Physiological Response to Feeding in Little Penguins

© 2006 by The University of Chicago.Specific dynamic action (SDA), the increase in metabolic rate above resting levels that accompanies the processes of digestion and assimilation of food, can form a substantial part of the daily energy budget of free-ranging animals. We measured heart rate (fH) and rate of oxygen consumption ( ) in 12 little penguins while they digested a meal of sardines in order to determine whether they show specific dynamic action. In contrast to some studies of other penguin species, little penguins showed a substantial SDA, the magnitude of which was proportional to the size of the meal. The energy utilized in SDA was equivalent to 13.4% of the available energy content of the fish. Furthermore, animals such as penguins that forage in a cold environment will probably expend further energy in heating their food to body temperature to facilitate efficient digestion. It is estimated that this additional energy expenditure was equivalent to 1.6%-2.3% of the available energy content of the fish, depending on the time of year and therefore the temperature of the water. Changes in fH during digestion were qualitatively similar to those in , implying that there were no substantial circulatory adjustments during digestion and that the relationship between fH and in penguins is unaffected by digestive state

Binding, thermodynamics, and selectivity of a non-peptide antagonist to the melanocortin-4 receptor

The melanocortin-4 receptor (MC4R) is a potential drug target for treatment of obesity, anxiety, depression, and sexual dysfunction. Crystal structures for MC4R are not yet available, which has hindered successful structure-based drug design. Using microsecond-scale molecular-dynamics simulations, we have investigated selective binding of the non-peptide antagonist MCL0129 to a homology model of human MC4R (hMC4R). This approach revealed that, at the end of a multi-step binding process, MCL0129 spontaneously adopts a binding mode in which it blocks the agonistic-binding site. This binding mode was confirmed in subsequent metadynamics simulations, which gave an affinity for human hMC4R that matches the experimentally determined value. Extending our simulations of MCL0129 binding to hMC1R and hMC3R, we find that receptor subtype selectivity for hMC4R depends on few amino acids located in various structural elements of the receptor. These insights may support rational drug design targeting the melanocortin systems

Factorial aerobic scope is independent of temperature and primarily modulated by heart rate in exercising Murray Cod (Maccullochella peelii peelii)

Several previous reports, often from studies utilising heavily instrumented animals, have indicated that for teleosts, the increase in cardiac output ( ) during exercise is mainly the result of an increase in cardiac stroke volume (VS) rather than in heart rate (fH). More recently, this contention has been questioned following studies on animals carrying less instrumentation, though the debate continues. In an attempt to shed more light on the situation, we examined the heart rates and oxygen consumption rates ( ; normalised to a mass of 1 kg, given as ) of six Murray cod (Maccullochella peelii peelii; kg) equipped with implanted fH and body temperature data loggers. Data were determined during exposure to varying temperatures and swimming speeds to encompass the majority of the biological scope of this species. An increase in body temperature (Tb) from 14°C to 29°C resulted in linear increases in (26.67-41.78 μmol min−1 kg−1) and fH (22.3-60.8 beats min−1) during routine exercise but a decrease in the oxygen pulse (the amount of oxygen extracted per heartbeat; 1.28-0.74 μmol beat−1 kg−1). During maximum exercise, the factorial increase in was calculated to be 3.7 at all temperatures and was the result of temperature-independent 2.2- and 1.7-fold increases in fH and oxygen pulse, respectively. The constant factorial increases in fH and oxygen pulse suggest that the cardiovascular variables of the Murray cod have temperature-independent maximum gains that contribute to maximal oxygen transport during exercise. At the expense of a larger factorial aerobic scope at an optimal temperature, as has been reported for species of salmon and trout, it is possible that the Murray cod has evolved a lower, but temperature-independent, factorial aerobic scope as an adaptation to the largely fluctuating and unpredictable thermal climate of southeastern Australia

Vegans, vegetarians, fish-eaters and meat-eaters in the UK show discrepant environmental impacts

Modelled estimates of the environmental burden associated with low meat consumption suggest that substantial benefits could accrue from shifts in diet. However, modelled dietary scenarios may not reflect true dietary practice and have not previously accounted for variation in the environmental burden of food due to sourcing and production methods. We link dietary data from a sample of 55,504 vegans, vegetarians, fish-eaters and meat-eaters with food-level data on greenhouse gas emissions (CO2, CH4 and N2O and three aggregated measures of CO2 equivalents), land use, water use, eutrophication risk and potential biodiversity loss from a review of 570 life cycle assessments covering more than 38,000 farms in 119 countries. By conducting Monte Carlo analyses drawing from food-level distributions of the environmental indicators that are due to variations in sourcing and production methods we estimate both mean impact and 95% uncertainty intervals for each diet group. We find that for all of the environmental indicators there is a positive association with amount of animal-based food consumed. Dietary impacts for vegans were 25.1% (95% uncertainty interval: 15.1% - 37.0%) of high meat-eaters (>=100g total meat consumed per day) for greenhouse gas emissions, 25.1% (7.1% - 44.5%) for land use, 46.4% (21.0% - 81.0%) for water use, 27.0% (19.4% - 40.4%) for eutrophication and 34.3% (12.0% - 65.3%) for biodiversity. Large differences (at least 30% for GHG emissions, eutrophication, and land use) in the environmental impact of diets are also observed between low (<50g/d) and high meat-eaters. Although there is substantial variation in environmental indicators due to where and how food is produced, the resultant uncertainty does not obscure the strong relationship between animal-based food consumption and environmental impact. Debate about sourcing and production of foods should therefore not prevent action aimed at reducing consumption of animal-based foods

Leukotriene B4, an activation product of mast cells, is a chemoattractant for their progenitors

Mast cells are tissue-resident cells with important functions in allergy and inflammation. Pluripotential hematopoietic stem cells in the bone marrow give rise to committed mast cell progenitors that transit via the blood to tissues throughout the body, where they mature. Knowledge is limited about the factors that release mast cell progenitors from the bone marrow or recruit them to remote tissues. Mouse femoral bone marrow cells were cultured with IL-3 for 2 wk and a range of chemotactic agents were tested on the c-kit+ population. Cells were remarkably refractory and no chemotaxis was induced by any chemokines tested. However, supernatants from activated mature mast cells induced pronounced chemotaxis, with the active principle identified as leukotriene (LT) B4. Other activation products were inactive. LTB4 was highly chemotactic for 2-wk-old cells, but not mature cells, correlating with a loss of mRNA for the LTB4 receptor, BLT1. Immature cells also accumulated in vivo in response to intradermally injected LTB4. Furthermore, LTB4 was highly potent in attracting mast cell progenitors from freshly isolated bone marrow cell suspensions. Finally, LTB4 was a potent chemoattractant for human cord blood–derived immature, but not mature, mast cells. These results suggest an autocrine role for LTB4 in regulating tissue mast cell numbers

De novo identification of differentially methylated regions in the human genome

Background: The identification and characterisation of differentially methylated regions (DMRs) between phenotypes in the human genome is of prime interest in epigenetics. We present a novel method, DMRcate, that fits replicated methylation measurements from the Illumina HM450K BeadChip (or 450K array) spatially across the genome using a Gaussian kernel. DMRcate identifies and ranks the most differentially methylated regions across the genome based on tunable kernel smoothing of the differential methylation (DM) signal. The method is agnostic to both genomic annotation and local change in the direction of the DM signal, removes the bias incurred from irregularly spaced methylation sites, and assigns significance to each DMR called via comparison to a null model. Results: We show that, for both simulated and real data, the predictive performance of DMRcate is superior to those of Bumphunter and Probe Lasso, and commensurate with that of comb-p. For the real data, we validate all array-derived DMRs from the candidate methods on a suite of DMRs derived from whole-genome bisulfite sequencing called from the same DNA samples, using two separate phenotype comparisons. Conclusions: The agglomeration of genomically localised individual methylation sites into discrete DMRs is currently best served by a combination of DM-signal smoothing and subsequent threshold specification. The findings also suggest the design of the 450K array shows preference for CpG sites that are more likely to be differentially methylated, but its overall coverage does not adequately reflect the depth and complexity of methylation signatures afforded by sequencing. For the convenience of the research community we have created a user-friendly R software package called DMRcate, downloadable from Bioconductor and compatible with existing preprocessing packages, which allows others to apply the same DMR-finding method on 450K array data

Estimands: bringing clarity and focus to research questions in clinical trials

Precise specification of the research question and associated treatment effect of interest is essential in clinical research, yet recent work shows that they are often incompletely specified. The ICH E9 (R1) Addendum on Estimands and Sensitivity Analysis in Clinical Trials introduces a framework that supports researchers in precisely and transparently specifying the treatment effect they aim to estimate in their clinical trial. In this paper, we present practical examples to demonstrate to all researchers involved in clinical trials how estimands can help them to specify the research question, lead to a better understanding of the treatment effect to be estimated and hence increase the probability of success of the trial