Serotonin is a common thread linking different classes of antidepressants.

Depression pathology remains elusive. The monoamine hypothesis has placed much focus on serotonin, but due to the variable clinical efficacy of monoamine reuptake inhibitors, the community is looking for alternative therapies such as ketamine (neurogenesis theory of antidepressant action). There is evidence that different classes of antidepressants may affect serotonin levels; a notion we test here. We measure hippocampal serotonin in mice with voltammetry and study the effects of acute challenges of escitalopram, fluoxetine, reboxetine, and ketamine. We find that pseudo-equivalent doses of these drugs similarly raise ambient serotonin levels, despite their differing pharmacodynamics because of differences in Uptake 1 and 2, rapid SERT trafficking, and modulation of serotonin by histamine. These antidepressants have different pharmacodynamics but have strikingly similar effects on extracellular serotonin. Our findings suggest that serotonin is a common thread that links clinically effective antidepressants, synergizing different theories of depression (synaptic plasticity, neurogenesis, and the monoamine hypothesis).

Smoothing spline assessment of the accuracy of enteric hydrogen and methane production measurements from dairy cattle using various sampling schemes.

Estimating daily enteric hydrogen (H2) and methane (CH4) emitted from dairy cattle using spot sampling techniques requires accurate sampling schemes. These sampling schemes determine the number of daily samplings and their intervals. This simulation study assessed the accuracy of daily H2 and CH4 emissions from dairy cattle using various sampling schemes for gas collection. Gas emission data were available from a crossover experiment with 28 cows fed twice daily at 80% to 95% of the ad libitum intake, and an experiment that used a repeated randomized block design with 16 cows twice daily fed ad libitum. Gases were sampled every 12 to 15 min for 3 consecutive days in climate respiration chambers. Feed was fed in 2 equal portions per day in both experiments. Per individual cow-period combination, generalized additive models were fitted to all diurnal H2 and CH4 emission profiles. Per profile, the models were fitted using the generalized cross-validation, REML, REML while assuming correlated residuals, and REML while assuming heteroscedastic residuals. The areas under the curve (AUC) of these 4 fits were numerically integrated over 24 h to compute the daily production and compared with the mean of all data points, which was considered the reference. Next, the best of the 4 fits was used to evaluate 9 different sampling schemes. This evaluation determined the average predicted values sampled at 0.5, 1, and 2 h intervals starting at 0 h from morning feeding, at 1 and 2 h intervals starting at 0.5 h from morning feeding, at 6 and 8 h intervals starting at 2 h from morning feeding, and at 2 unequally spaced intervals with 2 or 3 samples per day. Sampling every 0.5 h was needed to obtain daily H2 productions not different from the selected AUC for the restricted feeding experiment, whereas less frequent sampling had predictions varying from 47% to 233% of the AUC. For the ad libitum feeding experiment, sampling schemes had H2 productions from 85% to 155% of the corresponding AUC. For the restricted feeding experiment, daily CH4 production needed samplings every 2 h or shorter, or 1 h or shorter, depending on sampling time after feeding, whereas sampling scheme did not affect CH4 production for the twice daily ad libitum feeding experiment. In conclusion, sampling scheme had a major impact on predicted daily H2 production, particularly with restricted feeding, whereas daily CH4 production was less severely affected by sampling scheme.

Serotonin is a Common Thread Linking Different Classes of Antidepressants.

Depression pathology remains elusive. The monoamine hypothesis has placed much focus on serotonin, but due to the variable clinical efficacy of monoamine reuptake inhibitors, the community is looking for alternative therapies such as ketamine (synaptic plasticity and neurogenesis theory of antidepressant action). There is evidence that different classes of antidepressants may affect serotonin levels; a notion we test here. We measure hippocampal serotonin in mice with voltammetry and study the effects of acute challenges of antidepressants. We find that pseudo-equivalent doses of these drugs similarly raise ambient serotonin levels, despite their differing pharmacodynamics because of differences in Uptake 1 and 2, rapid SERT trafficking and modulation of serotonin by histamine. These antidepressants have different pharmacodynamics but have strikingly similar effects on extracellular serotonin. Our findings suggest that serotonin is a common thread that links clinically effective antidepressants, synergizing different theories of depression (synaptic plasticity, neurogenesis and the monoamine hypothesis).

Inhibited Methanogenesis in the Rumen of Cattle: Microbial Metabolism in Response to Supplemental 3-Nitrooxypropanol and Nitrate.

3-Nitrooxypropanol (3-NOP) supplementation to cattle diets mitigates enteric CH4 emissions and may also be economically beneficial at farm level. However, the wider rumen metabolic response to methanogenic inhibition by 3-NOP and the N O 2 - intermediary metabolite requires further exploration. Furthermore, N O 3 - supplementation potently decreases CH4 emissions from cattle. The reduction of N O 3 - utilizes H2 and yields N O 2 - , the latter of which may also inhibit rumen methanogens, although a different mode of action than for 3-NOP and its N O 2 - derivative was hypothesized. Our objective was to explore potential responses of the fermentative and methanogenic metabolism in the rumen to 3-NOP, N O 3 - and their metabolic derivatives using a dynamic mechanistic modeling approach. An extant mechanistic rumen fermentation model with state variables for carbohydrate substrates, bacteria and protozoa, gaseous and dissolved fermentation end products and methanogens was extended with a state variable of either 3-NOP or N O 3 - . Both new models were further extended with a N O 2 - state variable, with N O 2 - exerting methanogenic inhibition, although the modes of action of 3-NOP-derived and N O 3 - -derived N O 2 - are different. Feed composition and intake rate (twice daily feeding regime), and supplement inclusion were used as model inputs. Model parameters were estimated to experimental data collected from the literature. The extended 3-NOP and N O 3 - models both predicted a marked peak in H2 emission shortly after feeding, the magnitude of which increased with higher doses of supplement inclusion. The H2 emission rate appeared positively related to decreased acetate proportions and increased propionate and butyrate proportions. A decreased CH4 emission rate was associated with 3-NOP and N O 3 - supplementation. Omission of the N O 2 - state variable from the 3-NOP model did not change the overall dynamics of H2 and CH4 emission and other metabolites. However, omitting the N O 2 - state variable from the N O 3 - model did substantially change the dynamics of H2 and CH4 emissions indicated by a decrease in both H2 and CH4 emission after feeding. Simulations do not point to a strong relationship between methanogenic inhibition and the rate of N O 3 - and N O 2 - formation upon 3-NOP supplementation, whereas the metabolic response to N O 3 - supplementation may largely depend on methanogenic inhibition by N O 2 - .

Bayesian mechanistic modeling of thermodynamically controlled volatile fatty acid, hydrogen and methane production in the bovine rumen.

Dynamic modeling of mechanisms driving volatile fatty acid and hydrogen production in the rumen microbial ecosystem contributes to the heuristic prediction of CH4 emissions from dairy cattle into the environment. Existing mathematical rumen models, however, lack the representation of these mechanisms. A dynamic mechanistic model was developed that simulates the thermodynamic control of hydrogen partial pressure ( [Formula: see text] ) on volatile fatty acid (VFA) fermentation pathways via the NAD+ to NADH ratio in fermentative microbes, and methanogenesis in the bovine rumen. This model is unique and closely aligns with principles of reaction kinetics and thermodynamics. Model state variables represent ruminal carbohydrate substrates, bacteria and protozoa, methanogens, and gaseous and dissolved fermentation end products. The model was extended with static equations to model the hindgut metabolism. Feed composition and twice daily feeding were used as model inputs. Model parameters were estimated to experimental data using a Bayesian calibration procedure, after which the uncertainty of the parameter distribution on the model output was assessed. The model predicted a marked peak in [Formula: see text] after feeding that rapidly declined in time. This peak in [Formula: see text] caused a decrease in NAD+ to NADH ratio followed by an increased propionate molar proportion at the expense of acetate molar proportion, and an increase in CH4 production that steadily decreased in time, although the magnitude of increase for CH4 emission was less than for [Formula: see text] . A global sensitivity analysis indicated that parameters that determine the fractional passage rate and NADH oxidation rate altogether explained 86% of the variation in predicted daily CH4 emission. Model evaluation indicated over-prediction of in vivo CH4 emissions shortly after feeding, whereas under-prediction was indicated at later times. The present rumen fermentation modeling effort uniquely provides the integration of the [Formula: see text] controlled NAD+ to NADH ratio for dynamically predicting metabolic pathways that yield VFA, H2 and CH4.

Optimizing accuracy of protocols for measuring dry matter and nutrient yield of forage crops.

Farmers around the world must precisely manage nutrients applied to and removed from crop fields to maintain production and without causing nutrient pollution. This study is the first to quantify the baseline accuracy of current industry measurement protocols and achievable accuracy from intensifying protocols for measuring dry matter (DM), nitrogen (N), potassium (K), and phosphorus (P) yields from forage crops harvested for silage. The 'true' DM and nutrient yields of three fields each of corn, sorghum, and small grain were intensively measured by weighing and sampling every truckload of harvested forage. Simulations quantified the accuracy of practical sampling protocols by repeatedly subsampling the complete dataset for each field to measure average truckload weight and average DM and nutrient concentrations. Then uncertainty was propagated to DM, N, P, and K yield calculations using standard error equations. Yields measured using current industry protocols diverged from the true yields of some fields by more than ±40%, emphasizing the need for improved protocols. This study shows that improving average DM and nutrient concentration measurements is unlikely to improve accuracy of yield measurements if average load weight is not precisely measured. Accuracy did not come within 27% of true yields without weighing all truckloads on some fields even when DM and nutrient concentration measurements were perfectly accurate. Once all truckloads were weighed, the timing of forage sample collection to measure average DM concentration had the greatest impact on accuracy; precision improved by an average of 6.2% when >3 samples were evenly spaced throughout the harvest compared to the same number of consecutive samples. All crop fields are affected by within field variation in growing conditions that results in heterogeneity in DM and nutrient yield. Globally, this study provides foundational methodology to quantitatively evaluate and improve yield measurement protocols that ultimately support sustainable crop production.

Upregulation of orexin/hypocretin expression in aged rats: Effects on feeding latency and neurotransmission in the insular cortex.

Aging is associated with changes in numerous homeostatic functions, such as food intake, that are thought to be mediated by the hypothalamus. Orexin/hypocretin neurons of the hypothalamus regulate several physiological functions, including feeding, sleep and wakefulness. Evidence from both clinical and animal studies supports the notion that aging is associated with loss or dysregulation of the orexin system. Here, we used virus-mediated gene transfer to manipulate expression of orexin peptides in young and aged rats and examined behavioral and neurochemical correlates of food intake in these animals. Aged rats showed slower feeding latencies when presented with palatable food compared to young control rats, and these deficits were ameliorated by upregulation of orexin expression. Similarly, young animals treated with a virus designed to decrease preproorexin expression showed longer feeding latencies reminiscent of aged control rats. Feeding was also associated with increased acetylcholine, glutamate and GABA efflux in insular cortex of young control animals. Orexin upregulation did not restore deficits in feeding-elicited release of these neurotransmitters in aged rats, but did enhance basal neurotransmitter levels which may have contributed to the behavioral correlates of these genetic manipulations. These studies demonstrate that age-related deficits in behavioral and neurochemical measures of feeding are likely to be mediated, in part, by the orexin system. Because these same neurotransmitter systems have been shown to underlie orexin effects on cognition, treatments which increase orexin function may have potential for improving both physiological and cognitive manifestations of certain age-related disorders.

Resequencing and annotation of the Nostoc punctiforme ATTC 29133 genome: facilitating biofuel and high-value chemical production.

Cyanobacteria have the potential to produce bulk and fine chemicals and members belonging to Nostoc sp. have received particular attention due to their relatively fast growth rate and the relative ease with which they can be harvested. Nostoc punctiforme is an aerobic, motile, Gram-negative, filamentous cyanobacterium that has been studied intensively to enhance our understanding of microbial carbon and nitrogen fixation. The genome of the type strain N. punctiforme ATCC 29133 was sequenced in 2001 and the scientific community has used these genome data extensively since then. Advances in bioinformatics tools for sequence annotation and the importance of this organism prompted us to resequence and reanalyze its genome and to make both, the initial and improved annotation, available to the scientific community. The new draft genome has a total size of 9.1 Mbp and consists of 65 contiguous pieces of DNA with a GC content of 41.38% and 7664 protein-coding genes. Furthermore, the resequenced genome is slightly (5152 bp) larger and contains 987 more genes with functional prediction when compared to the previously published version. We deposited the annotation of both genomes in the Department of Energy's IMG database to facilitate easy genome exploration by the scientific community without the need of in-depth bioinformatics skills. We expect that an facilitated access and ability to search the N. punctiforme ATCC 29133 for genes of interest will significantly facilitate metabolic engineering and genome prospecting efforts and ultimately the synthesis of biofuels and natural products from this keystone organism and closely related cyanobacteria.

Development of growth rate, body lipid, moisture, and energy models for white sturgeon (Acipenser transmontanus) fed at various feeding rates.

The objectives were to develop and evaluate: 1) growth rate models, 2) body lipid, moisture, and energy models for white sturgeon fed at various feeding rates (FR; % body weight [BW] per day) and then evaluate responses at proportions of optimum feeding rate (OFR) across increasing BW (g). For objective 1, 19 datasets from the literature containing initial BW, FR and specific growth rate (SGR; % BW increase per day) were used. For objective 2, 12 datasets from the literature (11 from objective 1) containing SGR, FR, final BW, body lipid (%), protein (%), ash (%), moisture (%), and energy (kJ/g) were used. The average rearing temperatures was 19.2 ± 1.5 °C (mean ± SD). The average nutrient compositions and gross energy of the diets were 45.7 ± 4.3% protein, 14.8 ± 3.2% lipid, and 20.4 ± 1.3 kJ/g, respectively. The logistic model was used for objectives 1 and 2 to develop a statistical relationship between SGR and FR, then an iterative technique was used to estimate OFR for each dataset. For objective 2, the statistical relationship between body lipid, energy, and moisture and FR was established. Using the OFR estimate, SGR, body lipid, energy and moisture were computed at various FR as a proportion of OFR. Finally, a nonparametric fitting procedure was used to establish relationships between SGR, body lipid, energy and moisture (responses) compared with BW (predictor) at various proportions of OFR. This allows visualization of the effect of under- or over-feeding on the various responses. When examining the differences between OFR at 100% and various proportions of OFR, SGR differences decrease and moisture differences increase as BW increases. Lipid and energy differences decrease as BW increases. To our knowledge, these are the first description of changes in nutrient compositions when white sturgeon are fed at various FR. Because physiological and behavioral properties that are unique to sturgeon, results from this study are specific to sturgeon under the conditions of this study and cannot be compared directly with salmonids even if some of the results are similar. This research provides insight to designing future nutritional studies in sturgeon.

The protective effects of resveratrol on social stress-induced cytokine release and depressive-like behavior.

Social stress is a risk factor for psychiatric disorders, however only a subset of the population is susceptible while others remain resilient. Inflammation has been linked to the pathogenesis of psychosocial disorders in humans and may underlie these individual differences. Using a resident-intruder paradigm capable of revealing individual differences in coping behavior and inflammatory responses, the present study determined if resveratrol (RSV; 0, 10, 30mg/kg/day) protected against persistent stress-induced inflammation in socially defeated rats. Furthermore, the antidepressant efficacy of RSV was evaluated using the sucrose preference test. Active coping rats were characterized by more time spent in upright postures and increased defeat latencies versus passive coping rats. Five days after defeat, flow cytometry revealed enhanced stimulation of proinflammatory proteins (IL-ß, TNF-α) in spleen cells of passive rats as compared to active coping and controls, an effect that was blocked by both doses of RSV. Furthermore, only passive coping rats exhibited increased proinflammatory proteins (IL-1ß, TNF-α, GM-CSF) in the locus coeruleus (LC), a noradrenergic brain region implicated in depression. Notably, only 30mg/kg RSV blocked LC neuroinflammation and importantly, was the only dose that blocked anhedonia. Alternatively, while stress had minimal impact on resting cytokines in the dorsal raphe (DR), RSV dose-dependently reduced DR cytokine expression. However, this did not result in changes in indoleamine 2,3-dioxygenase activity or serotonin levels. Taken together, these data suggest that social stress-induced depressive-like behavior evident in passive coping rats may be driven by stress-induced neuroinflammation and highlight natural anti-inflammatory agents to protect against social stress-related consequences.

Correction: Thermodynamic Driving Force of Hydrogen on Rumen Microbial Metabolism: A Theoretical Investigation.

[This corrects the article DOI: 10.1371/journal.pone.0161362.].

Thermodynamic Driving Force of Hydrogen on Rumen Microbial Metabolism: A Theoretical Investigation.

Hydrogen is a key product of rumen fermentation and has been suggested to thermodynamically control the production of the various volatile fatty acids (VFA). Previous studies, however, have not accounted for the fact that only thermodynamic near-equilibrium conditions control the magnitude of reaction rate. Furthermore, the role of NAD, which is affected by hydrogen partial pressure (PH2), has often not been considered. The aim of this study was to quantify the control of PH2 on reaction rates of specific fermentation pathways, methanogenesis and NADH oxidation in rumen microbes. The control of PH2 was quantified using the thermodynamic potential factor (FT), which is a dimensionless factor that corrects a predicted kinetic reaction rate for the thermodynamic control exerted. Unity FT was calculated for all glucose fermentation pathways considered, indicating no inhibition of PH2 on the production of a specific type of VFA (e.g., acetate, propionate and butyrate) in the rumen. For NADH oxidation without ferredoxin oxidation, increasing PH2 within the rumen physiological range decreased FT from unity to zero for different NAD+ to NADH ratios and pH of 6.2 and 7.0, which indicates thermodynamic control of PH2. For NADH oxidation with ferredoxin oxidation, increasing PH2 within the rumen physiological range decreased FT from unity at pH of 7.0 only. For the acetate to propionate conversion, FT increased from 0.65 to unity with increasing PH2, which indicates thermodynamic control. For propionate to acetate and butyrate to acetate conversions, FT decreased to zero below the rumen range of PH2, indicating full thermodynamic suppression. For methanogenesis by archaea without cytochromes, FT differed from unity only below the rumen range of PH2, indicating no thermodynamic control. This theoretical investigation shows that thermodynamic control of PH2 on individual VFA produced and associated yield of hydrogen and methane cannot be explained without considering NADH oxidation.

Effects of feed restriction on salinity tolerance in white sturgeon (Acipenser transmontanus).

A multistressor study was conducted to investigate interactive effects of nutritional status and salinity on osmoregulation of juvenile white sturgeon. Our hypothesis was that lower nutritional status would decrease the salinity tolerance of juvenile white sturgeon. A four-week feed restriction (12.5%, 25%, 50%, 100% of optimum feeding rate: OFR defined as the rate (% body weight per day) at which growth is maximal) trial was performed, and relevant indices of nutritional status were measured. Following the trial, sturgeon were acutely exposed to various salinities (0, 8, 16, 24 ppt) for 120 h, and relevant osmoregulatory measurements were made at 12, 72, and 120 h post-salinity exposures. The feed-restriction trial resulted in a graded nutritional response with the most feed-restricted group (12.5% OFR) showing the lowest nutritional status. The salinity exposure trial showed clear evidence that lower nutritional status decreased the salinity tolerance of juvenile white sturgeon. Increasing salinities resulted in significant alterations in osmoregulatory indices of all feeding groups; however, a significantly slower acclimatory response to 24 ppt was detected in the most feed-restricted group compared to the non-feed-restricted group (100% OFR). Furthermore, evaluation of the effect of nutritional status on the relationship between osmoregulatory measurements and body size showed that there was a significant negative relationship between osmoregulatory performance and body size within the most feed-restricted group. This suggests that there is a certain body size range (200-300 g based on our finding) where juvenile white sturgeon can maximize osmoregulatory capacity at a salinity of 24 ppt.

Impact of nutrition and salinity changes on biological performances of green and white sturgeon.

Green and white sturgeon are species of high conservational and economic interest, particularly in the San Francisco Bay Delta (SFBD) for which significant climate change-derived alterations in salinity and nutritional patterns are forecasted. Although there is paucity of information, it is critical to test the network of biological responses underlying the capacity of animals to tolerate current environmental changes. Through nutrition and salinity challenges, climate change will likely have more physiological effect on young sturgeon stages, which in turn may affect growth performance. In this study, the two species were challenged in a multiple-factor experimental setting, first to levels of feeding rate, and then to salinity levels for different time periods. Data analysis included generalized additive models to select predictors of growth performance (measured by condition factor) among the environmental stressors considered and a suite of physiological variables. Using structural equation modeling, a path diagram is proposed to quantify the main linkages among nutrition status, salinity, osmoregulation variables, and growth performances. Three major trends were anticipated for the growth performance of green and white sturgeon in the juvenile stage in the SFBD: (i) a decrease in prey abundance will be highly detrimental for the growth of both species; (ii) an acute increase in salinity within the limits studied can be tolerated by both species but possibly the energy spent in osmoregulation may affect green sturgeon growth within the time window assessed; (iii) the mechanism of synergistic effects of nutrition and salinity changes will be more complex in green sturgeon, with condition factor responding nonlinearly to interactions of salinity and nutrition status or time of salinity exposure. Green sturgeon merits special scientific attention and conservation effort to offset the effects of feed restriction and salinity as key environmental stressors in the SFBD.

Effect of nutritional status on the osmoregulation of green sturgeon (Acipenser medirostris).

Anthropogenic climate change is linked to food web and salinity fluctuations in estuarine environments. Both decreased nutritional status and environmental salinity influence the physiological tolerance and health of fish populations; however, limited information on the interaction of these two factors and their physiological consequences is available. The green sturgeon (Acipenser medirostris) is a species of special concern in California, and the southern distinct population segment is listed as threatened. To test the hypothesis that poor nutrition negatively affects osmoregulation, juvenile green sturgeon (222 d posthatch) were randomly assigned to four feed restriction groups (12.5%, 25%, 50%, and 100% of the optimal feeding rate for 4 wk). Fish were then acutely exposed to 0-, 8-, 16-, or 32-ppt salinities and sampled at three time points (12, 72, or 120 h). Feed restriction significantly (P < 0.05) decreased specific growth rate, feed efficiency, condition factor, whole-body lipids, and protein content as well as plasma glucose, triglycerides, and proteins. Furthermore, feed restriction, salinity concentration, and salinity exposure time had significant effects on hematological indexes (hematocrit, hemoglobin), plasma values (osmolality, Na(+), K(+), Cl(-), glucose, lactate, cortisol), enzymatic activity (gill and pyloric ceca Na(+)/K(+) ATPase), and morphology of gill mitochondria-rich cells. The largest disturbances were observed at the highest salinity treatments across all feeding regimes. In addition, the interaction between feed restriction and acute salinity exposure at the highest salinity treatment resulted in high mortality rates during the first 72 h of salinity exposure. Evaluating the interactions of these environmental stressors and their implications on green sturgeon physiological tolerance will inform restoration and management efforts in rapidly changing estuarine environments.

Prediction of enteric methane emissions from cattle.

Agriculture has a key role in food production worldwide and it is a major component of the gross domestic product of several countries. Livestock production is essential for the generation of high quality protein foods and the delivery of foods in regions where animal products are the main food source. Environmental impacts of livestock production have been examined for decades, but recently emission of methane from enteric fermentation has been targeted as a substantial greenhouse gas source. The quantification of methane emissions from livestock on a global scale relies on prediction models because measurements require specialized equipment and may be expensive. The predictive ability of current methane emission models remains poor. Moreover, the availability of information on livestock production systems has increased substantially over the years enabling the development of more detailed methane prediction models. In this study, we have developed and evaluated prediction models based on a large database of enteric methane emissions from North American dairy and beef cattle. Most probable models of various complexity levels were identified using a Bayesian model selection procedure and were fitted under a hierarchical setting. Energy intake, dietary fiber and lipid proportions, animal body weight and milk fat proportion were identified as key explanatory variables for predicting emissions. Models here developed substantially outperformed models currently used in national greenhouse gas inventories. Additionally, estimates of repeatability of methane emissions were lower than the ones from the literature and multicollinearity diagnostics suggested that prediction models are stable. In this context, we propose various enteric methane prediction models which require different levels of information availability and can be readily implemented in national greenhouse gas inventories of different complexity levels. The utilization of such models may reduce errors associated with prediction of methane and allow a better examination and representation of policies regulating emissions from cattle.

Influence of chronic moderate sleep restriction and exercise training on anxiety, spatial memory, and associated neurobiological measures in mice.

Sleep deprivation can have deleterious effects on cognitive function and mental health. Moderate exercise training has myriad beneficial effects on cognition and mental health. However, physiological and behavioral effects of chronic moderate sleep restriction and its interaction with common activities, such as moderate exercise training, have received little investigation. The aims of this study were to examine the effects of chronic moderate sleep restriction and moderate exercise training on anxiety-related behavior, spatial memory, and neurobiological correlates in mice. Male mice were randomized to one of four 11-week treatments in a 2 [sleep restriction (∼4h loss/day) vs. ad libitum sleep] × 2 [exercise (1h/day/6 d/wk) vs. sedentary activity] experimental design. Anxiety-related behavior was assessed with the elevated-plus maze, and spatial learning and memory were assessed with the Morris water maze. Chronic moderate sleep restriction did not alter anxiety-related behavior, but exercise training significantly attenuated anxiety-related behavior. Spatial learning and recall, hippocampal cell activity (i.e., number of c-Fos positive cells), and brain derived neurotrophic factor were significantly lower after chronic moderate sleep restriction, but higher after exercise training. Further, the benefit of exercise training for some memory variables was evident under normal sleep, but not chronic moderate sleep restriction conditions. These data indicate clear detrimental effects of chronic moderate sleep restriction on spatial memory and that the benefits of exercise training were impaired after chronic moderate sleep restriction.

The interactive effects of selenomethionine and methylmercury on their absorption, disposition, and elimination in juvenile white sturgeon.

Selenium (Se) and mercury (Hg) are prevalent pollutants of industrialized watersheds. However, when co-administered, Se has protective effects on organisms from Hg. The mechanism is not fully understood, but it is thought that Se reduces Hg availability, either by forming biologically inert complexes and/or associating with selenoproteins. Despite concerns with aquatic contaminations, relatively little information is available on the interaction in aquatic organisms. In the present study, the interactive effects of Se and Hg on their absorption, disposition, and elimination were examined in juvenile white sturgeon, a benthic fish species at high risk to exposures of both contaminants. Selenium and Hg were provided as L-selenomethionine (SeMet) and methylmercury (MeHg), respectively. Groups of 10 sturgeon were orally intubated with a single dose of either 0 (control), SeMet (500 µg Se/kg body weight; BW), MeHg (850 µg Hg/kg BW), or their combination (Se/Hg; 500 µg Se/kg and 850 µg Hg/kg BW). The blood was repeatedly sampled and urine collected from the fish, over a 48 h post intubation period. At 48 h, the fish were sacrificed for Se and Hg tissue concentration and distribution. The co-administration of SeMet and MeHg significantly (p<0.05) lowered blood concentrations of both Se and Hg and tissue Se concentrations. Similarly, assimilation of Se and Hg was also reduced significantly. The interaction has a more quantitative effect on Se metabolism because the reduction in the overall tissue Se is a consequence of reduced Se absorption at the gut and not from the metabolic effects after absorption. In contrast, given the pulse increase in blood Hg concentration, tissue redistribution, and increased urinary elimination, the interactive effect on tissue Hg concentration is likely to be post-absorption. Even in the absence of exogenous SeMet, Se and Hg co-accumulated in tissue at a Se:Hg molar ratio greater than 1. Thus, similar to mammals, maintaining at least a 1:1 molar ratio of Se and Hg is of great physiological importance in the white sturgeon. Interestingly, SeMet did not divert Hg from the brain. Allocation of Se from the kidneys may have occurred in order to maintain the high Se:Hg molar ratios in the brain of white sturgeon. In the current study, the combined use of kinetic analysis and that of the conventional approach of measuring tissue concentration changes provided a comprehensive understanding of the interactive effect of SeMet and MeHg on their respective metabolic processes in juvenile white sturgeon.

This kinetic, bioavailability, and metabolism study of RRR-α-tocopherol in healthy adults suggests lower intake requirements than previous estimates.

Kinetic models enable nutrient needs and kinetic behaviors to be quantified and provide mechanistic insights into metabolism. Therefore, we modeled and quantified the kinetics, bioavailability, and metabolism of RRR-α-tocopherol in 12 healthy adults. Six men and 6 women, aged 27 ± 6 y, each ingested 1.81 nmol of [5(-14)CH(3)]-(2R, 4'R, 8'R)-α-tocopherol; each dose had 3.70 kBq of (14)C. Complete collections of urine and feces were made over the first 21 d from dosing. Serial blood samples were drawn over the first 70 d from dosing. All specimens were analyzed for RRR-α-tocopherol. Specimens were also analyzed for (14)C using accelerator MS. From these data, we modeled and quantified the kinetics of RRR-α-tocopherol in vivo in humans. The model had 11 compartments, 3 delay compartments, and reservoirs for urine and feces. Bioavailability of RRR-α-tocopherol was 81 ± 1%. The model estimated residence time and half-life of the slowest turning-over compartment of α-tocopherol (adipose tissue) at 499 ± 702 d and 184 ± 48 d, respectively. The total body store of RRR-α-tocopherol was 25,900 ± 6=220 µmol (11 ± 3 g) and we calculated the adipose tissue level to be 1.53 µmol/g (657 µg/g). We found that a daily intake of 9.2 µmol (4 mg) of RRR-α-tocopherol maintained plasma RRR-α-tocopherol concentrations at 23 µmol/L. These findings suggest that the dietary requirement for vitamin E may be less than that currently recommended and these results will be important for future updates of intake recommendations.

Gender and single nucleotide polymorphisms in MTHFR, BHMT, SPTLC1, CRBP2, CETP, and SCARB1 are significant predictors of plasma homocysteine normalized by RBC folate in healthy adults.

Using linear regression models, we studied the main and 2-way interaction effects of the predictor variables gender, age, BMI, and 64 folate/vitamin B-12/homocysteine (Hcy)/lipid/cholesterol-related single nucleotide polymorphisms (SNP) on log-transformed plasma Hcy normalized by RBC folate measurements (nHcy) in 373 healthy Caucasian adults (50% women). Variable selection was conducted by stepwise Akaike information criterion or least angle regression and both methods led to the same final model. Significant predictors (where P values were adjusted for false discovery rate) included type of blood sample [whole blood (WB) vs. plasma-depleted WB; P < 0.001] used for folate analysis, gender (P < 0.001), and SNP in genes SPTLC1 (rs11790991; P = 0.040), CRBP2 (rs2118981; P < 0.001), BHMT (rs3733890; P = 0.019), and CETP (rs5882; P = 0.017). Significant 2-way interaction effects included gender × MTHFR (rs1801131; P = 0.012), gender × CRBP2 (rs2118981; P = 0.011), and gender × SCARB1 (rs83882; P = 0.003). The relation of nHcy concentrations with the significant SNP (SPTLC1, BHMT, CETP, CRBP2, MTHFR, and SCARB1) is of interest, especially because we surveyed the main and interaction effects in healthy adults, but it is an important area for future study. As discussed, understanding Hcy and genetic regulation is important, because Hcy may be related to inflammation, obesity, cardiovascular disease, and diabetes mellitus. We conclude that gender and SNP significantly affect nHcy.