L-368,899 is a selective small-molecule oxytocin receptor (OXTR) antagonist originally developed in the 1990s to prevent preterm labor. Although its utility for that purpose was limited, L-368,899 is now one of the most commonly used drugs in animal research for the selective blockade of neural OXTR after peripheral delivery. A growing number of rodent and primate studies have used L-368,899 to evaluate whether certain behaviors are oxytocin dependent. These studies have improved our understanding of oxytocin's function in the brains of rodents and monkeys, but very little work has been done in other mammals, and only a single paper in macaques has provided any evidence that L-368,899 can be detected in the CNS after peripheral delivery. The current study sought to extend those findings in a novel species: coyotes ( Canis latrans ). Coyotes are ubiquitous North American canids that form long-term monogamous pair-bonds. Although monogamy is rare in rodents and primates, all wild canid species studied to date exhibit social monogamy. Coyotes are therefore an excellent model organism for the study of oxytocin and social bonds. Our goal was to determine whether L-368,899 is a viable candidate for future use in behavioral studies in coyotes. We used captive coyotes at the USDA National Wildlife Research Center's Predator Research Facility to evaluate the pharmacokinetics of L-368,899 in blood and CSF during a 90-min time course after intramuscular injection. We then characterized the binding affinity and selectivity of L-368,899 to coyote OXTR and the structurally similar vasopressin 1a receptor. We found that L-368,899 peaked in CSF at 15 to 30 min after intramuscular injection and slowly accumulated in blood. L-368,899 was 40 times more selective for OXTR than vasopressin 1a receptors and bound to the coyote OXTR with an affinity of 12 nM. These features of L-368,899 support its utility in future studies to probe the oxytocin system of coyotes.

Leukocyte antigen-related (LAR) phosphatase is a receptor-type protein tyrosine phosphatase involved in cellular signaling and associated with human disease including cancer and metabolic disorders. Selective inhibition of LAR phosphatase activity by well characterized and well validated small molecules would provide key insights into the roles of LAR phosphatase in health and disease, but identifying selective inhibitors of LAR phosphatase activity has been challenging. Recently, we described potent and selective inhibition of LAR phosphatase activity by the fungal natural product illudalic acid. Here we provide a detailed biochemical characterization of the adduct formed between LAR phosphatase and illudalic acid. A mass spectrometric analysis indicates that two cysteine residues are covalently labeled by illudalic acid and a related analog. Mutational analysis supports the hypothesis that inhibition of LAR phosphatase activity is due primarily to the adduct with the catalytic cysteine residue. A computational study suggests potential interactions between the illudalic acid moiety and the enzyme active site. Taken together, these data offer novel insights into the mechanism of inhibition of LAR phosphatase activity by illudalic acid.

Multiple sclerosis (MS) is a metabolically demanding disease involving immune-mediated destruction of myelin in the central nervous system. We previously demonstrated a significant alteration in disease course in the experimental autoimmune encephalomyelitis (EAE) preclinical model of MS due to diet. Based on the established crosstalk between metabolism and gut microbiota, we took an unbiased sampling of microbiota, in the stool, and metabolites, in the serum and stool, from mice (Mus musculus) on the two different diets, the Teklad global soy protein-free extruded rodent diet (irradiated diet) and the Teklad sterilisable rodent diet (autoclaved diet). Within the microbiota, the genus Lactobacillus was found to be inversely correlated with EAE severity. Therapeutic treatment with Lactobacillus paracasei resulted in a significant reduction in the incidence of disease, clinical scores and the amount of weight loss in EAE mice. Within the metabolites, we identified shifts in glycolysis and the tricarboxylic acid cycle that may explain the differences in disease severity between the different diets in EAE. This work begins to elucidate the relationship between diet, microbiota and metabolism in the EAE preclinical model of MS and identifies targets for further study with the goal to more specifically probe the complex metabolic interaction at play in EAE that may have translational relevance to MS patients.

Martha Nussbaum is now Freund Professor of Law and Ethics in the University of Chicago. Her published work spans five decades. ‘Political Emotions’ successfully enfolds knowledge, battle and song f...

UTRS Inc. has developed a novel two-step method to extract commercially viable titaniumalloys (patent pending no. 20130164167 [1]). This approach has proven its potential to produce a variety of titanium alloys (Ti-6Al-4V, TixAly, etc.,) and has demonstrated a number of advantages over the current commercial titanium production process. Additionally, the UTRS Process operates without producing-CO2 and eliminates the use of TiCl4. Step 1: Aluminothermic reduction makes available many types of ores that could otherwise not be used. Due to the aluminothermic reduction technique and the composition of the ore, metal extracted from this step will inherently contain non-titanium elements. Step 2: Electro-refining removes undesirable elements from the thermally extracted titanium. This refined metal has a dendritic morphology with a wool-like appearance that is referred to as "titanium wool". This new morphology of titanium allows it to have a diversity of end product types from titanium powder to bulk titanium.

ObjectiveWe have previously demonstrated that metabolic syndrome (MetS) exhibits multigenerational epigenetic inheritance in IUGR rats. Moreover, supplementation of essential nutrients (ENS) along the 1-carbon pathway and necessary for DNA methylation results in abrogation of adult MetS in the F2 generation. Here, we hypothesized that alterations in the metabolome would manifest prior to the onset of adult MetS, and could thus serve as potential biomarkers for later in life disease. We therefore sought to broadly profile blood metabolites in the F2 generation of our IUGR model at the time of weaning.Study DesignPregnant dams underwent uterine artery ligation or sham surgery at e19, and IUGR F1 pups were assigned ENS or control diet at weaning. Blood was collected from IUGRpat/IUGRmat or Shampat/Shammat F2 offspring at weaning (p21, n 76). Unbiased metabolome analysis was by GC-MS platforms, and metabolites of interest were identified and quantified by retention time and m/z.ResultsGreater than 70 spectra were altered among IUGR lineage destined for adult MetS on CD at p21 (ANOVA, p<0.05). Notably, lipid metabolites (cholesterol and palmitic acid), as well as creatinine, were increased 5.4, 2.3 and 3.6-fold respectively in the IUGR-control fed group, while methionine, serine, and ascorbic acid were decreased by 2.6, 1.7, and 28.5 fold. In the ENS rescued cohort, levels of ascorbic acid and creatinine were restored to control levels amongt those IUGR neonates who did not develop MetS in adult life. Multivariate PLS-DA analysis revealed distinct clustering of neonatal cohorts destined for later in life MetS (p<0.01; Figure).Conclusion ObjectiveWe have previously demonstrated that metabolic syndrome (MetS) exhibits multigenerational epigenetic inheritance in IUGR rats. Moreover, supplementation of essential nutrients (ENS) along the 1-carbon pathway and necessary for DNA methylation results in abrogation of adult MetS in the F2 generation. Here, we hypothesized that alterations in the metabolome would manifest prior to the onset of adult MetS, and could thus serve as potential biomarkers for later in life disease. We therefore sought to broadly profile blood metabolites in the F2 generation of our IUGR model at the time of weaning. We have previously demonstrated that metabolic syndrome (MetS) exhibits multigenerational epigenetic inheritance in IUGR rats. Moreover, supplementation of essential nutrients (ENS) along the 1-carbon pathway and necessary for DNA methylation results in abrogation of adult MetS in the F2 generation. Here, we hypothesized that alterations in the metabolome would manifest prior to the onset of adult MetS, and could thus serve as potential biomarkers for later in life disease. We therefore sought to broadly profile blood metabolites in the F2 generation of our IUGR model at the time of weaning. Study DesignPregnant dams underwent uterine artery ligation or sham surgery at e19, and IUGR F1 pups were assigned ENS or control diet at weaning. Blood was collected from IUGRpat/IUGRmat or Shampat/Shammat F2 offspring at weaning (p21, n 76). Unbiased metabolome analysis was by GC-MS platforms, and metabolites of interest were identified and quantified by retention time and m/z. Pregnant dams underwent uterine artery ligation or sham surgery at e19, and IUGR F1 pups were assigned ENS or control diet at weaning. Blood was collected from IUGRpat/IUGRmat or Shampat/Shammat F2 offspring at weaning (p21, n 76). Unbiased metabolome analysis was by GC-MS platforms, and metabolites of interest were identified and quantified by retention time and m/z. ResultsGreater than 70 spectra were altered among IUGR lineage destined for adult MetS on CD at p21 (ANOVA, p<0.05). Notably, lipid metabolites (cholesterol and palmitic acid), as well as creatinine, were increased 5.4, 2.3 and 3.6-fold respectively in the IUGR-control fed group, while methionine, serine, and ascorbic acid were decreased by 2.6, 1.7, and 28.5 fold. In the ENS rescued cohort, levels of ascorbic acid and creatinine were restored to control levels amongt those IUGR neonates who did not develop MetS in adult life. Multivariate PLS-DA analysis revealed distinct clustering of neonatal cohorts destined for later in life MetS (p<0.01; Figure). Greater than 70 spectra were altered among IUGR lineage destined for adult MetS on CD at p21 (ANOVA, p<0.05). Notably, lipid metabolites (cholesterol and palmitic acid), as well as creatinine, were increased 5.4, 2.3 and 3.6-fold respectively in the IUGR-control fed group, while methionine, serine, and ascorbic acid were decreased by 2.6, 1.7, and 28.5 fold. In the ENS rescued cohort, levels of ascorbic acid and creatinine were restored to control levels amongt those IUGR neonates who did not develop MetS in adult life. Multivariate PLS-DA analysis revealed distinct clustering of neonatal cohorts destined for later in life MetS (p<0.01; Figure). Conclusion

BACKGROUND:Immersion treatment (IT) provided in a camp setting has been shown to promote short-term improvements in weight and health status in obese adolescents. However, evidence of IT's long-term efficacy and efficacy for multi-ethnic and lower socioeconomic status (SES) adolescents is limited.METHODS:This was a cohort study with a pre/post design and longitudinal follow-up. The intervention was a 19-day camp-based IT program comprising (1) a nutrition curriculum and ad-lib access to a nutritious diet, (2) several hours of physical activity daily, (3) group therapy, and (4) cognitive-behavioral therapy (CBT). This analysis included 52 low-SES adolescents that participated in 2009 and 2010. A subgroup of 33 campers and their families was offered follow-up monthly for 10 months. Primary outcome measures were change in weight-related parameters immediately postcamp and after 10 months of follow-up.RESULTS:Campers had significant short-term improvements in mean waist circumference (mean [M], 2.6; standard deviation [SD], 3.2 cm), weight (M, 2.6; SD, 1.9 kg), BMI (M, 1.1; SD, 0.9 kg/m2), BMI z-score (M, 0.06; SD, 0.07), and percent overweight (M, 6.1; SD, 4.7). Campers offered follow-up had a modest increase in mean percent overweight (M, 2.0; SD, 8.4) during 10 months of follow-up. However, 33% experienced continuing decline in percent overweight during follow-up, and long-term follow-up was associated with significant overall (precamp vs. end of follow-up) improvements in percent overweight (M, 4.9; SD, 7.2).CONCLUSIONS:Camp-based IT with CBT is a promising intervention for improving short- and long-term weight status of low-SES adolescents. Additional research is needed to increase long-term efficacy.

The foraging ecology of mammalian herbivores is strongly shaped by plant secondary compounds (PSCs) that defend plants against herbivory. Conventional wisdom holds that gut microbes facilitate the ingestion of toxic plants; however, this notion lacks empirical evidence. We investigated the gut microbiota of desert woodrats (Neotoma lepida), some populations of which specialise on highly toxic creosote bush (Larrea tridentata). Here, we demonstrate that gut microbes are crucial in allowing herbivores to consume toxic plants. Creosote toxins altered the population structure of the gut microbiome to facilitate an increase in abundance of genes that metabolise toxic compounds. In addition, woodrats were unable to consume creosote toxins after the microbiota was disrupted with antibiotics. Last, ingestion of toxins by naïve hosts was increased through microbial transplants from experienced donors. These results demonstrate that microbes can enhance the ability of hosts to consume PSCs and therefore expand the dietary niche breadth of mammalian herbivores.

AOD9604 is a peptide consisting of the C-terminal fragment of human growth hormone from amino acids 177-191 with an additional tyrosine residue at the N-terminus of the peptide. It is reported to mimic the lipolytic properties of growth hormone without the diabetogenic side effects. Therefore, AOD9604 may be used as a performance enhancing drug and is banned by the World Anti-doping Agency (WADA). The peptide is available on several Internet websites and was recently identified in confiscated vials in the USA. To detect abuse of the peptide in athletes, a solid-phase extraction method was validated in urine with a limit of detection of 50 pg/mL. The method has good linearity, precision (<20%), specificity and recovery (62%). Six potential metabolites of the peptide were identified after incubation of AOD9604 in serum and urine. Quantification of the metabolites in serum identified a single metabolite, consisting of amino acids CRSVEGSCG, which is significantly more stable than the other metabolites or the parent compound. Screening for AOD9604 and the stable metabolite may potentially allow an increased window of detection.

Background: Medial patellofemoral ligament (MPFL) reconstruction in adults often utilizes screw fixation in the distal femur. The aim was to define the safety of similar fixation in young patients, with respect to their open physis. Purpose: To define the age-related relationship between the femoral insertion of the MPFL and the medial aspect of the distal femoral physis on magnetic resonance imaging (MRI) scans. The study investigates whether screw fixation at this point is safe with respect to patient age and screw inclination. Study Design: Cross-sectional study. Methods: Retrospective review of the MRI scans of 159 skeletally immature patients. The femoral insertion of the MPFL was defined with respect to the distal femoral physis. The predicted paths of 2-cm screw fixation were simulated both parallel to the joint line and 45° distally oblique; physeal and joint penetration were noted when present. Results are plotted against age and compared as quartile ranges. Results: The femoral insertion of the MPFL was found to be distal to the distal femoral physis in all patients by an average of 10 mm (range, 2-16 mm). The mean distance increases slightly with age in a nonlinear relationship (r = 0.51, P < .001) from 9 mm at age 10 years to 12 mm by age 16 years. For the classic, parallel screw, the risk of physeal breach is high for all age groups (mean, 64%). For the novel, oblique screw, joint penetration and physeal breach were less prevalent (mean, 13%), and importantly, the vast majority of these breaches were in younger children (age <9 years 9 months). With oblique screws, older children were at significantly lower risk than younger children (<3% vs 48%; P < .001). Conclusion: This study accurately defines the relationship between the femoral insertion of the MPFL and the distal femoral physis in children and adolescents. A high risk of potentially poor outcomes was found during anatomic reconstruction of the MPFL in children utilizing classic (parallel) screw fixation, irrespective of age. However, in children older than 10 years, a 20-mm screw, from the anatomic MPFL insertion and directed 45° distally oblique, should be safe in 98% of patients.

Impulsivity and poor inhibitory control are associated with higher rates of delay discounting (DD), or a greater preference for smaller, more immediate rewards at the expense of larger, but delayed rewards. Of the many functional magnetic resonance imaging (fMRI) studies of DD, few have investigated the correlation between individual differences in DD rate and brain activation related to DD trial difficulty, with difficult DD trials expected to activate putative executive function brain areas involved in impulse control. In the current study, we correlated patterns of brain activation as measured by fMRI during difficult vs. easy trials of a DD task with DD rate (k) in obese women. Difficulty was defined by how much a reward choice deviated from an individual's 'indifference point', or the point where the subjective preference for an immediate and a delayed reward was approximately equivalent. We found that greater delay discounting was correlated with less modulation of activation in putative executive function brain areas, such as the middle and superior frontal gyri and inferior parietal lobule, in response to difficult compared to easy DD trials. These results support the suggestion that increased impulsivity is associated with deficient functioning of executive function areas of the brain.

Obesity can be accompanied by abnormalities in executive function and related neural circuitry. A useful task for studying executive function is delay discounting (DD), in which an individual chooses between sooner and delayed, but greater, amounts of money or other commodities. We previously found that obese compared to normal-weight women made more immediate choices on a monetary DD task, or had greater delay discounting. In the present study, we performed functional magnetic resonance imaging (fMRI) of obese women during performance of a DD of money task. Confirming the results of previous studies, we found that more difficult compared to easy DD trials resulted in activation in putative executive function areas of the brain, the middle and inferior frontal gyri, and medial prefrontal cortex. Most interestingly, we also found that less activation in executive function areas such as the inferior, middle, and superior frontal gyri on difficult vs. easy DD trials predicted a greater rate of weight gain over the subsequent 1.3–2.9 years. These results suggest that suboptimal functioning of executive function areas such as prefrontal cortex contributes to the progression of obesity.

Rodents, particularly rats, are used in the majority of intrauterine growth restriction (IUGR) research. An important tool that is lacking in this field is the ability to impose IUGR on transgenic mice. We therefore developed a novel mouse model of chronic IUGR using U-46619, a thromboxane A(2) (TXA(2)) analog, infusion. TXA2 overproduction is prevalent in human pregnancies complicated by cigarette smoking, diabetes mellitus and preeclampsia. In this model, U-46619 micro-osmotic pump infusion in the last week of C57BL/6J mouse gestation caused maternal hypertension. IUGR pups weighed 15% less, had lighter brain, lung, liver and kidney weights, but had similar nose-to-anus lengths compared with sham pups at birth. Metabolically, IUGR pups showed increased essential branched-chain amino acids. They were normoglycemic yet hypoinsulinemic. They showed decreased hepatic mRNA levels of total insulin-like growth factor-1 and its variants, but increased level of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha. IUGR offspring were growth restricted from birth (P1) through postnatal day 21 (P21). IUGR males caught up with sham males in weight by P28, whereas IUGR females caught up with sham females by P77. IUGR males surpassed sham males in weight by P238. In summary, we have a non-brain sparing IUGR mouse model that has a relative ease of surgical IUGR induction and exhibits features similar to the chronic IUGR offspring of humans and other animal models. As transgenic technology predominates in mice, this model now permits the imposition of IUGR on transgenic mice to interrogate mechanisms of fetal origins of adult disease.

Behavioral studies have suggested that food cues have stronger motivating effects in obese than in normal-weight individuals, which may be a risk factor underlying obesity. Previous cross-sectional neuroimaging studies have suggested that this difference is mediated by increased reactivity to food cues in parts of the reward system in obese individuals. To date, however, only a few prospective neuroimaging studies have been conducted to examine whether individual differences in brain activation elicited by food cues can predict differences in weight change. We used functional magnetic resonance imaging (fMRI) to investigate activation in reward-system as well as other brain regions in response to viewing high-calorie food vs. control pictures in 25 obese individuals before and after a 12-week psychosocial weight-loss treatment and at 9-mo follow-up. In those obese individuals who were least successful in losing weight during the treatment, we found greater pre-treatment activation to high-calorie food vs. control pictures in brain regions implicated in reward-system processes, such as the nucleus accumbens, anterior cingulate, and insula. We found similar correlations with weight loss in brain regions implicated by other studies in vision and attention, such as superior occipital cortex, inferior and superior parietal lobule, and prefrontal cortex. Furthermore, less successful weight maintenance at 9-mo follow-up was predicted by greater post-treatment activation in such brain regions as insula, ventral tegmental area, putamen, and fusiform gyrus. In summary, we found that greater activation in brain regions mediating motivational and attentional salience of food cues in obese individuals at the start of a weight-loss program was predictive of less success in the program and that such activation following the program predicted poorer weight control over a 9-mo follow-up period.

Many articles have discussed the potential benefits of mobilebearing total knee arthroplasty (TKA) when compared to fixedbearing designs. Several manuscripts recently have been published that directly compare these two alternative designs. The goal of this review was to determine if the proposed theoretical advantages of mobile-bearing TKA result in any demonstrable improvement in clinical outcome. Mobile-bearing TKA was introduced in an effort to improve prosthetic longevity by minimizing polyethylene wear while reducing strain at the implant-bone interface. Knee simulator studies in vitro reveal superior wear characteristics for mobile-bearing prostheses when compared with fixed-bearing equivalent designs. The mobile-bearing design also has been shown to more closely match the kinematics of normal knees and patellofemoral joints. Suspicions regarding the disadvantages of mobile bearings, including bearing instability and the detrimental effects of backside wear, remain controversial but are not supported by recent literature. Longitudinal studies evaluating clinical outcomes, however, have been unable to reveal any significant advantage for either of these two different TKA designs. Both kinematic studies and in vitro investigations suggest certain theoretical benefits for mobile-bearing TKA when compared to fixed-bearing designs. Most importantly, however, clinical outcome studies consistently fail to demonstrate the superiority of mobile-bearing TKA with regard to longevity or functional results.

Exaggerated reactivity to food cues in obese women appears to be mediated in part by a hyperactive reward system that includes the nucleus accumbens, amygdala, and orbitofrontal cortex. The present study used functional magnetic resonance imaging (fMRI) to investigate whether differences between 12 obese and 12 normal-weight women in reward-related brain activation in response to food images can be explained by changes in the functional interactions between key reward network regions. A two-step path analysis/General Linear Model approach was used to test whether there were group differences in network connections between nucleus accumbens, amygdala, and orbitofrontal cortex in response to high- and low-calorie food images. There was abnormal connectivity in the obese group in response to both high- and low-calorie food cues compared to normal-weight controls. Compared to controls, the obese group had a relative deficiency in the amygdala's modulation of activation in both orbitofrontal cortex and nucleus accumbens, but excessive influence of orbitofrontal cortex's modulation of activation in nucleus accumbens. The deficient projections from the amygdala might relate to suboptimal modulation of the affective/emotional aspects of a food's reward value or an associated cue's motivational salience, whereas increased orbitofrontal cortex to nucleus accumbens connectivity might contribute to a heightened drive to eat in response to a food cue. Thus, it is possible that not only greater activation of the reward system, but also differences in the interaction of regions in this network may contribute to the relatively increased motivational value of foods in obese individuals.