Biased and g protein-independent signaling of chemokine receptors

Biased signaling or functional selectivity occurs when a 7TM receptor preferentially activates one of several available pathways. It can be divided into three distinct forms: ligand bias, receptor bias, and tissue or cell bias, where it is mediated by different ligands (on the same receptor), different receptors (with the same ligand) or different tissues or cells (for the same ligand-receptor pair). Most often biased signaling is differentiated into G protein-dependent and β-arrestin-dependent signaling. Yet, it may also cover signaling differences within these groups. Moreover, it may not be absolute, i.e. full versus no activation. Here we discuss biased signaling in the chemokine system, including the structural basis for biased signaling in chemokine receptors, as well as in class A 7TM receptors in general. This includes overall helical movements and the contributions of micro-switches based on recently published 7TM crystals and molecular dynamics studies. All three forms of biased signaling are abundant in the chemokine system. This challenges our understanding of classic redundancy inevitably ascribed to this system, where multiple chemokines bind to the same receptor and where a single chemokine may bind to several receptors – in both cases with the same functional outcome. The ubiquitous biased signaling confer a hitherto unknown specificity to the chemokine system with a complex interaction pattern that is better described as promiscuous with context-defined roles and different functional outcomes in a ligand-, receptor- or cell/tissue-defined manner. As the low number of successful drug development plans implies, there are great difficulties in targeting chemokine receptors; in particular with regard to receptor antagonists as anti-inflammatory drugs. Un-defined and putative non-selective targeting of the complete cellular signaling system could be the underlying cause of lack of success. Therefore, biased ligands could be the solution

Potentiale for flere uheldsdata på baggrund af fejlklassificeringer af ekstrauheld

Af tidligere studier vides det, at der er stor usikkerhed forbundet med den officielle uheldsdatabase, der er grundlag for trafiksikkerhedsarbejdet. Usikkerheden er ikke ønskelig, og lægger op til, at undersøge om der på andre måder kan opnås yderligere kendskab til flere uheldsdata. Andre måder at indsamle data på er ved selvrapportering, forsikringsdata og sygehusdata, dog kan ingen af de nævnte benyttes direkte i trafiksikkerhedsarbejdet, da uheldene ikke stedfæstes. Men hvilke muligheder er der så for flere uheldsdata? Hvis uheld skal indgå i det stedbestemte trafiksikkerhedsarbejde, skal de være stedfæstede. Uheld registreret af politiet stedfæstes. Dette omfatter person- og materielskadeuheld samt ekstrauheld, der alle er en del af den officielle uheldsstatistik. Generelt indgår ekstrauheld sjældent i trafiksikkerhedsarbejdet, og udviklingen i antal ekstrauheld præsenteres sjældent. Imidlertid er udviklingen i antal ekstrauheld interessant, da den afviger fra uheldsudviklingen generelt. Antallet af registrerede ekstrauheld er steget fra år 2000 til 2015, ligesom uheldsarten udgør en større og større andel af de samlede registrerede uheld. En stigning i ekstrauheld er ikke et problem i sig selv, men hvis stigingen skyldes, at uheldene ikke er korrekt registrerede, og uheldet dermed burde indgå i den officielle statistik, går værdifulde uheldsdata tabt. Det er således undersøgt, om der ligger et potentiale for flere uheldsdata i de registrerede ekstrauheld, grundet fejlklassificeringer

Intercultural matters : fiction and cultural identity

Socrates Programme 57087 - CP- 3- 2000- 1 - UK - Comenius-C31This booklet evolved from a European Teacher Training Intensive Course on “Fiction and Cultural Identity”, which took place during 2000 and 2001. The course, taught by teacher trainers from several European countries, had as its aim to explore, to compare, to analyse, through fiction, through cultural theories and theories of education an area of practice – literature, through which cultural difference, ordering and association are produced. Developed under the banner of program Comenius financed by the European Union, and with a view to promote Intercultural Education, the course had as its further aims the following: (a)to acknowledge the national and cultural diversity of Europe within its common aims and political/economical union; (b)to promote critical attitudes towards prejudices, stereotypes, social and cultural injustice; (c)to develop respect for those we see as ‘the other’ and understand the meaning of ‘difference’; (d)to develop competence for an European citizenship, i.e. an ‘interdependent citizenship’

The positive feedback loop between academic self-efficacy, academic initiative, and grade point average: a parallel process latent growth curve model

This study investigates the associations between students’ developmental changes in academic self-efficacy, academic initiative, and grade point average (GPA) during a three-year upper secondary education. The sample consisted of 1453 students aged 16–19 (60.6% girls; baseline mean age = 17.00, SD = .91; 56.1% high perceived family wealth; and 74.9% Norwegian-born). To explore how changes in academic self-efficacy, academic initiative, and GPA were related, we investigated a theoretical parallel process latent growth curve model. The results implied that, during upper secondary school, academic self-efficacy declined, while academic initiative and GPA remained stable. We found possible ceiling effects within and between several of the study’s constructs. The main finding was support for a positive feedback loop between the developmental trajectories of academic self-efficacy, academic initiative, and GPA. The present study adds new insight that should be taken into consideration when promoting positive educational development during late secondary school.publishedVersio