Aspartate semialdehyde dehydrogenase inhibition suppresses the growth of the pathogenic fungus Candida albicans.

Potent inhibitors of an essential microbial enzyme have been shown to be effective growth inhibitors of Candida albicans, a pathogenic fungus. C. albicans is the main cause of oropharyngeal candidiasis, and also causes invasive fungal infections, including systemic sepsis, leading to serious complications in immunocompromised patients. As the rates of drug-resistant fungal infections continue to rise novel antifungal treatments are desperately needed. The enzyme aspartate semialdehyde dehydrogenase (ASADH) is critical for the functioning of the aspartate biosynthetic pathway in microbes and plants. Because the aspartate pathway is absent in humans, ASADH has the potential to be a promising new target for antifungal research. Deleting the asd gene encoding for ASADH significantly decreases the survival of C. albicans, establishing this enzyme as essential for this organism. Previously developed ASADH inhibitors were tested against several strains of C. albicans to measure their possible therapeutic impact. The more potent inhibitors show a good correlation between enzyme inhibitor potency and fungal growth inhibition. Growth curves generated by incubating different C. albicans strains with varying enzyme inhibitor levels show significant slowing of fungal growth by these inhibitors against each of these strains, similar to the effect observed with a clinical antifungal drug. The most effective inhibitors also demonstrated relatively low cytotoxicity against a human epithelial cell line. Taken together, these results establish that the ASADH enzyme is a promising new target for further development as a novel antifungal treatment against C. albicans and related fungal species.

IL-17 Receptor Signaling in Oral Epithelial Cells Is Critical for Protection against Oropharyngeal Candidiasis.

Signaling through the IL-17 receptor (IL-17R) is required to prevent oropharyngeal candidiasis (OPC) in mice and humans. However, the IL-17-responsive cell type(s) that mediate protection are unknown. Using radiation chimeras, we were able to rule out a requirement for IL-17RA in the hematopoietic compartment. We saw remarkable concordance of IL-17-controlled gene expression in C. albicans-infected human oral epithelial cells (OECs) and in tongue tissue from mice with OPC. To interrogate the role of the IL-17R in OECs, we generated mice with conditional deletion of IL-17RA in superficial oral and esophageal epithelial cells (Il17raΔK13). Following oral Candida infection, Il17raΔK13 mice exhibited fungal loads and weight loss indistinguishable from Il17ra-/- mice. Susceptibility in Il17raΔK13 mice correlated with expression of the antimicrobial peptide ß-defensin 3 (BD3, Defb3). Consistently, Defb3-/- mice were susceptible to OPC. Thus, OECs dominantly control IL-17R-dependent responses to OPC through regulation of BD3 expression.

Relationships between ground reaction force impulse and kinematics of sprint-running acceleration.

The literature contains some hypotheses regarding the most favorable ground reaction force (GRF) for sprint running and how it might be achieved. This study tested the relevance of these hypotheses to the acceleration phase of a sprint, using GRF impulse as the GRF variable of interest. Thirty-six athletes performed maximal-effort sprints from which video and GRF data were collected at the 16-m mark. Associations between GRF impulse (expressed relative to body mass) and various kinematic measures were explored with simple and multiple linear regressions and paired t-tests. The regression results showed that relative propulsive impulse accounted for 57% of variance in sprint velocity. Relative braking impulse accounted for only 7% of variance in sprint velocity. In addition, the faster athletes tended to produce only moderate magnitudes of relative vertical impulse. Paired t-tests revealed that lower magnitudes of relative braking impulse were associated with a smaller touchdown distance (p < 0.01) and a more active touchdown (p < 0.001). Also, greater magnitudes of relative propulsive impulse were associated with a high mean hip extension velocity of the stance limb (p < 0.05). In conclusion, it is likely that high magnitudes of propulsion are required to achieve high acceleration. Although there was a weak trend for faster athletes to produce lower magnitudes of braking, the possibility of braking having some advantages could not be ruled out. Further research is required to see if braking, propulsive, and vertical impulses can be modified with specific training. This will also provide insight into how a change in one GRF component might affect the others.

Segment-interaction analysis of the stance limb in sprint running.

A high angular velocity of the thigh of the stance limb, generated by hip extensor musculature, is commonly thought to be a performance-determining factor in sprint running. However, the thigh segment is a component of a linked system (i.e., the lower limb), therefore, it is unlikely that the kinematics of the thigh will be due exclusively to the resultant joint moment (RJM) at the hip. The purpose of this study was to quantify, by means of segment-interaction analysis, the determinants of sagittal plane kinematics of the lower limb segments during the stance phase of sprint running. Video and ground reaction force data were collected from four male athletes performing maximal-effort sprints. The analysis revealed that during the first-third of the stance phase, a hip extension moment was the major determinant of the increasing angular velocity of the thigh. However, during the mid-third of stance, hip and knee extension moments and segment interaction effects all contributed to the thigh attaining its peak angular velocity. Extension moments at the ankle, and to a lesser extent the knee, were attributed with preventing the 'collapse' of the shank under the effects of the interactive moment due to ground reaction force. The angular acceleration of the foot was determined almost completely by the RJM at the ankle and the interactive moment due to ground reaction force. Further research is required to determine if similar results exit for a wide range of athletes and for other stages of a sprint race (e.g. early acceleration, maximal velocity, and deceleration phases).

Reliability of biomechanical variables of sprint running.

PURPOSE: The purpose of this paper was to report the reliability of variables used in the biomechanical assessment of sprint running and to document how these reliability measures are likely to improve when using the average score of multiple trials. METHODS: Twenty-eight male athletes performed maximal-effort sprints. Video and ground reaction force data were collected at the 16-m mark. The reliability (systematic bias, random error, and retest correlation) for a single score was calculated for 26 kinematic and 7 kinetic variables. In addition, the reliability (random error and retest correlation) for the average score of 2, 3, 4, and 5 trials was predicted from the reliability of a single score. RESULTS: For all variables, there was no evidence of systematic bias. The measures of random error and retest correlation differed widely among the variables. Variables describing horizontal velocity of the body's center of mass were the most reliable, whereas variables based on vertical displacement of the body's center of mass or braking ground reaction force were the least reliable. For all variables, reliability improved notably when the average score of multiple trials was the measurement of interest. CONCLUSION: Although it is up to the researcher to judge whether a measurement is reliable enough for its intended use, some of the lower-reliability variables were possibly too unreliable to monitor small changes in an athlete's performance. Nonetheless, there was a consistent trend for reliability to improve notably when the average score of multiple trials was the measurement of interest. Subsequently, if resources permit, researchers and applied sports-scientists may like to consider using the average score of multiple trials to gain the advantages that improved reliability offers.

Interaction of step length and step rate during sprint running.

UNLABELLED: A "negative interaction" between step length and step rate refers to an increase in one factor resulting in a decrease in the other. PURPOSES: There were three main purposes: a) to investigate the relative influence of the determinants of step length and step rate, b) to determine the sources of negative interaction between step length and step rate, and c) to investigate the effects of manipulation of this interaction. METHODS: Thirty-six athletes performed maximal-effort sprints. Video and ground reaction force data were collected at the 16-m mark. Sprint velocity, step length, step rate, and their underlying determinants were calculated. Analyses included correlations, multiple linear regressions, paired t-tests, and a simple simulation based on alterations in flight determining parameters. RESULTS: A wide range of step length and step rate combinations was evident, even for subgroups of athletes with similar sprint velocities. This was partly due to a negative interaction that existed between step length and step rate; that is, those athletes who used a longer step length tended to have a lower step rate and vice versa. Vertical velocity of takeoff was the most prominent source of the negative interaction. CONCLUSIONS: Leg length, height of takeoff, and vertical velocity of takeoff are all possible sources of a negative interaction between step length and step rate. The very high step lengths and step rates achieved by elite sprinters may be possible only by a technique that involves a high horizontal and low vertical velocity of takeoff. However, a greater vertical velocity of takeoff might be of advantage when an athlete is fatigued and struggling to maintain a high step rate.

Effects of power and flexibility training on vertical jump technique.

PURPOSE: The purpose of this study was to assess the effects of power and flexibility training on countermovement and drop jump techniques. METHOD: All jumps were executed with the goal of attaining maximum height and no restrictions were placed on the magnitude of countermovement or ground contact time. Subjects underwent initial testing followed by random allocation to one of four groups: power training to increase vertical jump height (P), stretching to increase flexibility (S), a combination of power and stretch training (PS), and a control group (C). Training lasted for 10 wk, followed by retesting. Jump height was calculated in addition to the following technique variables: eccentric lower-limb stiffness produced during the countermovement phase, magnitude of countermovement, and in the case of the drop jumps, ground contact time. RESULTS: Groups PS, P, and S all increased countermovement jump (CMJ) height, but only groups PS and P increased drop jump height (DJ30, DJ60, and DJ90 for drop jumps performed from 30-, 60-, and 90-cm drop heights). The technique changes associated with power training were increases in magnitude of countermovement (CMJ, DJ30, DJ60, and DJ90) and increases in ground contact time (DJ30 and DJ60). In addition, the eccentric lower-limb stiffness produced during the countermovement phase of the jumps increased for CMJ and decreased for DJ30, DJ60, and DJ90. Stretching appeared to have no significant effect on CMJ or drop jump technique. CONCLUSION: The results of this study show that when the training goal is maximum jump height alone, it is likely that drop jump technique will change in the direction of a lower eccentric leg stiffness, greater depth of countermovement, and a longer ground contact time, whereas for a countermovement jump eccentric leg stiffness and the depth of countermovement will both increase. It is proposed that these technique changes are a result of attempting to optimize a complex combination of factors involved in jumping (e.g., utilization of elastic energy, Golgi tendon organ inhibition, and contractile component contribution).