Circadian acclimatization of performance, sleep, and 6-sulfatoxymelatonin using multiple phase shifting stimuli.

Misalignment between the environment and one's circadian system is a common phenomenon (e.g., jet lag) which can have myriad negative effects on physical and mental health, mental and physiological performance, and sleep. Absent any intervention, the circadian system adjusts only 0.5-1.0 h per day to a shifted light-dark and sleep-wake schedule. Bright light facilitates circadian adjustment, but in field studies, bright light is only modestly better than no stimulus. Evidence indicates that exercise and melatonin can be combined with bright light to elicit larger shifts but no study has combined all of these stimuli or administered them at the times that are known to elicit the largest effects on the circadian system. The aims of this study are to compare the effects of different treatments on circadian adjustment to simulated jet lag in a laboratory. Following 2 weeks of home recording, 36 adults will spend 6.5 consecutive days in the laboratory. Following an 8 h period of baseline sleep recording on the participant's usual sleep schedule on Night 1 (e.g., 0000-0800 h), participants will undergo a 26 h circadian assessment protocol involving 2 h wake intervals in dim light and 1 h of sleep in darkness, repeated throughout the 26 h. During this protocol, all urine voidings will be collected; mood, sleepiness, psychomotor vigilance, and pain sensitivity will be assessed every 3 h, forehead temperature will be assessed every 90 min, and anaerobic performance (Wingate test) will be tested every 6 h. Following, the circadian assessment protocol, the participant's sleep-wake and light dark schedule will be delayed by 8 h compared with baseline (e.g., 0800-1400 h), analogous to travelling 8 times zones westward. This shifted schedule will be maintained for 3 days. During the 3 days on the delayed schedule, participants will be randomized to one of 3 treatments: (1) Dim Red Light + Placebo Capsules, (2) Bright Light Alone, (3) Bright Light + Exercise + Melatonin. During the final 26 h, all conditions and measures of the baseline circadian protocol will be repeated. Acclimatization will be defined by shifts in circadian rhythms of aMT6s, psychomotor vigilance, Wingate Anaerobic performance, mood, and sleepiness, and less impairments in these measures during the shifted schedule compared with baseline. We posit that Bright Light Alone and Bright Light + Exercise + Melatonin will elicit greater shifts in circadian rhythms and less impairments in sleep, mood, performance, and sleepiness compared with Dim Red Light + Placebo Capsules. We also posit that Bright Light + Exercise + Melatonin will elicit greater shifts and less impairments than Bright Light Alone.

In vitro suppression of inflammatory cytokine response by methionine sulfoximine.

BACKGROUND: The glutamine synthetase inhibitor methionine sulfoximine (MSO), shown previously to prevent death caused by an inflammatory liver response in mice, was tested on in vitro production of cytokines by mouse peritoneal macrophages triggered with lipopolysaccharide (LPS). RESULTS: MSO significantly reduced the production of Interleukin 6 (IL-6) and Tumor Necrosis Factor Alpha (TNFα) at 4 and 6 h after LPS-treatment. This reduction did not result from decreased transcription of IL-6 and TNFα genes, and therefore appeared to result from post-transcriptional inhibition of synthesis of these cytokines. MSO treatment did not inhibit total protein synthesis and did not reduce the production of a third LPS-triggered cytokine CXCL1, so the effect was not a toxic or global downregulation of the LPS response. The anti-inflammatory effects of a glutamine synthetase inhibitor were seen even though the medium contained abundant (2 mM) glutamine, suggesting that the target for this activity was not glutamine synthetase. In agreement with this hypothesis, the L,R isomer of MSO, which does not inhibit glutamine synthetase and was previously thought to be inert, both significantly reduced IL-6 secretion in isolated macrophages and increased survival in a mouse model for inflammatory liver failure. CONCLUSIONS: Our findings provide evidence for a novel target of MSO. Future attempts to identify the additional target would therefore also provide a target for therapies to treat diseases involving damaging cytokine responses.

Therapeutic effects of methionine sulfoximine in multiple diseases include and extend beyond inhibition of glutamine synthetase.

INTRODUCTION: Methionine sulfoximine (MSO), a well-characterized inhibitor of glutamine synthetase, displays significant therapeutic benefits in animal models for several human diseases. This amino acid might therefore be a viable candidate for drug development to treat diseases for which there are few effective therapies. Areas covered: We describe the effects of MSO on brain swelling occurring in overt hepatic encephalopathy resulting from liver failure, the effects of MSO on excitotoxic damage involved in amyotrophic lateral sclerosis (ALS) or resulting from stroke, and the effects of MSO on a model for an inflammatory immune response involved in a range of diseases. We conclude that these results imply the existence of another therapeutic target for MSO in addition to glutamine synthetase. Expert opinion: We summarize the various diseases for which MSO treatment might be a candidate for drug development. We discuss why MSO has limited enthusiasm in the scientific and medical communities for use in humans, with a rebuttal to those negative opinions. And we conclude that MSO should be considered a candidate drug to treat brain swelling involved in overt hepatic encephalopathy and diseases involving an inflammatory immune response.

Acute Atrazine Exposure has Lasting Effects on Chemosensory Responses to Food Odors in Crayfish (Orconectes virilis).

The herbicide atrazine is known to impact negatively olfactory-mediated behaviors in aquatic animals. We have shown that atrazine exposure has deleterious effects on olfactory-mediated behavioral responses to food odors in crayfish; however, recovery of chemosensory abilities post-atrazine exposure has not been investigated. We examined whether crayfish (Orconectes virilis) recovered chemosensory abilities after a 96-h exposure to sublethal, environmentally relevant concentrations of 80 ppb (µg/L) atrazine. Following treatment, we analyzed the ability of the crayfish to locate a food source using a Y-maze with one arm containing fish-flavored gelatin and the other containing unflavored gelatin. We compared the time spent in the food arm of the Y-maze, near the food source, as well as moving and walking speed of control and atrazine-treated crayfish. We also compared the number of crayfish that handled the food source and the amount of food consumed. Following 24-, 48-, and 72-h recovery periods in fresh water, behavioral trials were repeated to determine if there was any observable recovery of chemosensory-mediated behaviors. Atrazine-treated crayfish spent less time in the food arm, at the odor source, and were less successful at finding the food odor source than control crayfish for all times tested. Additionally, atrazine-treated crayfish consumed less fish-flavored than control crayfish; however, treatment did not affect locomotion. Overall, we found that crayfish are not able to recover chemosensory abilities 72 h post-atrazine exposure. Because crayfish rely heavily on their chemosensory abilities to acquire food, the negative impacts of atrazine exposure could affect population size in areas where atrazine is heavily applied.

Atrazine exposure affects the ability of crayfish (Orconectes rusticus) to localize a food odor source.

Environmental pollutants, found in aquatic ecosystems, have been shown to have an effect on olfactory-mediated behaviors including feeding, mate attraction, and other important social behaviors. Crayfish are polytrophic, meaning that they feed on and become prey for all levels of the aquatic food web as well as are also important for the transfer of energy between benthic and terrestrial food webs. Because crayfish are a keystone species, it is important to investigate any factors that may affect their population size. Crayfish are active at night and rely heavily on their sensory appendages (e.g., antennulues, maxillipeds, and pereopods) to localize food sources. In this experiment, we investigated the effects of atrazine (ATR) exposure on the chemosensory responses of male and female crayfish to food odors. We exposed crayfish to environmentally relevant, sublethal levels of ATR [80 ppb (µg/L)] for 72 h and then examined the behavioral responses of both ATR-treated and control crayfish to food odor delivered from one end of a test arena. We used Noldus Ethovision XT software to measure odor localization and locomotory behaviors of crayfish in response to food (fish) odor. We found that control crayfish spent more time in the proximal region of the test arena and at the odor source compared with ATR-treated crayfish. Furthermore, there were no differences in the time spent moving and not moving, total distance travelled in the tank, and walking speed (cm/s) when control and ATR-treated crayfish were compared. Overall, this indicates that acute ATR exposure alters chemosensory abilities of crayfish, whereas overall motor function remains unchanged.