Respective Contributions of Single and Compound Granule Fusion to Secretion by Activated Platelets

Although granule secretion is pivotal in many platelet responses, the fusion routes of α and δ granule release remain uncertain. We used a 3D reconstruction approach based on electron microscopy to visualize the spatial organization of granules in unstimulated and activated platelets. Two modes of exocytosis were identified: a single mode that leads to release of the contents of individual granules and a compound mode that leads to the formation of granule-to-granule fusion, resulting in the formation of large multigranular compartments. Both modes occur during the course of platelet secretion. Single fusion events are more visible at lower levels of stimulation and early time points, whereas large multigranular compartments are present at higher levels of agonist and at later time points. Although α granules released their contents through both modes of exocytosis, δ granules underwent only single exocytosis. To define the underlying molecular mechanisms, we examined platelets from vesicle-associated membrane protein 8 (VAMP8) null mice. After weak stimulation, compound exocytosis was abolished and single exocytosis decreased in VAMP8 null platelets. Higher concentrations of thrombin bypassed the VAMP8 requirement, indicating that this isoform is a key but not a required factor for single and/or compound exocytosis. Concerning the biological relevance of our findings, compound exocytosis was observed in thrombi formed after severe laser injury of the vessel wall with thrombin generation. After superficial injury without thrombin generation, no multigranular compartments were detected. Our studies suggest that platelets use both modes of membrane fusion to control the extent of agonist-induced exocytosis

Structural dysconnectivity in offspring of individuals with bipolar disorder: The effect of co-existing clinical-high-risk for bipolar disorder

Background: Bipolar disorder (BD) might be associated in disturbances in brain networks. However, little is known about the abnormalities in structural brain connectivity which might be related to vulnerability to BD and predictive of the emergence of manic symptoms. No previous study has investigated the effect of subthreshold syndromes on structural dysconnectivity in offspring of parents with BD (BDoff)

Neurocognitive heterogeneity in young offspring of patients with bipolar disorder: The effect of putative clinical stages

Background: Bipolar disorder (BD) is associated with significant cognitive heterogeneity. In recent years, a number of studies have investigated cognitive subgroups in BD using data-driven methods and found that BD includes several subgroups including a severely impaired and a neurocognitively intact cluster. Studies in offspring of BD (BDoff) are particularly important to establish the timing of emergence of cognitive subgroups but studies investigating cognitive heterogeneity in BDoff are lacking. Our aim was to investigate cognitive heterogeneity in BDoff and the relationship between cognitive heterogeneity and putative clinical stages of BD

Neurocognition in young offspring of individuals with bipolar disorder: The role of co-existing familial and clinical high-risk for bipolar disorder

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Qualification Design and Sanitation for Pure Drinkable Water:A Project Study

Drinking water quality management has been a key element of primary prevention and control of waterborne diseases for a long time. This chapter is based on the EU Project “Implementation of ECVET for Qualification Design in Drinking Water Treatment Plants and Sanitation for Pure Drinkable Water PUREH2O” that contributes to the recognition and transparency of qualifications at the EU level and provides an innovative model for competencies for the potable water sector. The main dilemma that PURE-H2O intends to tackle is the lack of mutual recognition of qualification that is often impaired by national restrictions by applying EUROPASS, European/National Qualification Framework (EQF/.NQF), and the European Credit System for Vocational Education and Training (ECVET) instruments. The aim of the project is to enhance the quality and performance of VET system improving education in drinking water supply and development. This project could also be achieved through promoting creativity, innovation, and transfer of EQF/NQF principles in education of the main target group in the sector

Combination of Epstein-Barr virus nuclear antigen 1, 3 and lytic antigen BZLF1 peptide pools allows fast and efficient stimulation of Epstein-Barr virus-specific T cells for adoptive immunotherapy

International audienceBackground: Epstein-Barr virus (EBV) infection is a major cause of morbidity following hematopoietic stem cell transplantation. EBV-infected B cells may not respond to rituximab treatment and may lead to a life-threatening post-transplantation lymphoproliferative disorder. Adoptive cellular immunotherapy using EBV-lymphoblastoid cell lines (LCL) as stimulating antigen has proved effective in restoring specific immunity. However, EBV presents several immunodominant antigens, and developing a swift and effective clinical-grade immunotherapy relies on the definition of a Good Manufacturing Practices (GMP) universal stimulating antigen.Methods: Peripheral blood mononuclear cells (PBMCs) from six donors with a cellular immune response against EBV were immunoselected after stimulation with a new EBV antigen associated with an EBNA3 peptide pool.Results: After immunoselection, a mean of 0.53 ± 0.25 × 106 cells was recovered consisting of a mean of 24.77 ± 18.01% CD4+-secreting interferon (IFN)-γ and 51.42 ± 26.92% CD8+-secreting IFN-γ. The T memory stem cell sub-population was identified. EBV-specific T cells were expanded in vitro, and their ability to secrete IFN-γ and to proliferate after re-stimulation with EBV antigen was confirmed. A specific lysis was observed against autologous target cells pulsed with EBV peptide pools (57.6 ± 11.5%) and against autologous EBV-LCL (18.3 ± 7.3%). A mean decrease of 94.7 ± 3.3% in alloreactivity against third-party donor mononuclear cells with EBV-specific T cells was observed compared with PBMCs before selection.Conclusions: Our results show that a combination of peptide pools including EBNA3 is needed to generate EBV-specific T cells with good specific cytotoxicity and devoid of alloreactivity, but as yet GMP grade is not fully achieved