Oncostatin M, an Underestimated Player in the Central Nervous System

For a long time, the central nervous system (CNS) was believed to be an immune privileged organ. In the last decades, it became apparent that the immune system interacts with the CNS not only in pathological, but also in homeostatic situations. It is now clear that immune cells infiltrate the healthy CNS as part of immune surveillance and that immune cells communicate through cytokines with CNS resident cells. In pathological conditions, an enhanced infiltration of immune cells takes place to fight the pathogen. A well-known family of cytokines is the interleukin (IL)-6 cytokine family. All members are important in cell communication and cell signaling in the immune system. One of these members is oncostatin M (OSM), for which the receptor is expressed on several cells of the CNS. However, the biological function of OSM in the CNS is not studied in detail. Here, we briefly describe the general aspects related to OSM biology, including signaling and receptor binding. Thereafter, the current understanding of OSM during CNS homeostasis and pathology is summarized

Realising the potential of mHealth to improve asthma and allergy care : how to shape the future

Non peer reviewe

Deciphering the morphology of motor evoked potentials

Motor Evoked Potentials (MEPs) are used to monitor disability progression in multiple sclerosis (MS). Their morphology plays an important role in this process. Currently, however, there is no clear definition of what constitutes a normal or abnormal morphology. To address this, five experts independently labeled the morphology (normal or abnormal) of the same set of 1,000 MEPs. The intra- and inter-rater agreement between the experts indicates they agree on the concept of morphology, but differ in their choice of threshold between normal and abnormal morphology. We subsequently performed an automated extraction of 5,943 time series features from the MEPs to identify a valid proxy for morphology, based on the provided labels. To do this, we compared the cross-validation performances of one-dimensional logistic regression models fitted to each of the features individually. We find that the approximate entropy (ApEn) feature can accurately reproduce the majority-vote labels. The performance of this feature is evaluated on an independent test set by comparing to the majority vote of the neurologists, obtaining an AUC score of 0.92. The model slightly outperforms the average neurologist at reproducing the neurologists consensus-vote labels. We can conclude that MEP morphology can be consistently defined by pooling the interpretations from multiple neurologists and that ApEn is a valid continuous score for this. Having an objective and reproducible MEP morphological abnormality score will allow researchers to include this feature in their models, without manual annotation becoming a bottleneck. This is crucial for large-scale, multi-center datasets. An exploratory analysis on a large single-center dataset shows that ApEn is potentially clinically useful. Introducing an automated, objective, and reproducible definition of morphology could help overcome some of the barriers that are currently obstructing broad adoption of evoked potentials in daily care and patient follow-up, such as standardization of measurements between different centers, and formulating guidelines for clinical use

Glycine and Glycine Receptor Signalling in Non-Neuronal Cells

Glycine is an inhibitory neurotransmitter acting mainly in the caudal part of the central nervous system. Besides this neurotransmitter function, glycine has cytoprotective and modulatory effects in different non-neuronal cell types. Modulatory effects were mainly described in immune cells, endothelial cells and macroglial cells, where glycine modulates proliferation, differentiation, migration and cytokine production. Activation of glycine receptors (GlyRs) causes membrane potential changes that in turn modulate calcium flux and downstream effects in these cells. Cytoprotective effects were mainly described in renal cells, hepatocytes and endothelial cells, where glycine protects cells from ischemic cell death. In these cell types, glycine has been suggested to stabilize porous defects that develop in the plasma membranes of ischemic cells, leading to leakage of macromolecules and subsequent cell death. Although there is some evidence linking these effects to the activation of GlyRs, they seem to operate in an entirely different mode from classical neuronal subtypes

Differential Runx3, Eomes, and T-bet expression subdivides MS-associated CD4⁺ T cells with brain-homing capacity

Multiple sclerosis (MS) is a common and devastating chronic inflammatory disease of the CNS. CD4 + T cells are assumed to be the first to cross the blood–central nervous system (CNS) barrier and trigger local inflammation. Here, we explored how pathogenicity-associated effector programs define CD4 + T cell subsets with brain-homing ability in MS. Runx3- and Eomes-, but not T-bet-expressing CD4 + memory cells were diminished in the blood of MS patients. This decline reversed following natalizumab treatment and was supported by a Runx3 +Eomes +T-bet − enrichment in cerebrospinal fluid samples of treatment-naïve MS patients. This transcription factor profile was associated with high granzyme K (GZMK) and CCR5 levels and was most prominent in Th17.1 cells (CCR6 +CXCR3 +CCR4 −/dim). Previously published CD28 − CD4 T cells were characterized by a Runx3 +Eomes −T-bet + phenotype that coincided with intermediate CCR5 and a higher granzyme B (GZMB) and perforin expression, indicating the presence of two separate subsets. Under steady-state conditions, granzyme K high Th17.1 cells spontaneously passed the blood–brain barrier in vitro. This was only found for other subsets including CD28 − cells when using inflamed barriers. Altogether, CD4 + T cells contain small fractions with separate pathogenic features, of which Th17.1 seems to breach the blood–brain barrier as a possible early event in MS.</p

Dietary Sargassum fusiforme improves memory and reduces amyloid plaque load in an Alzheimer's disease mouse model

Activation of liver X receptors (LXRs) by synthetic agonists was found to improve cognition in Alzheimer's disease (AD) mice. However, these LXR agonists induce hypertriglyceridemia and hepatic steatosis, hampering their use in the clinic. We hypothesized that phytosterols as LXR agonists enhance cognition in AD without affecting plasma and hepatic triglycerides. Phytosterols previously reported to activate LXRs were tested in a luciferase-based LXR reporter assay. Using this assay, we found that phytosterols commonly present in a Western type diet in physiological concentrations do not activate LXRs. However, a lipid extract of the 24(S)-Saringosterol-containing seaweed Sargassum fusiforme did potently activate LXR beta. Dietary supplementation of crude Sargassum fusiforme or a Sargassum fusiforme-derived lipid extract to AD mice significantly improved short-term memory and reduced hippocampal A beta plaque load by 81%. Notably, none of the side effects typically induced by full synthetic LXR agonists were observed. In contrast, administration of the synthetic LXRa activator, AZ876, did not improve cognition and resulted in the accumulation of lipid droplets in the liver. Administration of Sargassum fusiforme-derived 24(S)-Saringosterol to cultured neurons reduced the secretion of A beta 42. Moreover, conditioned medium from 24(S)-Saringosterol-treated astrocytes added to microglia increased phagocytosis of A beta. Our data show that Sargassum fusiforme improves cognition and alleviates AD pathology. This may be explained at least partly by 24(S)-Saringosterol-mediated LXR beta activation.</p

The insulin-like growth factor system and adenocarcinoma of the colon

The insulin-like growth factor (IGF) system is important in normal growth and development. However, it is also known to be involved with malignant transformation and cellular proliferation. IGF binding proteins modulate the biological activity of IGF-I, either potentiating or inhibiting its activity, as well as determining how much enters the circulation at any one time. IGF binding protein-4 (IGFBP-4), for example is believed to be inhibitory to the effects of IGF-I. This thesis shows that the colon cancer cell lines Colo 205, HT29 and WiDR proliferate in response to IGF-I, and that IGFBP-4 at high concentrations inhibits their growth. However, it was found that with lower concentrationsof IGFBP-4, proliferation in HT29 and WiDR cells increased. Nevertheless in two cell lines, IGFBP-4 partially negated the proliferative effects of IGF-I. An antibody against IGFBP-4 was used to show that endogenous IGFBP-4 plays an important role in modifying cell growth. In order to start in vivo experiments which required considerable quantities of IGFBP-4, this protein was produced in an expression system and purified using an immunoaffinity column method. The rhIGFBP-4 thus produced was shown to be functional and to inhibit colorectal cancer cell growth in vitro. A nude mouse model of colon cancer was produced and the expression of components of the IGF system in this model determined using PCR. Experiments were performed using conditioned medium from Colo 205 cells to investigate IGFBP-4 protease activity. This thesis shows that manipulation of the IGF system is a potential target for further research into treatment for adenocarcinoma of the colon