Sphingosine 1-phosphate receptor 5 mediates the immune quiescence of the human brain endothelial barrier

BACKGROUND: The sphingosine 1-phosphate (S1P) receptor modulator FTY720P (Gilenya®) potently reduces relapse rate and lesion activity in the neuroinflammatory disorder multiple sclerosis. Although most of its efficacy has been shown to be related to immunosuppression through the induction of lymphopenia, it has been suggested that a number of its beneficial effects are related to altered endothelial and blood–brain barrier (BBB) functionality. However, to date it remains unknown whether brain endothelial S1P receptors are involved in the maintenance of the function of the BBB thereby mediating immune quiescence of the brain. Here we demonstrate that the brain endothelial receptor S1P(5) largely contributes to the maintenance of brain endothelial barrier function. METHODS: We analyzed the expression of S1P(5) in human post-mortem tissues using immunohistochemistry. The function of S1P(5) at the BBB was assessed in cultured human brain endothelial cells (ECs) using agonists and lentivirus-mediated knockdown of S1P(5). Subsequent analyses of different aspects of the brain EC barrier included the formation of a tight barrier, the expression of BBB proteins and markers of inflammation and monocyte transmigration. RESULTS: We show that activation of S1P(5) on cultured human brain ECs by a selective agonist elicits enhanced barrier integrity and reduced transendothelial migration of monocytes in vitro. These results were corroborated by genetically silencing S1P(5) in brain ECs. Interestingly, functional studies with these cells revealed that S1P(5) strongly contributes to brain EC barrier function and underlies the expression of specific BBB endothelial characteristics such as tight junctions and permeability. In addition, S1P(5) maintains the immunoquiescent state of brain ECs with low expression levels of leukocyte adhesion molecules and inflammatory chemokines and cytokines through lowering the activation of the transcription factor NFκB. CONCLUSION: Our findings demonstrate that S1P(5) in brain ECs contributes to optimal barrier formation and maintenance of immune quiescence of the barrier endothelium

Instructions for Authors

Nonadherence to medical therapy is frequently encountered in patients with inflammatory bowel disease (IBD). We aimed to identify predictors for future (non)adherence in IBD

Evolution of costs of inflammatory bowel disease over two years of follow-up

Background: With the increasing use of anti-TNF therapy in inflammatory bowel disease (IBD), a shift of costs has been observed with medication costs replacing hospitalization and surgery as major cost driver. We aimed to explore the evolution of IBD-related costs over two years of follow-up. Methods and Findings: In total 1,307 Crohn's disease (CD) patients and 915 ulcerative colitis (UC) patients were prospectively followed for two years by three-monthly web-based questionnaires. Changes of healthcare costs, productivity costs and out-of-pocket costs over time were assessed using mixed model analysis. Multivariable logistic regression analysis was used to identify costs drivers. In total 737 CD patients and 566 UC were included. Total costs were stable over two years of follow-up, with annual total costs of € 7,835 in CD and € 3,600 in UC. However, within healthcare costs, the proportion of anti-TNF therapy-related costs increased from 64% to 72% in CD (p<0.01) and from 31% to 39% in UC (p < 0.01). In contrast, the proportion of hospitalization costs decreased from 19% to 13% in CD (p<0.01), and 22% to 15% in UC (p < 0.01). Penetrating disease course predicted an increase of healthcare costs (adjusted odds ratio (adj. OR) 1.95 (95% CI 1.02-3.37) in CD and age <40 years in UC (adj. OR 4.72 (95% CI 1.61-13.86)). Conclusions: BD-related costs remained stable over two years. However, the proportion of anti-TNFrelated healthcare costs increased, while hospitalization costs decreased. Factors associated with increased costs were penetrating disease course in CD and age <40 in UC

Assessment of surface melt with (In)SAR on Blue Ice Areas at the King Baudouin Ice Shelf

Blue ice areas, are areas in Antarctica where, either due to local heat sources (areas with lower albedo and thus more absorption of shortwave radiation - i.e. Nunataks) or high windspeed, all the snow is melted or eroded away and the underlying (blue) ice is visible. This occurs often around the grounding line between the ice sheet and ice shelf. At this grounding line area, a micro climate exists above the blue ice, which increase surface melt, due to a combination of decreased albedo and warming due to the mixing of cold and warm air. Detection of surface melt on this blue ice is important because this warmer surface melt water results in the increase of hydrofracturing and as a result, the decrease of ice shelf stability. Radar imagery above snow areas is a effective method to detect surface melt, which also ensures a continuous data record. Above blue ice, this is continuous data record of surface melt is also desired, but not done yet and therefore the focus of this thesis is surface melt detection on blue ice with radar imagery. By using the method of Hui et al., 2014 to classify blue ice areas, it is shown that the blue ice area extent (non-stable blue ice) is increasing over the years in the peak of the melt season. However, the extent is slightly decreasing during the non-melt season (stable blue ice). The data of Sentinel-1B is used during the austral summer of 2017/2018, to detectsurface melt on blue ice. This is done via interferometry (and the corresponding coherence) and with the backscatter coefficient. Coherence turns out the be an unreliable method to detect surface melt, since the influence of wind and precipitation on the decrease of coherence is dominant. Thus, surface melt detection via this method is difficult. Backscatter showed some potential to detect surface melt on blue ice, but due to the larger standard deviation than the actual decrease of backscatter (assumed due to surface melt), a clear distinction between blue ice and surface melt can not be made. Melt features, such as rivers, lakes and ponds are detectable with the backscatter, due to their distinctive shape. Since these melt features are linked to surface melt, backscatter can indirectly be used to detect surface melt on blue ice.Applied Earth Science

Remote Sensing of Japanese WWII airstrips in the Papua Province Republic of Indonesia: Classification of the area surrounding three WWII airstrips (Mongosah, Otawiri and Sagan)

In the Second World War Dutch New Guinea was a strategic battle front for both the Japanese and the Allied forces in the Pacific War. A lot of airstrips were constructed and bombed during this time, of which at least three (Mongosah, Otowari and Sagan) have never been visited after the war. This provided a great opportunity to find potential war heritage and airstrip equipment. Later this year an additional research team will go on an in-situ exploration to potentially find those objects. To do so, they needed a classification map giving information on the type and location of the vegetation. This map helps to know where to land with a helicopter, to setup base camp, to find travel ways, etc. Thus, the main objective of this thesis is to check whether it is possible to create a proper classification image with the available data. I used data obtained from the Sentinel 2 Mission (Optical data), the ALOS PALSAR Mission (L-Band Radar data) and the SRTM Mission (Digital elevation data). I pre-processed the data and used the supervised classification method, “Maximum Likelihood Classification” (MLC). I masked clouds via three different cloud masking methods, MLC Method, Threshold Method and Sen2cor (scene classification) Method. I compared the three different methods with each other and there is no significant difference between them. The classifications have been cross-validated with a reference validation dataset and the classified pixels are on average about 90% correctly classified

Contract design in service triads: The role of buyer inputs

In buyer-supplier-customer service triads, buyers contract with suppliers that deliver their services to the customer. Whereas in dyadic service exchange, customers provide certain inputs to the service production process, service triads typically also involve inputs from the buyer. We draw on survey data on 107 Dutch service triads to investigate to what extent the level of buyer inputs into the service process affects the extent to which outcome and process provisions have been arranged in detail. We also investigate the effect of buyer inputs on the specificity of rewards and of general provisions. We find that the level of buyer inputs has a positive and significant effect on specificity of outcome provisions. Buyer inputs do not significantly affect process provisions, rewards or general provisions