Combined Analysis of Phenotypic and Target-Based Screening in Assay Networks.

Small-molecule screens are an integral part of drug discovery. Public domain data in PubChem alone represent more than 158 million measurements, 1.2 million molecules, and 4300 assays. We conducted a global analysis of these data, building a network of assays and connecting the assays if they shared nonpromiscuous active molecules. This network spans both phenotypic and target-based screens, recapitulates known biology, and identifies new polypharmacology. Phenotypic screens are extremely important for drug discovery, contributing to the discovery of a large proportion of new drugs. Connections between phenotypic and biochemical, target-based screens can suggest strategies for repurposing both small-molecule and biologic drugs. For example, a screen for molecules that prevent cell death from a mutated version of superoxide-dismutase is linked with ALOX15. This connection suggests a therapeutic role for ALOX15 inhibitors in amyotrophic lateral sclerosis. An interactive version of the network is available online (http://swami.wustl.edu/flow/assay_network.html).

Relationship between physiological loss, performance decrement, and age in master athletes.

BACKGROUND: The use of master athletes to describe an idealized rate of physiological loss associated with aging is quite common. The results of such studies suggest that older athletes may be able to reduce the rate of decline in functional loss. The findings of such studies have been questioned due to their limited sample size and the age range and gender of their subjects. METHODS: We examined a group of 146 male and 82 female master athletes over the age of 40 years. Physiological parameters included maximal oxygen uptake (VO2max), body composition, muscle strength, bone density, and blood chemistries. Medical histories and training records were obtained via questionnaire. RESULTS: Results demonstrated gender differences in body composition, blood chemistries, blood pressure, VO2max, muscle strength, bone density, and performance (p <.05). All metabolic parameters for men and most for women demonstrated significant losses across the age range (p <.05). In addition, strength and performance for men and women and bone density for women declined significantly with age (p <.05). The demonstrated loss rates did not differ by gender. CONCLUSIONS: Although limited by the lack of a sedentary comparison group, these data suggest that age-related losses in VO2max may not be different from data previously reported for older sedentary adults and that loss in muscle strength and performance with aging is not linear.

Maximal aerobic power, lactate threshold, and running performance in master athletes.

PURPOSE: This study sought to determine how lactate threshold (LT) is related to running performance in older male and female runners, if LT changes significantly with age, and if gender alters the relationship between LT and performance in older runners. METHODS: Subjects were 168 master runners (111 men, 57 women) selected from a longitudinal study, who ran at least 10 miles x wk(-1) for 5 yr or more. VO2max was measured on a treadmill and body composition by hydrostatic weighing. Blood samples taken each minute of exercise were analyzed for lactate concentration and LT determined as the breakpoint in lactate accumulation. Performance times and training histories were self-reported by questionnaire. RESULTS: Men had significantly greater body mass, fat-free mass (FFM), and VO2max (L x min(-1); mL x kg(-1) x min(-1)) than women. FFM and VO2max (L x min(-1); mL x kg(-1) x min(-1)) declined with age in both men and women. Running performance was significantly different between men and women and declined with age in both. LT (L x min(-1); mL x kg(-1) x min(-1)) was significantly different between men and women, and declined significantly with age in men, whereas LT (%VO2max) did not differ between men and women and increased significantly with age in both. VO2max (mL x kg(-1) x min(-1)) was the most significant predictor of performance in both men and women, whereas LT (L x min(-1)) added to the prediction of 5-km and 10-km performance in women. CONCLUSION: The results of this study demonstrate that VO2max (mL x kg(-1) x min(-1)) is a better predictor of performance than LT in older male and female runners. Additionally, LT as a percentage of VO2max increases significantly with age.

The inability of hormone replacement therapy or chronic running to maintain bone mass in master athletes.

BACKGROUND: Previous studies have demonstrated equivocal findings on the effect of chronic running on bone mass in post-menopausal women. The purpose of this study was to determine the effect of chronic running alone and in conjunction with hormone replacement therapy (HRT) on bone mineral density (BMD) in postmenopausal women. METHODS: Forty-three women [15 premenopausal 48.1 +/- .4 yrs (Pre); 13 postmenopausal 57.3 +/- 2.3 yrs (Post); and 15 HRT-treated postmenopausal 56.8 +/- 1.5 yrs (PostE)] served as subjects. All were chronic runners (duration > 5 yrs, > 10 miles per week). BMD was determined by dual energy x-ray absorptiometry, VO2 max on a treadmill, body composition by hydrostatic weighing, knee strength by KinCom dynamometer, and training and menstrual history by questionnaire. Analysis of covariance with Tukey post hoc tests was utilized to compare the groups. RESULTS: The groups were similar in body weight, VO2 max, years training, and miles run per week. Pre and PostE did not differ in total or spine BMD. However, Pre had greater hip BMD than PostE (.973 +/- .03 vs .876 +/- .03 g/cm2; p < .05). As well, Pre had greater BMD of the hip (.973 +/- .03 vs .805 +/- .03 g/cm2; p < .05), spine (1.047 +/- .04 vs .870 +/- .04 g/cm2; p < .05), and total body (1.115 +/- .02 vs .996 +/- .03 g/cm2; p < .05) than Post. CONCLUSIONS: These results suggest that (a) chronic running + HRT is insufficient to protect hip BMD and (b) chronic running alone provides no protection for bone mass in postmenopausal women.

A comparison of cardiopulmonary adaptations to exercise in pregnancy at sea level and altitude.

OBJECTIVE: The purpose of this study was to compare maternal cardiopulmonary and fetal responses of lowlander pregnant women in the third trimester to exercise at sea level and at an altitude of 6000 feet. STUDY DESIGN: Seven women at 33.86 +/- 1 weeks' gestation performed a symptom-limited maximal exercise test and a submaximal cardiac output exercise test at sea level at an altitude of 6000 feet. Cardiopulmonary and metabolic variables were measured and compared at sea level and altitude. RESULTS: Maximal oxygen consumption and work levels were limited by short-term altitude exposure. Ventilatory variables were not significantly influenced by altitude exposure. During submaximal exercise no alteration in exercise efficiency or response was seen for most of the variables when altitude and sea level data were compared. Both cardiac output and stroke volume were elevated at altitude at rest but not during exercise, suggesting a lower reserve for both variables at altitude. Level of plasma glucose, lactate, norepinephrine, and epinephrine were not significantly influenced by altitude exposure. Fetal heart rate responses did not differ between the sea level and altitude conditions. CONDITIONS: Lowlander pregnant women in the third trimester have some limitations to maximal aerobic capacity but not submaximal exercise on short-term altitude exposure. No ominous fetal responses have been observed during this study. The results suggest that pregnant women may engage in at least brief moderate exercise bouts at moderate altitude without adverse consequences.

Exercise as a treatment modality to maintain normoglycemia in gestational diabetes.

Exercise can be a safe alternative to insulin therapy and may possibly eliminate the need for insulin in GDM. Exercise therapy should be explored as an additional means to maintain normoglycemia, preconceptionally as well as throughout pregnancy.