Eicosanoid receptors as therapeutic targets for asthma

Eicosanoids comprise a group of oxidation products of arachidonic and 5,8,11,14,17-eicosapentaenoic acids formed by oxygenases and downstream enzymes. The two major pathways for eicosanoid formation are initiated by the actions of 5-lipoxygenase (5-LO), leading to leukotrienes (LTs) and 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), and cyclooxygenase (COX), leading to prostaglandins (PGs) and thromboxane (TX). A third group (specialized pro-resolving mediators; SPMs), including lipoxin A4 (LXA4) and resolvins (Rvs), are formed by the combined actions of different oxygenases. The actions of the above eicosanoids are mediated by approximately 20 G protein-coupled receptors, resulting in a variety of both detrimental and beneficial effects on airway smooth muscle and inflammatory cells that are strongly implicated in asthma pathophysiology. Drugs targeting proinflammatory eicosanoid receptors, including CysLT1, the receptor for LTD4 (montelukast) and TP, the receptor for TXA2 (seratrodast) are currently in use, whereas antagonists of a number of other receptors, including DP2 (PGD2), BLT1 (LTB4), and OXE (5-oxo-ETE) are under investigation. Agonists targeting anti-inflammatory/pro-resolving eicosanoid receptors such as EP2/4 (PGE2), IP (PGI2), ALX/FPR2 (LXA4), and Chemerin1 (RvE1/2) are also being examined. This review summarizes the contributions of eicosanoid receptors to the pathophysiology of asthma and the potential therapeutic benefits of drugs that target these receptors. Because of the multifactorial nature of asthma and the diverse pathways affected by eicosanoid receptors, it will be important to identify subgroups of asthmatics that are likely to respond to any given therapy.

Design and analysis of a Cross Car frame. Proposal of a three-level appraisal methodology

This paper analyses the structural design process of a Cross Car frame. Existing international and national technical regulations were analysed. The analysis of the regulatory guidelines led to the conclusion that the design only includes geometric or material restrictions at the international level. There are other more demanding national regulations (Spanish, for instance) that include structural verifications through static calculations for unidirectional actions (vertical, longitudinal or lateral). The main contribution of this paper is a novel three-level appraisal and a proposed redesign methodology. At the first level, a geometric and material verification is carried out. The second level involves the verification under unidirectional static actions. The third level entails a dynamic verification of three-dimensional combined actions. The load case is obtained from the computer multibody dynamics simulation of the full vehicle assembly in the worst case of driving conditions on circuits. This methodology is a far more detailed tool than traditional design processes. The use of this methodology allows for design optimisation, including all the effects of powertrain, brakes, suspension, steering and driver.

Evaluation of Anti-Cancer Effects of Lycopene extracted from Pink Guava Psidium guajava L. and its Combination with Apigenin or Resveratrol

Background Active biomolecules extracted from plant biodiversity appear to offer an alternative to the frequently toxic chemotherapy methods used to treat cancer. The micronutrients obtained from certain fruits, including pink guava Psidium guajava L., appear to have this property. We therefore focused on three biomolecules of interest: lycopene and apigenin, the main components in pink guava, and resveratrol, a reference biomolecule with recognized beneficial effects. Our aim was to assess and compare the activities of these micronutrients, first separately and then in combination, on LNCaP cells (prostate cancer) and UACC cells (melanoma). Methods MTT assays and confocal microscopy using anti-PCNA and anti-5-α-reductase antibodies enabled us to establish a ranking for these micronutrients for the first time, when they were studied separately to begin with, in terms of their anti-proliferative action. Results Apigenin was found to be the most active biomolecule in this respect, followed by lycopene and then resveratrol. In a subsequent study of the combined actions of these molecules, specifically “lycopene-apigenin” and “lycopene-resveratrol”, we found that the “lycopene-apigenin” combination has a stronger anti-cancer activity than the biomolecules used separately, and it is also superior to the “lycopene-resveratrol” combination. Conclusions Our study demonstrated the synergistic modes of action of lycopene and apigenin in the guava fruit and the importance of the combination of these two micronutrients in pink guava in order to obtain a high anti-cancer activity.

Intergenerational Ethics and Individual Duties

This chapter defends a cooperative promotional model of individual intergenerational moral duties. The individual can feel powerless and detached in the face of intergenerational moral challenges, which generally result from the combined actions of billions of people and require global-level solutions. Two individual duties are commonly debated: to promote effective collective action and to minimize one’s own contribution to the problem, for example, by cutting one’s carbon footprint. The cooperative promotional model incorporates both possibilities, including in many cases a duty to have a small family. The argument starts by assuming a shared or “weakly collective” duty requiring the global affluent to organize to avoid severe intergenerational injustice, a claim widely defended on positive and negative grounds. On the cooperative promotional model, each individual must cooperate with motivated others as far as reasonably possible to promote fair, effective, efficient collective-level progress toward this collective end. In determining how to act, individuals must consider collective or reliably coordinated action as well as the chance of triggering significant change through adding to aggregated individual actions. The account does not automatically require “taking up the slack” for obstructive individuals and institutions—it will often mandate cooperating to increase compliance—but is complicated by the need to adjust for unwilling duty bearers.

Tripartite suppression of fission yeast TORC1 signaling by the GATOR1-Sea3 complex, the TSC complex, and Gcn2 kinase

Mammalian target of rapamycin complex 1 (TORC1) is controlled by the GATOR complex composed of the GATOR1 subcomplex and its inhibitor, the GATOR2 subcomplex, sensitive to amino acid starvation. Previously, we identified fission yeast GATOR1 that prevents deregulated activation of TORC1 (Chia et al., 2017). Here, we report identification and characterization of GATOR2 in fission yeast. Unexpectedly, the GATOR2 subunit Sea3, an ortholog of mammalian WDR59, is physically and functionally proximal to GATOR1, rather than GATOR2, attenuating TORC1 activity. The fission yeast GATOR complex is dispensable for TORC1 regulation in response to amino acid starvation, which instead activates the Gcn2 pathway to inhibit TORC1 and induce autophagy. On the other hand, nitrogen starvation suppresses TORC1 through the combined actions of the GATOR1-Sea3 complex, the Gcn2 pathway, and the TSC complex, another conserved TORC1 inhibitor. Thus, multiple, parallel signaling pathways implement negative regulation of TORC1 to ensure proper cellular starvation responses.

A Novel Test of the Duchenne Marker: Smiles After Botulinum Toxin Treatment for Crow’s Feet Wrinkles

Smiles that vary in muscular configuration also vary in how they are perceived. Previous research suggests that “Duchenne smiles,” indicated by the combined actions of the orbicularis oculi (cheek raiser) and the zygomaticus major muscles (lip corner puller), signal enjoyment. This research has compared perceptions of Duchenne smiles with non-Duchenne smiles among individuals voluntarily innervating or inhibiting the orbicularis oculi muscle. Here we used a novel set of highly controlled stimuli: photographs of patients taken before and after receiving botulinum toxin treatment for crow’s feet lines that selectively paralyzed the lateral orbicularis oculi muscle and removed visible lateral eye wrinkles, to test perception of smiles. Smiles in which the orbicularis muscle was active (prior to treatment) were rated as more felt, spontaneous, intense, and happier. Post treatment patients looked younger, although not more attractive. We discuss the potential implications of these findings within the context of emotion science and clinical research on botulinum toxin.

An elastic-viscous-plastic structured UH model

On the basis of the structured unified hardening model (structured UH model) considering soil structured collapse, the time effect is take into account, and an elastic-viscous-plastic structured UH model is extended. In the presented model, the moving normal compression line (MNCL) is extended to a moving instant normal compression line (MINCL) for simulating both soil structure effect and time effect. Then the instance plastic strains irrespective of time effect are calculated by referring the MINCL, and the plastic strains due to time effect are calculated by referring the traditional instant normal compression line. Comparisons between test data and model simulation indicate that the presented elastic-viscous-plastic structured UH model is qualified to simulate the combined actions of soil structure and time effects both in compression and in shearing.