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

Neuroprotection of the newborn brain: therapeutic targets & behavioral outcome

The research described in this thesis focuses on the evaluation of neuroprotective strategies in animal models for neonatal HI. Neuroprotection was assessed by not only by histology but was focused on the behavioral outcome seen in animal models for neonatal HI. First the role of erythropoietin after hypoxic-ischemic (HI) brain injury was studied. An overview of the studies in which erythropoietin (EPO) has been used as a neuroprotective agent in in vitro and in vivo models for HI-injury is provided. Next the potential beneficial consequences of combining two individually neuroprotective compounds; EPO and DFO was explored. Furthermore, it is shown that severe but also mild cerebral injury could lead to distinct long-term motor impairments. Moreover it was demonstrated that the modified hole board was sensitive enough as a test to visualize impairments in cognition after severe and mild HI. Next the beneficial effects on histological and functional (motor- and cognitive) outcome of inhibition of the NF-?B pathway after neonatal HI was explored using a specific NEMO-binding domain peptide. The histological improvements of JNK-inhibition and the molecular basis that may underlie the neuroprotection afforded by the specific JNK-binding domain (JBD)-peptide were demonstrated. In addition we employed behavioral tests to show improved motor functions and cognition after JBD-treatment

Neuropharmacology of the mesolimbic system and associated circuits on social hierarchies

Most socially living species are organized hierarchically, primarily based on individual differences in social dominance. Dominant individuals typically gain privileged access to important resources, such as food, mating partners and territories, whereas submissive conspecifics are often devoid of such benefits. The benefits associated with a high social status provide a strong incentive to become dominant. Importantly, motivational- and reward-related processes are regulated, to a large extent, by the mesolimbic system. Consequently, several studies point to a key role for the mesolimbic system in social hierarchy formation. This review summarizes the growing body of literature that implicates the mesolimbic system, and associated neural circuits, on social hierarchies. In particular, we discuss the neurochemical and pharmacological studies that have highlighted the contributions of the mesolimbic system and associated circuits including dopamine signaling through the D1 or D2 receptors, GABAergic neurotransmission, the androgen receptor system, and mitochondria and bioenergetics. Given that low social status has been linked to the emergence of anxiety- and depressive-like disorders, a greater understanding of the neurochemistry underlying social dominance could be of tremendous benefit for the development of pharmacological treatments to dysfunctions in social behaviors

Susac syndrome: a report of four cases and a review of the literature

Pathophysiology and treatment of rheumatic disease

On the stability and morphology of complex coacervate core micelles : from spherical to wormlike micelles

We present a systematic study of the stability and morphology of complex coacervate core micelles (C3Ms) formed from poly(acrylic acid) (PAA) and poly(N-methyl-2-vinylpyridinium)-b-poly(ethylene oxide) (PM2VP-b-PEO). We use polarized and depolarized dynamic and static light scattering, combined with small-angle X-ray scattering, to investigate how the polymer chain length and salt concentration affect the stability, size, and shape of these micelles. We show that C3Ms are formed in aqueous solution below a critical salt concentration, which increases considerably with increasing PAA and PM2VP length and levels off for long chains. This trend is in good agreement with a mean-field model of polyelectrolyte complexation based on the Voorn–Overbeek theory. In addition, we find that salt induces morphological changes in C3Ms when the PAA homopolymer is sufficiently short: from spherical micelles with a diameter of several tens of nanometers at low salt concentration to wormlike micelles with a contour length of several hundreds of nanometers just before the critical salt concentration. By contrast, C3Ms of long PAA homopolymers remain spherical upon addition of salt and shrink slightly. A critical review of existing literature on other C3Ms reveals that the transition from spherical to wormlike micelles is probably a general phenomenon, which can be rationalized in terms of a classical packing parameter for amphiphiles

Mathematics bridging education using an online, adaptive e-tutorial

This contribution describes and evaluates a postsecondary remediation program in mathematics, aiming to ease the transition from high school to university and to improve the success rates in the first year of bachelor studies. The remediation program consists of the administration of an entry test and the organisation of voluntary bridging education in the format of an online summer course, using the adaptive e-tutorial ALEKS. Participants are prospective students of the university programs business and economics of Maastricht University, and are mostly students with an international background. Effect analysis suggests a strong treatment effect of successful participation in the summer course. However, given the quasi-experimental setup of this study, with non-equivalent groups, selection effects may be responsible for part of that effect. Correction of the treatment effect by applying the propensity score method indicates that indeed a selection effect is present, but that a substantial treatment effect remains, of about 50% the size of the effect of being educated in advanced math versus basic math, in high school