Expression and function of proteinase-activated receptor 2 in human bronchial smooth muscle

Trypsin and mast cell tryptase cleave proteinase-activated receptor 2 (PAR2) to induce alterations in contraction of airway smooth muscle that have been implicated in asthma in experimental animals. Although tryptase inhibitors are under development for treatment of asthma, little is known about the localization and function of PAR2 in human airways. We detected PAR2 expression in primary cultures of human airway smooth muscle cells using reverse transcriptase/polymerase chain reaction (RT-PCR) and immunofluorescence. The PAR2 agonists trypsin, tryptase, and an activating peptide (SLIGKV-NH2) stimulated calcium mobilization in these cells. PAR2 agonists strongly desensitized responses to a second challenge of trypsin and SLIGKV-NH2, but not to thrombin, indicating that they activate a receptor distinct from the thrombin receptors. Immunoreactive PAR2 was detected in smooth muscle, epithelium, glands, and endothelium of human bronchi. Trypsin, SLIGKV-NH2, and tryptase stimulated contraction of isolated human bronchi. Contraction was increased by removal of the epithelium and diminished by indomethacin. Thus, PAR2 is expressed by human bronchial smooth muscle where its activation mobilizes intracellular Ca2+ and induces contraction. These results are consistent with the hypothesis that PAR2 agonists, including tryptase, induce bronchoconstriction of human airway by stimulating smooth muscle contraction. PAR2 antagonists may be useful drugs to prevent bronchoconstriction.

Impacts of plant-based foods in ancestral hominin diets on the metabolism and function of gut microbiota in vitro

Ancestral human populations had diets containing more indigestible plant material than present-day diets in industrialized countries. One hypothesis for the rise in prevalence of obesity is that physiological mechanisms for controlling appetite evolved to match a diet with plant fiber content higher than that of present-day diets. We investigated how diet affects gut microbiota and colon cells by comparing human microbial communities with those from a primate that has an extreme plant-based diet, namely, the gelada baboon, which is a grazer. The effects of potato (high starch) versus grass (high lignin and cellulose) diets on human-derived versus gelada-derived fecal communities were compared in vitro. We especially focused on the production of short-chain fatty acids, which are hypothesized to be key metabolites influencing appetite regulation pathways. The results confirmed that diet has a major effect on bacterial numbers, short-chain fatty acid production, and the release of hormones involved in appetite suppression. The potato diet yielded greater production of short-chain fatty acids and hormone release than the grass diet, even in the gelada cultures, which we had expected should be better adapted to the grass diet. The strong effects of diet on hormone release could not be explained, however, solely by short-chain fatty acid concentrations. Nuclear magnetic resonance spectroscopy found changes in additional metabolites, including betaine and isoleucine, that might play key roles in inhibiting and stimulating appetite suppression pathways. Our study results indicate that a broader array of metabolites might be involved in triggering gut hormone release in humans than previously thought. IMPORTANCE: One theory for rising levels of obesity in western populations is that the body's mechanisms for controlling appetite evolved to match ancestral diets with more low-energy plant foods. We investigated this idea by comparing the effects of diet on appetite suppression pathways via the use of gut bacterial communities from humans and gelada baboons, which are modern-day primates with an extreme diet of low-energy plant food, namely, grass. We found that diet does play a major role in affecting gut bacteria and the production of a hormone that suppresses appetite but not in the direction predicted by the ancestral diet hypothesis. Also, bacterial products were correlated with hormone release that were different from those normally thought to play this role. By comparing microbiota and diets outside the natural range for modern humans, we found a relationship between diet and appetite pathways that was more complex than previously hypothesized on the basis of more-controlled studies of the effects of single compounds.

Art, value and function

Is the concept of a work of art an evaluative concept: does its application imply a positive evaluation? I shall discuss this question by considering two opposing attempts at defining art, namely the Institutional Theory and the view that art is a functional concept. I shall argue that the concept of art does not imply an unconditionally positive evaluation, but that art is a prestige concept. Moreover, it will be shown that functional definitions of art are flawed.

Symmorphosis through dietary regulation: a combinatorial role for proteolysis, autophagy and protein synthesis in normalising muscle metabolism and function of hypertrophic mice after acute starvation

Animals are imbued with adaptive mechanisms spanning from the tissue/organ to the cellular scale which insure that processes of homeostasis are preserved in the landscape of size change. However we and others have postulated that the degree of adaptation is limited and that once outside the normal levels of size fluctuations, cells and tissues function in an aberant manner. In this study we examine the function of muscle in the myostatin null mouse which is an excellent model for hypertrophy beyond levels of normal growth and consequeces of acute starvation to restore mass. We show that muscle growth is sustained through protein synthesis driven by Serum/Glucocorticoid Kinase 1 (SGK1) rather than Akt1. Furthermore our metabonomic profiling of hypertrophic muscle shows that carbon from nutrient sources is being channelled for the production of biomass rather than ATP production. However the muscle displays elevated levels of autophagy and decreased levels of muscle tension. We demonstrate the myostatin null muscle is acutely sensitive to changes in diet and activates both the proteolytic and autophagy programmes and shutting down protein synthesis more extensively than is the case for wild-types. Poignantly we show that acute starvation which is detrimental to wild-type animals is beneficial in terms of metabolism and muscle function in the myostatin null mice by normalising tension production.

A novel interaction between FlnA and Syk regulates platelet ITAM-mediated receptor signaling and function

Filamin A (FlnA) cross-links actin filaments and connects the Von Willebrand factor receptor GPIb-IX-V to the underlying cytoskeleton in platelets. Because FlnA deficiency is embryonic lethal, mice lacking FlnA in platelets were generated by breeding FlnA(loxP/loxP) females with GATA1-Cre males. FlnA(loxP/y) GATA1-Cre males have a macrothrombocytopenia and increased tail bleeding times. FlnA-null platelets have decreased expression and altered surface distribution of GPIbalpha because they lack the normal cytoskeletal linkage of GPIbalpha to underlying actin filaments. This results in approximately 70% less platelet coverage on collagen-coated surfaces at shear rates of 1,500/s, compared with wild-type platelets. Unexpectedly, however, immunoreceptor tyrosine-based activation motif (ITAM)- and ITAM-like-mediated signals are severely compromised in FlnA-null platelets. FlnA-null platelets fail to spread and have decreased alpha-granule secretion, integrin alphaIIbbeta3 activation, and protein tyrosine phosphorylation, particularly that of the protein tyrosine kinase Syk and phospholipase C-gamma2, in response to stimulation through the collagen receptor GPVI and the C-type lectin-like receptor 2. This signaling defect was traced to the loss of a novel FlnA-Syk interaction, as Syk binds to FlnA at immunoglobulin-like repeat 5. Our findings reveal that the interaction between FlnA and Syk regulates ITAM- and ITAM-like-containing receptor signaling and platelet function.

The cooler side of mycorrhizas: their occurrence and functioning at low temperatures

Mycorrhizal associations occur in a range of habitats in which soils are subject to low temperature (≤15 °C) for a significant part of the year. Despite this, most of our understanding of mycorrhizal fungi and their interactions with their plant hosts is based on physiological investigations conducted in the range 20–37 °C using fungi of temperate origin. Comparatively little consideration has been given to the cold edaphic conditions in which many mycorrhizas survive and prosper, and the physiological and ecological consequences of their low temperature environments. In this review, we consider the distribution and persistence of arbuscular and ectomycorrhizal mycorrhizal associations in cold environments and highlight progress in understanding adaptations to freezing resistance and nutrient acquisition at low temperature in mycorrhizal fungi.

Role of FTO in adipocyte development and function: recent insights

In 2007, FTO was identified as the first genome-wide association study (GWAS) gene associated with obesity in humans. Since then, various animal models have served to establish the mechanistic basis behind this association. Many earlier studies focussed on FTO’s effects on food intake via central mechanisms. Emerging evidence, however, implicates adipose tissue development and function in the causal relationship between perturbations in FTO expression and obesity. The purpose of this mini review is to shed light on these new studies of FTO function in adipose tissue and present a clearer picture of its impact on obesity susceptibility.

Ubiquitous monitoring and behavioural change: a semiotic perspective

We are soon approaching the pervasive-era ofcomputing, where computers are embedded intoobjects and the environment in order to provide newservices to users. Significant levels of data arerequired in order for these services to function asintended, and it is this collection of data which werefer to as ubiquitous monitoring. Existing monitoringtechniques have often been known to cause undesirableeffects, and it is anticipated that ubiquitousmonitoring, with its increased coverage, will lead toincreases in their occurrence and impact. To date, theeffects of ubiquitous monitoring on human behaviourhave not been sufficiently investigated, furtherincreasing the risk of undesirable effects. We propose apreliminary model consisting of a series of factorsbelieved to influence human behavior and augmentedby the Theory of Planned Behaviour. This model mayallow us to understand, predict, and therefore preventany undesirable effects caused by ubiquitousmonitoring.

The variability of tropical ice cloud properties as a function of the large-scale context from ground-based radar-lidar observations over Darwin, Australia

The high complexity of cloud parameterizations now held in models puts more pressure on observational studies to provide useful means to evaluate them. One approach to the problem put forth in the modelling community is to evaluate under what atmospheric conditions the parameterizations fail to simulate the cloud properties and under what conditions they do a good job. It is the ambition of this paper to characterize the variability of the statistical properties of tropical ice clouds in different tropical "regimes" recently identified in the literature to aid the development of better process-oriented parameterizations in models. For this purpose, the statistical properties of non-precipitating tropical ice clouds over Darwin, Australia are characterized using ground-based radar-lidar observations from the Atmospheric Radiation Measurement (ARM) Program. The ice cloud properties analysed are the frequency of ice cloud occurrence, the morphological properties (cloud top height and thickness), and the microphysical and radiative properties (ice water content, visible extinction, effective radius, and total concentration). The variability of these tropical ice cloud properties is then studied as a function of the large-scale cloud regimes derived from the International Satellite Cloud Climatology Project (ISCCP), the amplitude and phase of the Madden-Julian Oscillation (MJO), and the large-scale atmospheric regime as derived from a long-term record of radiosonde observations over Darwin. The vertical variability of ice cloud occurrence and microphysical properties is largest in all regimes (1.5 order of magnitude for ice water content and extinction, a factor 3 in effective radius, and three orders of magnitude in concentration, typically). 98 % of ice clouds in our dataset are characterized by either a small cloud fraction (smaller than 0.3) or a very large cloud fraction (larger than 0.9). In the ice part of the troposphere three distinct layers characterized by different statistically-dominant microphysical processes are identified. The variability of the ice cloud properties as a function of the large-scale atmospheric regime, cloud regime, and MJO phase is large, producing mean differences of up to a factor 8 in the frequency of ice cloud occurrence between large-scale atmospheric regimes and mean differences of a factor 2 typically in all microphysical properties. Finally, the diurnal cycle of the frequency of occurrence of ice clouds is also very different between regimes and MJO phases, with diurnal amplitudes of the vertically-integrated frequency of ice cloud occurrence ranging from as low as 0.2 (weak diurnal amplitude) to values in excess of 2.0 (very large diurnal amplitude). Modellers should now use these results to check if their model cloud parameterizations are capable of translating a given atmospheric forcing into the correct statistical ice cloud properties.

Tangeretin regulates platelet function through inhibition of phosphoinositide 3-Kinase and cyclic nucleotide signaling

OBJECTIVE: Dietary flavonoids have long been appreciated in reducing cardiovascular disease risk factors, but their mechanisms of action are complex in nature. In this study, the effects of tangeretin, a dietary flavonoid, were explored on platelet function, signaling, and hemostasis. APPROACH AND RESULTS: Tangeretin inhibited agonist-induced human platelet activation in a concentration-dependent manner. It inhibited agonist-induced integrin αIIbβ3 inside-out and outside-in signaling, intracellular calcium mobilization, and granule secretion. Tangeretin also inhibited human platelet adhesion and subsequent thrombus formation on collagen-coated surfaces under arterial flow conditions in vitro and reduced hemostasis in mice. Further characterization to explore the mechanism by which tangeretin inhibits platelet function revealed distinctive effects of platelet signaling. Tangeretin was found to inhibit phosphoinositide 3-kinase-mediated signaling and increase cGMP levels in platelets, although phosphodiesterase activity was unaffected. Consistent with increased cGMP levels, tangeretin increased the phosphorylation of vasodilator-stimulated phosphoprotein at S239. CONCLUSIONS: This study provides support for the ability and mechanisms of action of dietary flavonoids to modulate platelet signaling and function, which may affect the risk of thrombotic disease.

Assessing species’ habitat associations from occurrence records, standardised monitoring data and expert opinion: a test with British butterflies

Accurate knowledge of species’ habitat associations is important for conservation planning and policy. Assessing habitat associations is a vital precursor to selecting appropriate indicator species for prioritising sites for conservation or assessing trends in habitat quality. However, much existing knowledge is based on qualitative expert opinion or local scale studies, and may not remain accurate across different spatial scales or geographic locations. Data from biological recording schemes have the potential to provide objective measures of habitat association, with the ability to account for spatial variation. We used data on 50 British butterfly species as a test case to investigate the correspondence of data-derived measures of habitat association with expert opinion, from two different butterfly recording schemes. One scheme collected large quantities of occurrence data (c. 3 million records) and the other, lower quantities of standardised monitoring data (c. 1400 sites). We used general linear mixed effects models to derive scores of association with broad-leaf woodland for both datasets and compared them with scores canvassed from experts. Scores derived from occurrence and abundance data both showed strongly positive correlations with expert opinion. However, only for occurrence data did these fell within the range of correlations between experts. Data-derived scores showed regional spatial variation in the strength of butterfly associations with broad-leaf woodland, with a significant latitudinal trend in 26% of species. Sub-sampling of the data suggested a mean sample size of 5000 occurrence records per species to gain an accurate estimation of habitat association, although habitat specialists are likely to be readily detected using several hundred records. Occurrence data from recording schemes can thus provide easily obtained, objective, quantitative measures of habitat association.