Inhibition of glucocorticoid-induced apoptosis by targeting splice variants of \u3ci\u3eBIM\u3c/i\u3e mRNA with small interfering RNA and short hairpin RNA.

Glucocorticoids (GCs) induce apoptosis in lymphocytes and are effective agents for the treatment of leukemia. The activated glucocorticoid receptor (GR) initiates a transcriptional program leading to caspase activation and cell death, but the critical signaling intermediates in GC-induced apoptosis remain largely undefined. We have observed that GC induction of the three major protein products of the Bcl-2 relative Bim (BimEL, BimS and BimL) correlates with GC sensitivity in a panel of human pre-B acute lymphoblastic leukemia (ALL) cell lines. To test the hypothesis that Bim facilitates GC-induced apoptosis, we reduced BIM mRNA levels and Bim protein levels by RNA interference (RNAi) in highly GC-sensitive pre-B ALL cells. Reducing Bim proteins by either electroporation of synthetic siRNA duplexes or lentiviral-mediated stable expression of shRNA inhibited activation of caspase-3 and increased cell viability following GC exposure. We also observed that the extent of GC resistance correlated with siRNA silencing potency. siRNA duplexes that reduced only BimEL or BimEL and BimL (but not BimS) exhibited less GC resistance than a potent siRNA that silenced all three major isoforms, implying that induction of all three Bim proteins contributes to cell death. Finally, the modulation of GC-induced apoptosis caused by Bim silencing was independent of Bcl-2 expression levels, negating the hypothesis that the ratio of Bim to Bcl-2 regulates apoptosis. These results offer evidence that induction of Bim by GC is a required event for the complete apoptotic response in pre-B ALL cells

The Effects of Supplemental Fish Oil on Blood Pressure and Morning Cortisol in Normotensive Adults: A Pilot Study

Purpose: To determine the effects of 6wk of supplementation with fish oil (FO) on blood pressure and the morning salivary cortisol concentration in normotensive adults. Methods: Testing was performed following an overnight fast. Subjects (n=40; 35+/-13y, mean+/-SD) rested supine for 40 min, at which time blood pressure and heart rate were measured. Saliva was collected and analyzed for cortisol. Subjects were then randomly assigned to either: 4g/d of Safflower Oil (SO); pr 4g/d of FO supplying 1,600mg/d eicosapentaenoic acid and 800mg/d docosahexaenoic acid. Testing was repeated following 6wk treatment. Results: Compared to SO, there was a significant decrease in systolic blood pressure with FO (SO= 1.3+/-5.8 mmHg; FO= -6.8+/-10.2 mmHg; p=0.004), a significant reduction in pulse pressure with FO (SO= 0.2+/-7.8 mmHg; FO= -6.4+/-8.8 mmHg; p=0.02), and a tendency for a decrease in mean arterial pressure (SO= 1.2+/-5.3 mmHg; FO= -2.5+/-7.3 mmHg; p=0.08). There was a tendency for salivary cortisol to decrease with FO (SO= 0.005+/-0.129 µg/dL; FO= -0.068+/-0.148 µg/dL; p=0.072), however, this change was not significant;y correlated with the change in systolic blood pressure (r=0.021, p=0.929). Conclusion: 6wk of supplementation with FO significantly decreases systolic blood pressure in normotensive adults and this change was not significantly correlated with a reduction in salivary cortisol

The effects of an acute dose of Rhodiola rosea on exercise performance and cognitive function

Background: The purpose of this study was to determine the effects of an acute oral dose of 3 mg/kg of Rhodiola rosea (R. rosea) on endurance exercise performance, mood, and cognitive function. Methods: A total of 15 recreationally active college women (21.3 ± 0.09 y, 56.1 ± 6.3 kg; mean ± SD) participated in this study. 2–7 d after a familiarization trial subjects ingested in a double blind, random crossover manner, either R. rosea or a carbohydrate placebo 1 h prior to testing. Exercise testing consisted of a 10 minute warm-up, standardized to 80% of the average watts produced during the familiarization trial, followed by a 6 mile simulated indoor time trial on a Velotron electronic bicycle ergometer. Every 5 min during the time trial, subjects rated their level of perceived exertion using a BORG 10 pt scale. A blood sample was taken pre warm-up, 2 minutes post warm-up, and 2 minutes following completion of the time trial, and was analyzed for lactate concentration. Subjects also completed a Profile of Mood States (POMS) questionnaire and a Stroop\u27s color test pre-warm up and following the completion of the time trial. Subjects returned to the lab 2–7 d later to repeat the testing with the other condition. Results: A 3 mg/kg acute does of R. rosea resulted in a shorter time to completion of the 6 mile time trial course (R. rosea 1544.7 ± 155.2 s, Placebo 1569.5 ± 179.4 s; mean ± SD; p = 0.06) as well as a lower average heart rate during the standardized warm up (R. rosea 138.6 ± 13.3 bpm, Placebo 143.7 ± 12.4 bpm; mean ± SD; p = 0.001). There were no significant differences between treatment conditions for rating of perceived exertion during the time trial. Both treatments resulted in a significant increase in the POMS fatigue score following exercise (p = 0.001), as well as a significant improvement following exercise for the Stroop\u27s test of incongruent words (p = 0.001). No other significant differences between treatments were observed. Conclusion: Acute Rhodiola rosea ingestion decreases the heart rate response to sub-maximal exercise, and appears to improve endurance exercise performance

Supplemental fish oil decreases urinary excretion of a marker of bone resorption in healthy adults

Background: Incorporation of fish oil (FO) into the diet of rodents has been shown to result in positive changes in bone health. Currently it is poorly understood if FO has the same effects on bone health in humans. The purpose of this study was to determine the effects of supplemental FO on levels of urinary N-terminal cross-linked telopeptide (NTx), which is a marker of bone breakdown, and how this is related to the morning levels of salivary cortisol and urinary excretion of interleukin 6 (IL-6). Methods: A total of twenty-eight females and twelve males(35 ± 13yrs; 69.1 ± 14.1kg; 29.4 ± 9.2% body fat; mean ± SD) participated in this study. All testing was conducted in the morning following an overnight fast. Baseline measurements of salivary cortisol were collected via passive drool and baseline measurements of urinary NTxand IL- 6 were collected from the second void of the day and corrected for creatinine excretion. After baseline testing, subjects were assigned randomly in a double blind manner to one of two groups: 4 g/d of Safflower Oil (SO) or 4 g/d of FO supplying 1,600 mg/d eicosapentaenoic acid (EPA) and 800 mg/d docosahexaenoic acid (DHA). All tests were repeated following 6wk of treatment. A treatment by time, repeated measures ANOVA was used to evaluate differences between groups over time, and a standard Pearson’s r was used to evaluate correlations. Additionally, within group pre-post differences were evaluated using a repeated measures t-test. For all analysis, the alpha level was set at p\u3c0.05. Results: Compared to the SO group, there was a significant decrease in urinary creatinine corrected NTx excretion following FO treatment (SO = 17.5 ± 42.9 BCE/mM; FO = -11.3 ± 27.7 BCE/mM; p=0.02). There was also a tendency for urinary creatinine corrected IL-6 excretion (SO = -0.08 ± 1.18pg/mg; FO = -1.8 ± 3.8 pg/mg; p=0.08), and salivary cortisol (SO = 0.029±0.283 μg/dL; FO = -0.069 ± 0.144 μg/dL; p=0.13) to decrease following FO treatment.When analyzed independently, however, there was a significant pre-post reduction for salivary cortisol in the FO group (p=0.04), with no change in the SO group (p=0.68), as well as a significant reduction pre-post for urinary IL-6 in the FO group (p=0.05), with no change in the SO group (p=0.78). However, the change in urinary NTx concentrationwas not related to the change insalivary cortisol concentration( r=-0.017, p=0.9), or the change in urinary IL-6 concentration (r=-0.323, p=0.26). Conclusions: Six weeks of supplementation with FO in adults significantly decreased urinary NTx excretion, but this change was not related to changes in cortisol or IL-6

Evaluation of glucocorticoid sensitivity in 697 pre-B acute lymphoblastic leukemia cells after overexpression or silencing of MAP Kinase Phosphotase-1

PURPOSE: To determine the effect of reducing MAP kinase phosphatase-1 (MKP-1) levels on cell death induced by glucocorticoid (GC) or hydroxyurea (HU) treatment in the human pre-B acute lymphoblastic leukemia cell line 697. METHODS: Stable MKP-1 overexpressing transformants of the 697 pre-B ALL cell line were created and tested for sensitivity to the GC triamcinolone acetonide (TA) and HU, and compared to a control 697 cell line containing normal MKP-1 expression levels. Small interfering RNAs (siRNAs) were designed to inhibit MKP-1 expression and evaluated for their effect on GC-mediated cell death. RESULTS: MKP-1 overexpression caused a phenotype of partial resistance to HU-induced apoptosis but not to GC-induced apoptosis. Electroporation of siRNAs effectively silenced MKP-1 expression, and increased sensitivity to TA by 9.6±1.9%. CONCLUSIONS: Because MKP-1 protects certain tumor cells from chemotherapy-induced apoptosis, its inhibition is being considered as a possible strategy for combination cancer therapy. However, this study suggests that while MKP-1 inhibition may improve the efficacy of DNA damaging agents, it may have only limited utility in combination with glucocorticoids

Recovery from a cycling time trial is enhanced with carbohydrate-protein supplementation vs. isoenergetic carbohydrate supplementation

Background: In this study we assessed whether a liquid carbohydrate-protein (C+P) supplement (0.8 g/kg C; 0.4 g/kg P) ingested early during recovery from a cycling time trial could enhance a subsequent 60 min effort on the same day vs. an isoenergetic liquid carbohydrate (CHO) supplement (1.2 g/kg). Methods: Two hours after a standardized breakfast, 15 trained male cyclists completed a time trial in which they cycled as far as they could in 60 min (AMex) using a Computrainer indoor trainer. Following AMex, subjects ingested either C+P, or CHO at 10, 60 and 120 min, followed by a standardized meal at 4 h post exercise. At 6 h post AMex subjects repeated the time trial (PMex). Results: There was a significant reduction in performance for both groups in PMex versus AMex. However, performance and power decreases between PMex and AMex were significantly greater (p ≤ 0.05) with CHO (-1.05 ± 0.44 km and -16.50 ± 6.74 W) vs C+P (-0.30 ± 0.50 km and -3.86 ± 6.47 W). Fat oxidation estimated from RER values was significantly greater (p ≤ 0.05) in the C+P vs CHO during the PMex, despite a higher average workload in the C+P group. Conclusion: Under these experimental conditions, liquid C+P ingestion immediately after exercise increases fat oxidation, increases recovery, and improves subsequent same day, 60 min efforts relative to isoenergetic CHO ingestion

Is Congress\u27 Latest Effort to De-Juice Professional Sports Unconstitutional?

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The effect of caffeine ingestion on perception of muscle pain during a sustained submaximal isometric contraction of the quadriceps

Background: The purpose of this study was to determine the effects of an acute dose of 5 mg/kg of caffeine on perceived pain of the quadriceps during a sustained submaximal isometric contraction. Methods: A total of 15 low caffeine consuming college aged women (20.5 ± 1.4 y, 66.0 ± 9.0 kg; mean ± SD) participated in this study. 2–7 d after a familiarization trial subjects ingested, in a double blind random crossover manner, either 5 mg/kg caffeine (Caf) or a placebo (P), 1 h prior to performing a 2 min isometric leg extension at 45% of peak torque using visual cues to maintain force production. Every 15 s subjects rated their level of pain using the Borg CR10 pain scale. Subjects returned to the lab 2–7 d later to repeat the testing with the other condition. Data were analyzed using a repeated measures ANOVA with a Tukey\u27s HSD post hoc. Results: Caffeine ingestion resulted in a lower pain score at all time points during the 2 min isometric contraction. This difference approached significance at 90 s (Caf = 3.2 ± 1.4, P = 4.1 ± 1.4; p \u3c 0.10), and became significantly different at 105 s (Caf = 3.8 ± 1.2, P = 4.9 ± 1.5; p \u3c 0.05) and at 120 s (Caf = 4.4 ± 1.5, P = 5.4 ± 1.5; p \u3c 0.05). Conclusion: Acute caffeine ingestion attenuates perception of muscle pain in the quadriceps during a sustained submaximal isometric contraction. This effect become

Activity patterns, time use, and travel of millennials: a generation in transition?

Millennials, defined in this study as those born between 1979 and 2000, became the largest population segment in the United States in 2015. Compared to recent previous generations, they have been found to travel less, own fewer cars, have lower driver’s licensure rates, and use alternative modes more. But to what extent will these differences in behaviour persist as millennials move through various phases of the lifecycle? To address this question, this paper presents the results of a longitudinal analysis of the 2003--2013 American Time Use Survey data series. In early adulthood, younger millennials (born 1988--1994) are found to spend significantly more time in-home than older millennials (born 1979--1985), which indicates that there are substantial differences in activity-time use patterns across generations in early adulthood. Older millennials are, however, showing activity-time use patterns similar to their prior generation counterparts as they age, although some differences -- particularly in time spent as a car driver -- persist. Millennials appear to exhibit a lag in adopting the activity patterns of predecessor generations due to delayed lifecycle milestones (e.g. completing their education, getting jobs, marrying, and having children) and lingering effects of the economic recession, suggesting that travel demand will resume growth in the future

Tectonic controls on sediment provenance evolution in rift basins: Detrital zircon U–Pb and Hf isotope analysis from the Perth Basin, Western Australia

The role of tectonics in controlling temporal and spatial variations in sediment provenance during the evolution of extensional basins from initial rifting to continental breakup and passive margin development are not well established. We test the influence of tectonics in a rift basin that has experienced minimal uplift but significant extension throughout its history: the Perth Basin, Western Australia. We use published zircon U–Pb and Hf isotope data from basin inception through to continental drift and complement this with new data from samples deposited synchronously with the continental breakup of eastern Gondwana. Three primary source regions are inferred, namely the Archean Yilgarn Craton to the east, the Paleo- and Mesoproterozoic Albany–Fraser–Wilkes Orogen to the south and east, and the Mesoproterozoic and Ediacaran–Cambrian Pinjarra Orogen underlying the rift basin and comprising the dominant crustal components to the west and southwest. From mid-Paleozoic basin inception to Early Cretaceous breakup of eastern Gondwana, drainage in the Perth Basin was primarily north- to northwest-directed as evidenced by the dominant Mesoproterozoic detrital zircon cargo, paleodrainage patterns and paleocurrent directions. Thus, provenance was primarily parallel to the rift axis and perpendicular to the extension direction, particularly during periods of thermal subsidence. During episodes of mechanical extension, detrital zircon ages are polymodal and consistently dominated by Paleo- and Mesoproterozoic grains derived from the Albany–Fraser–Wilkes Orogen, but with significant Archean and Neoproterozoic inputs from the rift margins. It is inferred that during mechanical extension the rate of subsidence exceeded sediment supply, which generated basin-margin scarps and enhanced direct input from the rift shoulders. Detrital zircon spectra from temporally-equivalent samples at the rift margin and in the rift axis reveal that distinct sedimentary routing operated on the flanks. In summary, sediment provenance in the Perth Basin (and probably other rift basins) is tectonically controlled by: (1) extension direction, (2) episodes of mechanical extension (rift) or thermal subsidence (post-rift), and (3) proximity to rift axis or rift margin