Targeting the P2Y13 receptor suppresses IL-33 and HMGB1 release and ameliorates experimental asthma

Rationale:The alarmins IL-33 and HMGB1 (high mobility group box 1) contribute to type 2 inflammation and asthma pathogenesis. Objectives: To determine whether P2Y13-R (P2Y13 receptor), a purinergic GPCR (G protein-coupled receptor) and risk allele for asthma, regulates the release of IL-33 and HMGB1. Methods: Bronchial biopsy specimens were obtained from healthy subjects and subjects with asthma. Primary human airway epithelial cells (AECs), primary mouse AECs, or C57Bl/6 mice were inoculated with various aeroallergens or respiratory viruses, and the nuclear-to-cytoplasmic translocation and release of alarmins was measured by using immunohistochemistry and an ELISA. The role of P2Y13-R in AEC function and in the onset, progression, and exacerbation of experimental asthma was assessed by using pharmacological antagonists and mice with P2Y13-R gene deletion. Measurements and Main Results: Aeroallergen exposure induced the extracellular release of ADP and ATP, nucleotides that activate P2Y13-R. ATP, ADP, and aeroallergen (house dust mite, cockroach, or Alternaria antigen) or virus exposure induced the nuclear-to-cytoplasmic translocation and subsequent release of IL-33 and HMGB1, and this response was ablated by genetic deletion or pharmacological antagonism of P2Y13. In mice, prophylactic or therapeutic P2Y13-R blockade attenuated asthma onset and, critically, ablated the severity of a rhinovirus-associated exacerbation in a high-fidelity experimental model of chronic asthma. Moreover, P2Y13-R antagonism derepressed antiviral immunity, increasing IFN-λ production and decreasing viral copies in the lung. Conclusions: We identify P2Y13-R as a novel gatekeeper of the nuclear alarmins IL-33 and HMGB1 and demonstrate that the targeting of this GPCR via genetic deletion or treatment with a small-molecule antagonist protects against the onset and exacerbations of experimental asthma. </p

Ett samtal om samtal : Chefers upplevelse av medarbetarsamtalet som förändringsverktyg

Studien syftar till att undersöka medarbetarsamtal utifrån ett chefsperspektiv och studien intresserar sig för vilka effekter cheferna upplever att samtalet generar i verksamheten och hur de använder sig av samtalet i utveckling av verksamheten. Metoden är kvalitativ och utgörs av åtta stycken semistrukturerade intervjuer, där individer med personalansvar fick möjlighet att berätta sina upplevelser och erfarenheter av samtalet samt reflektera runt dess betydelse utifrån deras position i organisationen. Resultatet visar att medarbetarsamtalet är en tids- och energikrävande insats för cheferna som ibland måste ställa sin fritid till förfogande. Dialog och social kompetens lyfts fram som nyckelfaktorer för ett bra samtal och deltagarna i studien förlitar sig på sin upparbetade erfarenhet och känner en trygghet i sin yrkesroll vid genomförandet av samtalet. Denna studie bidrar till djupare kunskap om chefernas upplevelse av medarbetarsamtalet och dess potential som styrverktyg inom organisationer och kan medverka till framtida forskning som ett komplement till studier rörande medarbetarnas upplevelse. Studien visar att det även kan vara av intresse att via observationer av samtalet undersöka hur väl det praktiska genomförandet stämmer överens med chefens intentioner om verksamhetsutveckling.This study aims to examine employee review, based on a manager perspective with an interest in what effects leaders' experience it is generating, and how they use the employee review in the development of their organization. The method used in this study is qualitative and comprises eight semi-structured interviews, in which individuals with personnel responsibility where given the opportunity to share their comprehension off and experience from the phenomenon employee review, and its importance based on their position in the organization. The result shows that the employee review is a time and energy-intensive effort for the managers who sometimes have to make their spare time available for the task.Dialogue and social skills are highlighted as key factors for a good conversation, and the participants in the study relies on their self-generated experience and feel confident in their professional role in the implementation of employee review. This study contributes to deeper knowledge of the managers' experience regarding the employee review and its potential as an organizational management tool, and can contribute to future research as a complement to studies regarding the employees' experience. The results shows that it may also be of interest to study employee reviews through observations of the interview, how well the practical implementation is in line with the manager's intentions on business development

Nanotechnology and Drug Delivery

Nowadays nanotechnology represents an expanding field that is providing powerfultools for the pharmaceutical industry such as polymeric, solid lipid, metallic, and magnetic NPs, liposomes, dendrimers, and other nanostructures. The development of nanopharmaceutics allows the understanding of some of the major mechanisms of current diseases on a molecular basis. Particularly, drug delivery mediated by nanosystems is relevant since NPs are able to reach the target organ and deliver the drug with a desirable profile according to the pathology needs, minimizing undesirable side effects. The main physicochemical properties of nanosystems are related with the increase in the surface-to-volume ratio of the particles, their permeability across biological barriers, and the surface modification of nanodevices. These parameters are relevant in drug loading and release and particularly for the targeted delivery to cells showing specific markers or receptors in the membrane surface.Fil: Islan, German Abel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; ArgentinaFil: Martin Saldaña, Sergio. Gihon Laboratorios Químicos SRL; ArgentinaFil: Chevalier, Merari Tumin. Gihon Laboratorios Químicos SRL; ArgentinaFil: Alvarez, Vera Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y Tecnología de Materiales. Universidad Nacional de Mar del Plata. Facultad de Ingeniería. Instituto de Investigaciones en Ciencia y Tecnología de Materiales; ArgentinaFil: Castro, Guillermo Raul. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; Argentin