25 research outputs found
Cytoskeletal mechanics of proplatelet maturation and platelet release
New steps in the process of conversion of proplatelet extensions from megakaryocytes into mature platelets are defined
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A model of the PI cycle reveals the regulating roles of lipid-binding proteins and pitfalls of using mosaic biological data
The phosphatidylinositol (PI) cycle is central to eukaryotic cell signaling. Its complexity, due to the number of reactions and lipid and inositol phosphate intermediates involved makes it difficult to analyze experimentally. Computational modelling approaches are seen as a way forward to elucidate complex biological regulatory mechanisms when this cannot be achieved solely through experimental approaches. Whilst mathematical modelling is well established in informing biological systems, many models are often informed by data sourced from multiple unrelated cell types (mosaic data) or from purified enzyme data. In this work, we develop a model of the PI cycle informed by experimental and omics data taken from a single cell type, namely platelets. We were able to make a number of predictions regarding the regulation of PI cycle enzymes, the importance of the number of receptors required for successful GPCR signaling and the importance of lipid- and protein-binding proteins in regulating second messenger outputs. We then consider how pathway behavior differs, when fully informed by data for HeLa cells and show that model predictions remain consistent. However, when informed by mosaic experimental data model predictions greatly vary illustrating the risks of using mosaic datasets from unrelated cell types
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Immobilization of nonactivated unfixed platelets for real-time single-cell analysis
Existing methods for measuring the response of individual platelets to stimulation are limited. They either measure each platelet at one discrete time-point (flow cytometry) or rely on adhesive ligands to immobilize platelets that concomitantly generate activation signals (microscopy). Such methods of immobilization make it impossible to assess resting platelets, the changes that occur as platelets transition from resting to active states, or the signals generated by soluble agonists, such as ADP and thrombin, or by mechanical stimulus, independently from those generated by the adhesive ligand. Here we describe a microscopy method that allows the immobilization of platelets to a glass cover slip without triggering platelet activation. This method makes use of specific antibodies that bind platelet PECAM-1 without activating it. Platelets can therefore be immobilized to PECAM-1 antibody coated biochips without causing activation and perfused with agonists or inhibitors. Using this method, platelets can be stimulated by an array of soluble agonists at any concentration or combination, in the presence or absence of inhibitors or shear forces. This chapter describes in detail this PECAM-1 mediated immobilized platelet method and its use for measuring changes in Ca2+ signaling in individual platelets under a number of different conditions. While we focus on the measurement of Ca2+ dynamics in this chapter, it is important to consider that the basic method we describe will easily lend its self to other measures of platelet activation (integrin activation, shape change, actin dynamics, degranulation), and may, therefore, be used to measure almost any facet of platelet activation
Lower incidence of Pneumocystis jirovecii pneumonia among Africans in the Netherlands host or environmental factors?
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128541.pdf (publisher's version ) (Closed access)BACKGROUND AND OBJECTIVE: HIV-associated Pneumocystis jirovecii pneumonia (PJP) remains one of the commonest opportunistic infections in Western countries. Although it has been suggested that racial differences in PJP incidence exist, early studies report conflicting results. This study aimed to investigate differences in PJP incidence in a developed country among patients originating from sub-Saharan Africa compared with other regions of origin. DESIGN AND METHODS: A retrospective observational cohort study was performed among 13,844 HIV-infected patients from the Dutch ATHENA cohort. The main outcome measure was occurrence of PJP. RESULTS: A total number of 1055 PJP infections were diagnosed. Patients originating from sub-Saharan Africa had a significantly lower risk of having PJP at the time of HIV diagnosis after adjustment of confounders compared with patients from Western origin [Western Europe, Australia and New Zealand; adjusted odds ratio (aOR) 0.21 (95% confidence interval (CI) 0.15-0.29)]. Other factors associated with higher PJP risk were increasing age [aOR 1.01 per year (95% CI 1.00-1.02)], a low CD4 count at HIV diagnosis [CD4 350 cells/mul aOR 123.3 (95% CI 77.8-195.5)] and a high plasma HIV-RNA (>100,000 copies/ml) at HIV diagnosis [aOR 1.41 (95% CI 1.19-1.66)]. Moreover, a clearly lower risk for PJP acquisition later during follow-up was observed among sub-Saharan Africans versus Western patients [adjusted hazard ratio 0.60 (95% CI 0.39-0.90)]. CONCLUSION: Among HIV-infected patients living in the Netherlands, PJP occurrence is substantially lower in patients originating from sub-Saharan Africa, as compared to Western patients. Differences in genetic susceptibility may partially explain the lower PJP incidence in these patients