The metabolism and de-bromination of bromotyrosine in vivo

During inflammation, leukocyte-derived eosinophil peroxidase catalyses the formation of hypobromous acid, which can brominate tyrosine residues in proteins to form bromotyrosine. Since eosinophils are involved in the pathogenesis of allergic reactions, such as asthma, urinary bromotyrosine level has been used for the assessment of children with asthma. However, little is known about the metabolism and disposition of bromotyrosine in vivo. The aim of this study was to identify the major urinary metabolites formed during bromotyrosine metabolism and to develop mass spectrometric methods for their quantitation. Deuterium-labeled bromotyrosine was synthesized by deuterium exchange. [D3]bromotyrosine (500 nmole) was injected intraperitoneally into Sprague-Dawley rats and urine was collected for 24 h in a metabolic cage. 13C-labeled derivatives of bromotyrosine and its major urinary metabolite were synthesized and used as internal standards for quantitation. Following solid phase extraction, urine samples were derivatized to the pentafluorobenzyl ester, and analyzed using isotope dilution gas chromatography and negative-ion chemical ionization mass spectrometry. A novel brominated metabolite, 3-bromo-4-hydroxyphenylacetic acid (bromo-HPA), was identified as the major brominated metabolite of bromotyrosine. Bromo-HPA only accounted for 0.43±0.04% of infused [D3]bromotyrosine and 0.12±0.02% of infused [D3]bromotyrosine was excreted in the urine unchanged. However, ~1.3% (6.66±1.33 nmole) of infused [D3]bromotyrosine was excreted in the urine as the de-brominated metabolite, [D3]4-hydroxyphenylacetic acid, which is also a urinary metabolite of tyrosine in mammals. We also tested whether or not iodotyrosine dehalogenase can catalyse de-bromination of bromotyrosine and showed that iodotyrosine dehalogenase is able to de-brominate free bromotyrosine in vitro. We identified bromo-HPA as the main brominated urinary metabolite of bromotyrosine in rats. However, de-halogenation of bromotyrosine is the major metabolic pathway to eliminate free brominated tyrosine in vivo

Evaluation of the reliability of the measurement of key magnetocaloric properties: a round robin study of La(Fe,Si,Mn)Hδ conducted by the SSEEC consortium of European laboratories

Managing refrigeration of our homes, our food and our work environments in energy efficient ways is of increasing importance. Refrigeration using solid state magnetic cooling is one of a number of technologies that may make a significant contribution to addressing this problem. In order to develop materials that may enable commercial development of this increasingly relevant field it is important to review the reliability of methods used to extract key physical properties, so that as the field matures the community can develop recognised standards of measurement. Here we measure key physical properties in one composition taken from a series of La(Fe,Si,Mn)Hδ 1:13‐type samples grown by a source laboratory and measured independently in a consortium of European laboratories using both commercial and bespoke facilities

Substructures in lens galaxies: PG1115+080 and B1555+375, two fold configurations

We study the anomalous flux ratio which is observed in some four-image lens systems, where the source lies close to a fold caustic. In this case two of the images are close to the critical curve and their flux ratio should be equal to unity, instead in several cases the observed value differs significantly. The most plausible solution is to invoke the presence of substructures, as for instance predicted by the Cold Dark Matter scenario, located near the two images. In particular, we analyze the two fold lens systems PG1115+080 and B1555+375, for which there are not yet satisfactory models which explain the observed anomalous flux ratios. We add to a smooth lens model, which reproduces well the positions of the images but not the anomalous fluxes, one or two substructures described as singular isothermal spheres. For PG1115+080 we consider a smooth model with the influence of the group of galaxies described by a SIS and a substructure with mass $\sim 10^{5} M_{\odot}$ as well as a smooth model with an external shear and one substructure with mass $\sim 10^{8} M_{\odot}$ . For B1555+375 either a strong external shear or two substructures with mass $\sim 10^{7} M_{\odot}$ reproduce the data quite well.Comment: 26 pages, updated bibliography, Accepted for publication in Astrophysics & Space Scienc

Snacking characteristics and patterns and their associations with diet quality and BMI in the Childhood Obesity Prevention and Treatment Research Consortium

Objective: To describe snacking characteristics and patterns in children and examine associations with diet quality and BMI. Design: Children's weight and height were measured. Participants/adult proxies completed multiple 24 h dietary recalls. Snack occasions were self-identified. Snack patterns were derived for each sample using exploratory factor analysis. Associations of snacking characteristics and patterns with Healthy Eating Index-2010 (HEI-2010) score and BMI were examined using multivariable linear regression models. Setting: Childhood Obesity Prevention and Treatment Research (COPTR) Consortium, USA: NET-Works, GROW, GOALS and IMPACT studies. Participants: Predominantly low-income, racial/ethnic minorities: NET-Works (n 534, 2-4-year-olds); GROW (n 610, 3-5-year-olds); GOALS (n 241, 7-11-year-olds); IMPACT (n 360, 10-13-year-olds).Results: Two snack patterns were derived for three studies: a meal-like pattern and a beverage pattern. The IMPACT study had a similar meal-like pattern and a dairy/grains pattern. A positive association was observed between meal-like pattern adherence and HEI-2010 score (P for trend < 0-01) and snack occasion frequency and HEI-2010 score (β coefficient (95 % CI): NET-Works, 0-14 (0-04, 0-23); GROW, 0-12 (0-02, 0-21)) among younger children. A preference for snacking while using a screen was inversely associated with HEI-2010 score in all studies except IMPACT (β coefficient (95 % CI): NET-Works, -3-15 (-5-37, -0-92); GROW, -2-44 (-4-27, -0-61); GOALS, -5-80 (-8-74, -2-86)). Associations with BMI were almost all null. Conclusions: Meal-like and beverage patterns described most children's snack intake, although patterns for non-Hispanic Blacks or adolescents may differ. Diets of 2-5-year-olds may benefit from frequent meal-like pattern snack consumption and diets of all children may benefit from decreasing screen use during eating occasions

Role of the nitric oxide pathway and the endocannabinoid system in neurogenic relaxation of corpus cavernosum from biliary cirrhotic rats

Background and purpose: Relaxation of corpus cavernosum, which is mediated by nitric oxide (NO) released from non-adrenergic non-cholinergic (NANC) neurotransmission, is critical for inducing penile erection and can be affected by many pathophysiological conditions. However, the peripheral effect of liver cirrhosis on erectile function is as yet unknown. The aim of the present study was to investigate the effect of biliary cirrhosis on NANC-mediated relaxation of rat corpus cavernosum and the possible roles of endocannabinoid and nitric oxide systems in this model. Experimental approach: Cirrhosis was induced by bile duct ligation. Controls underwent sham operation. Four weeks later, strips of corpus cavernosum were mounted in a standard organ bath and NANC-mediated relaxations were obtained by applying electrical field stimulation. Key results: The NANC-mediated relaxation was enhanced in corporal strips from cirrhotic animals. Anandamide potentiated the relaxations in both groups. Either AM251 (CB 1 antagonist) or capsazepine (vanilloid VR 1 antagonist), but not AM630 (CB 2 antagonist), prevented the enhanced relaxations of cirrhotic strips. Either the non-selective NOS inhibitor L-NAME or the selective neuronal NOS inhibitor L-NPA inhibited relaxations in both groups, but cirrhotic groups were more resistant to the inhibitory effects of these agents. Relaxations to sodium nitroprusside (NO donor) were similar in tissues from the two groups. Conclusions and implications: Cirrhosis potentiates the neurogenic relaxation of rat corpus cavernosum probably via the NO pathway and involving cannabinoid CB 1 and vanilloid VR 1 receptors. © 2007 Nature Publishing Group All rights reserved

Ralph: A Visible/Infrared Imager for the New Horizons Pluto/Kuiper Belt Mission

The New Horizons instrument named Ralph is a visible/near infrared multi-spectral imager and a short wavelength infrared spectral imager. It is one of the core instruments on New Horizons, NASA's first mission to the Pluto/Charon system and the Kuiper Belt. Ralph combines panchromatic and color imaging capabilities with IR imaging spectroscopy. Its primary purpose is to map the surface geology and composition of these objects, but it will also be used for atmospheric studies and to map the surface temperature. It is a compact, low-mass (10.5 kg), power efficient (7.1 W peak), and robust instrument with good sensitivity and excellent imaging characteristics. Other than a door opened once in flight, it has no moving parts. These characteristics and its high degree of redundancy make Ralph ideally suited to this long-duration flyby reconnaissance mission.Comment: 18 pages, 15 figures, 4 tables; To appear in a special volume of Space Science Reviews on the New Horizons missio

Performance of Braford steers grazing on cultivated pastures and fed or not fed an energy supplement

This experiment evaluated the performance of 84 Braford steers grazing on summer and winter cultivated pastures fed or not fed an energy-protein supplement. Steers were 10 months old and weighed, on average, 165 kg at the beginning of the trial. Steers grazed on cultivated winter pasture, consisting of black oats (Avena strigosa) and ryegrass (Lolium multiflorum Lam.), and then on cultivated summer pasture, consisting of Napier grass (Pennisetum purpureum). The following treatments were applied: SS - supplement was fed during both seasons; SN - supplement was fed only during the winter; NS - supplement was fed only during the summer; and NN - steers were not fed any supplement. Supplementation resulted in higher body weight and better body condition score (SS: 369.2 and 4.52; SN: 335.2 and 4.01; NS: 352.5 and 4.49; SS: 322.5 and 3.83). Longissimus dorsi area was larger in supplemented steers, which also presented thicker backfat when compared with those not fed any supplement (3.67 and 2.29 mm, respectively)

PD-1 blockade in recurrent or metastatic cervical cancer: Data from cemiplimab phase I expansion cohorts and characterization of PD-L1 expression in cervical cancer

Objectives: To characterize the safety, tolerability, and anti-tumor activity of cemiplimab as monotherapy or in combination with hypofractionated radiation therapy (hfRT) in patients with recurrent or metastatic cervical cancer. To determine the association between histology and programmed death-ligand 1 (PD-L1) expression. Methods: In non-randomized phase I expansion cohorts, patients (squamous or non-squamous histology) received cemiplimab 3 mg/kg intravenously every 2 weeks for 48 weeks, either alone (monotherapy cohort) or with hfRT during week 2 (combination cohort). Due to insufficient tissue material, PD-L1 protein expression was evaluated in commercially purchased samples and mRNA expression levels were analyzed from The Cancer Genome Atlas (TCGA). Results: Twenty patients enrolled in both cohorts in total; 10 had squamous histology. The most common adverse events of any grade were diarrhea, fatigue, and hypokalemia, occurring in 35%, 25%, and 25%, respectively. Objective response rate was 10% in each cohort; responders had squamous histology. Duration of response was 11.2 months and 6.4 months for the responder in the monotherapy and combination cohort, respectively. Irradiated lesions were not included in the response assessments. In separate archived specimens (N = 155), PD-L1 protein expression in tumor and immune cells was negative (<1%) more commonly in adenocarcinoma than in squamous tumors. PD-L1 mRNA levels were lower in adenocarcinoma than squamous cell tumors (1.2 vs 5.0 mean transcripts per million, respectively) in TCGA. Conclusions: Cemiplimab has activity in cervical squamous cell carcinoma. The phase I results, combined with results from other anti-PD-1 trials in cervical cancer and our biomarker analyses have informed the design of the ongoing phase III trial, with the primary overall survival hierarchical analyses being done first in patients with squamous histology

Two family interventions to reduce BMI in low-income urban youth: A randomized trial

BACKGROUND: Our primary aim was to evaluate the effects of 2 family-based obesity management interventions compared with a control group on BMI in low-income adolescents with overweight or obesity. METHODS: In this randomized clinical trial, 360 urban-residing youth and a parent were randomly assigned to 1 of 2 behaviorally distinct family interventions or an education-only control group. Eligible children were entering the sixth grade with a BMI $85th percentile. Interventions were 3 years in length; data were collected annually for 3 years. Effects of the interventions on BMI slope (primary outcome) over 3 years and a set of secondary outcomes were assessed. RESULTS: Participants were primarily African American (77%), had a family income of,25 000 per year, and obese at enrollment (68%). BMI increased over time in all study groups, with group increases ranging from 0.95 to 1.08. In an intent-to-treat analysis, no significant differences were found in adjusted BMI slopes between either of the family-based interventions and the control group (P = .35). No differences were found between the experimental and control groups on secondary outcomes of diet, physical activity, sleep, perceived stress, or cardiometabolic factors. No evidence of effect modification of the study arms by sex, race and/or ethnicity, household income, baseline levels of child and parent obesity, or exposure to a school fitness program were found. CONCLUSIONS: In this low-income, adolescent population, neither of the family-based interventions improved BMI or health-related secondary outcomes. Future interventions should more fully address poverty and other social issues contributing to childhood obesity