearmint, and rosemary can be easily distinguished. Short fiber exposure times of approximately 6 s to the headspace above submicroliter quantities of the selected oils are all that is required to obtain both the required sensitivity and resolution to afford analyses with excellent reproducibilities (relative standard deviation values consistently less than 5.0%).

Glenohumeral joint kinematics and kinetics for three coordinate system representations during wheelchair propulsion.

The shoulder plays a very important role during manual wheelchair propulsion. Unfortunately, substantial numbers of manual wheelchair users eventually develop shoulder injury or pain. Recently, studies have begun to investigate the etiology of wheelchair user shoulder injuries. This study compared three coordinate systems used to represent the shoulder during wheelchair propulsion. Our results show statistically significant differences between the three shoulder representations analyzed. Differences are seen for individuals and for the subjects as a group. Based upon our results, the fixed-z model appears preferable over the other representations due to its simplicity, low hardware requirements, and the similarity of the results to the free representation. This article also provides some insight into maximal shoulder joint forces and moments recorded during manual wheelchair propulsion. Future work should include more sophisticated models of the shoulder complex.

Fatigue-life of two manual wheelchair cross-brace designs.

OBJECTIVE: To compare the durability of two designs of cross-braces for folding manual wheelchairs and to determine the nature of wheelchair cross-brace failures. DESIGN: Fatigue testing of two folding wheelchair cross-brace designs (one with a rectangular cross-section and the other with a circular cross-section). A total of 20 cross-brace pairs were tested. RESULTS: The cross-braces with a circular cross-section endured a mean +/- SD of 100,159 +/- 45,814 cycles before experiencing a fatigue failure, whereas the cross-braces with a rectangular cross-section endured an average of 261,254 +/- 160,741 cycles. A t test showed significant differences (p = .01) in fatigue-life between cross-braces with a circular cross-section versus cross-braces with a rectangular cross-section. All 20 cross-braces experienced similar fatigue failures that would develop at the bolt hole where the two cross-braces connect to form a hinge. CONCLUSION: The results suggest that the rectangular cross-brace design has a longer fatigue-life than the circular cross-brace design. People should regularly inspect the cross-brace for cracks. The area around the bolt forming the hinge should be inspected carefully. If a crack is observed, the cross-brace should be replaced immediately.