β2 adrenergic receptor desensitization through chronic stimulation of Natural Killer cells

Stress is a ubiquitous phenomenon that impacts the health of populations across all social strata. While acute stress can be beneficial, chronic stress elevates the risk for various diseases. A major part of the body’s stress response operates through the Sympathetic-Adrenal-Medullary (SAM) axis, leading to the release of epinephrine. This stress mediator can impact the immune system and alter the immune defense response. Natural Killer (NK) cells play a critical role in early immune responses, defending against pathogens and malignant cells. During stressful situations, NK cells are recruited to the blood circulation within minutes. The expression of adrenergic receptors, particularly β2 adrenergic receptors (β2AR), renders them sensitive to epinephrine. This study analyzed the response of NK cells to acute and chronic β2AR stimulation. We confirmed that acute β2AR stimulation inhibits NK cell functions in vitro. Epinephrine showed potent inhibitory effects, suppressing the activation of NK cells independent of the activation signal. The β2AR stimulation reduced NK cell adhesion, IFNγ secretion, degranulation, and cytotoxicity. We could show that β2AR stimulation effectively blocked the LFA-1 activity and led to the detachment from its ligand ICAM-1. The effect was rescued through the addition of Propranolol, a beta blocker, or ADRB2 knock out implicating LFA-1 inhibition as critical role for NK cell mobilization. The metabolic analysis revealed that β2AR agonists influenced the metabolic profile upon NK cell activation, leading to a prolonged glycolysis activity displayed by Seahorse ECAR values. In contrast, chronic β2AR stimulation nullified NK cell inhibition. After five days of β2AR treatment, NK cells were no longer responsive to a β2AR agonist. Chronic β2AR stimulation did not alter protein translation but led to receptor phosphorylation through the PKA feedback loop, initiating a G-protein switch and receptor desensitization. The β2AR treatment with long-acting β2 agonist (LABA) Indacaterol and epinephrine displayed different properties. While epinephrine inhibited NK cells only transiently as long as the β2AR agonist was abundant, Indacaterol could not be washed away and continuously stimulated the receptor. For this reason, a single LABA treatment was sufficient to induce NK cell desensitization. However, peripheral NK cells from LABA-treated patients remained responsive to epinephrine. They did not exhibit inhibition but showed an overall correlation in NK cell fitness with asthma severity. Taken together, the transient, inhibitory effect of epinephrine indicate that the hormone plays a crucial role in NK cell recruitment during acute stressful situations while repeated β2AR stimulation leads to desensitization

An Animal – Many Persons? Animal Personhood in Face of the Modularity of Mind

This essay analyzes how the Modularity of Mind impacts the anthrozoological argument that non-human animals are persons. Comparative research on human and animal minds suggests that human and other-than-human minds differ in their mental architecture such that animal cognition is largely modular whereas human thought fluidly integrates contents across modules. If animal minds are modular, then the idea of non-human personhood is challenged. Specifically, an animal with a modularized mind would not be one person facing the world and reflecting on itself in an integral manner, but would be an individual made of many persons: The animal would experience one reality and one self pertaining to each module (or partly-integrated domain of thought) and thus “be“ one distinct person in each of these worlds. Yet, within the framework of human-animal encounters, animal personhood can be meaningfully construed despite modularity of animal minds. On this account, animal personhood is conceived by virtue of the human ability to meta-integrate mental contents: The human mind meta-integrates the animal mind's modularized experience for the animal. Thus, in human-animal interactions, humans face the animal as a functional whole, as an integral animal person

Novas ferramentas de comunicação online, arquivo e anotação em vídeo para base de dados nas artes performativas

Artigo baseado na comunicação proferida no 8º Congresso SOPCOM: Comunicação Global, Cultura e Tecnologia, realizado na Escola Superior de Comunicação Social (ESCS-IPL), Lisboa, Portugal, 17-19 de outubro de 2013Vivemos num mundo em constante mudança. A uma velocidade impressionante, todos os dias surgem novos recursos tecnológicos. Utilizamos cada vez mais a Internet para obter e partilhar informações e assistimos ao aparecimento recursivo de novas ferramentas de comunicação online. Os últimos anos trouxeram-nos o Facebook, o Twitter, o YouTube e outras plataformas de comunicação. Elas permitem uma interatividade ainda maior entre emissor e recetor. Ao mesmo tempo, assistimos a uma disponibilização de conteúdos como nunca antes. Estamos cada vez mais a partilhar textos, vídeos, fotos, etc. Esta comunicação pretende explorar o potencial que essas novas ferramentas de comunicação online têm no âmbito cultural, nomeadamente qual o seu papel na criação de novos públicos, em fornecer informação, bem como qual o contributo para a construção da memória das organizações. A transitoriedade das artes performativas é acompanhada pela necessidade de contrariar essa transitoriedade, por meio de documentação e registos. Este desejo de "salvar" os eventos e o processo criativo atinge a sua expressão com o arquivo de informações dos diferentes momentos de produção, bem como a oportunidade de registar o evento e o processo de criação e produção do mesmo e apresentá-los através, por exemplo, das plataformas digitais. Esta comunicação pretende responder às seguintes questões: quais as novas ferramentas de comunicação online utilizadas pelas companhias de teatro de Lisboa e Vale do Tejo? De que forma a disponibilidade de conteúdos e respetivo arquivo contribuem para a memória das organizações? Como poderá ficar registado o processo criativo? Entre as várias referências, abordaremos o modelo de comunicação de dois sentidos que Grunig e Hunt (1984) nos apresentam e o conceito de mass self-communication de Castells (2010). Para Kirsner (2010), entramos na era da criatividade digital, em que os artistas têm as ferramentas para fazer o que imaginam e o público já não quer apenas consumir os bens culturais, mas sim, ter uma voz e participar. O processo criativo está agora dependente da escolha do público enquanto vagueia pelo ecrã. É o recetor que é detentor de um objeto que pode ser trocado. A realidade virtual tem incentivado o receptor a abandonar a sua posição de observador passivo e tornar-se um agente participante, o que implica um desafio às organizações: inventar novas formas de interface. É igualmente relevante falar de Foucault (1969) e Gisbourne (2008), que abordam as questões do arquivo e da disponibilidade de conteúdo. Na comunicação é também apresentado o projeto TBK (Transmedia Knowledge-Base for Performing Arts), uma base de conhecimento, em que podem existir diferentes tipos de materiais, documentos anotados e peças de autores que se interessam pela partilha dos seus conhecimentos específicos. No âmbito do projeto foi criada a ferramenta creation-tool, um anotador vídeo original, concebido para auxiliar os processos criativos nas artes performativas, funcionando como um caderno digital para anotações pessoais. É nossa intenção apresentar novas e eficazes ferramentas online que podem ser utilizadas pelas organizações culturais, a melhor forma de as gerir e como a disponibilização de conteúdos online e o seu arquivo podem contribuir para memória das organizações.info:eu-repo/semantics/publishedVersio

Consumer Psychology

This book provides students with a clear and concise guide to studying undergraduate courses in qualitative consumer research and ethnography. The authors present the major qualitative research approaches used in consumer and marketing research as well as practical procedures and theoretical aspects of research design, report presentation etc. In addition to that a weekly study guide, including comprehensive reading lists, completes the book

Consumer Psychology

This book provides students with a clear and concise guide to studying undergraduate courses in qualitative consumer research and ethnography. The authors present the major qualitative research approaches used in consumer and marketing research as well as practical procedures and theoretical aspects of research design, report presentation etc. In addition to that a weekly study guide, including comprehensive reading lists, completes the book

The Big Bad Wolf: The Formation of a Stereotype

In our essay, we explore this image of a stereotypical Big Bad Wolf, and we explain how many of the themes, which keep resurfacing in debates about wolves in present-day culture, can be thought of as being associated with this stereotype. In order to investigate these possible associations, we consider human perceptions of wolf behavior and evaluate how these may correspond to attributes associated with immorality or wickedness especially as such human characteristics are expressed in the Jungian shadow archetype of evil. We further explore how the stereotype of the Big Bad Wolf may be created through the unconscious merger of actual wolf behavior with notions associated with evil in human beings. We first delineate the agenda of this essay and then provide a short overview of research on human-wolf relations in Central Europe. We then review aspects of wolf biology that may be particularly salient and potentially problematic to a peaceful coexistence between wolves and humans. Finally, we identify correspondences between those aspects of wolf behavior and the human understanding of what constitutes an evil act and how this correspondence may reinforce the concept of the Big Bad Wolf

Exploring the C^N^C theme: Synthesis and biological properties of tridentate cyclometalated gold(III) complexes

A family of cyclometalated Au(III) complexes featuring a tridentate CNC scaffold has been synthesized and characterized. Microwave assisted synthesis of the ligands has also been exploited and optimized. The biological properties of the thus formed compounds have been studied in cancer cells and demonstrate generally moderate antiproliferative effects. Initial mechanistic insights have also been gained on the gold complex [Au(CNC)(GluS)] (3), and support the idea that the thioredoxin system may be a target for this family of compounds together with other relevant intracellular thiol-containing molecules. (C) 2017 Elsevier Ltd. All rights reserved

The NOD2 Single Nucleotide Polymorphisms rs2066843 and rs2076756 Are Novel and Common Crohn's Disease Susceptibility Gene Variants

Background: The aims were to analyze two novel NOD2 variants (rs2066843 and rs2076756) in a large cohort of patients with inflammatory bowel disease and to elucidate phenotypic consequences. Methodology/Principal Findings: Genomic DNA from 2700 Caucasians including 812 patients with Crohn's disease (CD), 442 patients with ulcerative colitis (UC), and 1446 healthy controls was analyzed for the NOD2 SNPs rs2066843 and rs2076756 and the three main CD-associated NOD2 variants p.Arg702Trp (rs2066844), p.Gly908Arg (rs2066847), and p.Leu1007fsX1008 (rs2066847). Haplotype and genotype-phenotype analyses were performed. The SNPs rs2066843 (p = 3.01×10−5, OR 1.48, [95% CI 1.23-1.78]) and rs2076756 (p = 4.01×10−6; OR 1.54, [95% CI 1.28-1.86]) were significantly associated with CD but not with UC susceptibility. Haplotype analysis revealed a number of significant associations with CD susceptibility with omnibus p values 0.9). However, in CD, SNPs rs2066843 and rs2076756 were more frequently observed than the other three common NOD2 mutations (minor allele frequencies for rs2066843 and rs2076756: 0.390 and 0.380, respectively). In CD patients homozygous for these novel NOD2 variants, genotype-phenotype analysis revealed higher rates of a penetrating phenotype (rs2076756: p = 0.015) and fistulas (rs2076756: p = 0.015) and significant associations with CD-related surgery (rs2076756: p = 0.003; rs2066843: p = 0.015). However, in multivariate analysis only disease localization (p<2×10−16) and behaviour (p = 0.02) were significantly associated with the need for surgery. Conclusion/Significance: The NOD2 variants rs2066843 and rs2076756 are novel and common CD susceptibility gene variants

The histone deacetylase inhibitor SAHA acts in synergism with fenretinide and doxorubicin to control growth of rhabdoid tumor cells

Background: Rhabdoid tumors are highly aggressive malignancies affecting infants and very young children. In many instances these tumors are resistant to conventional type chemotherapy necessitating alternative approaches. Methods: Proliferation assays (MTT), apoptosis (propidium iodide/annexin V) and cell cycle analysis (DAPI), RNA expression microarrays and western blots were used to identify synergism of the HDAC (histone deacetylase) inhibitor SAHA with fenretinide, tamoxifen and doxorubicin in rhabdoidtumor cell lines. Results: HDAC1 and HDAC2 are overexpressed in primary rhabdoid tumors and rhabdoid tumor cell lines. Targeting HDACs in rhabdoid tumors induces cell cycle arrest and apoptosis. On the other hand HDAC inhibition induces deregulated gene programs (MYCC-, RB program and the stem cell program) in rhabdoid tumors. These programs are in general associated with cell cycle progression. Targeting these activated pro-proliferative genes by combined approaches of HDAC-inhibitors plus fenretinide, which inhibits cyclinD1, exhibit strong synergistic effects on induction of apoptosis. Furthermore, HDAC inhibition sensitizes rhabdoid tumor cell lines to cell death induced by chemotherapy. Conclusion: Our data demonstrate that HDAC inhibitor treatment in combination with fenretinide or conventional chemotherapy is a promising tool for the treatment of chemoresistant rhabdoid tumors.<br