61 research outputs found
The regulatory mechanisms of NG2/CSPG4 expression
Neuron-glial antigen 2 (NG2), also known as chondroitin sulphate proteoglycan 4 (CSPG4), is a surface type I transmembrane core proteoglycan that is crucially involved in cell survival, migration and angiogenesis. NG2 is frequently used as a marker for the identification and characterization of certain cell types, but little is known about the mechanisms regulating its expression. In this review, we provide evidence that the regulation of NG2 expression underlies inflammation and hypoxia and is mediated by methyltransferases, transcription factors, including Sp1, paired box (Pax) 3 and Egr-1, and the microRNA miR129-2. These regulatory factors crucially determine NG2-mediated cellular processes such as glial scar formation in the central nervous system (CNS) or tumor growth and metastasis. Therefore, they are potential targets for the establishment of novel NG2-based therapeutic strategies in the treatment of CNS injuries, cancer and other conditions of these types
Protein Kinase CK2 Regulates Nerve/Glial Antigen (NG)2-Mediated Angiogenic Activity of Human Pericytes
Protein kinase CK2 is a crucial regulator of endothelial cell proliferation, migration and
sprouting during angiogenesis. However, it is still unknown whether this kinase additionally affects
the angiogenic activity of other vessel-associated cells. In this study, we investigated the effect of
CK2 inhibition on primary human pericytes. We found that CK2 inhibition reduces the expression of
nerve/glial antigen (NG)2, a crucial factor which is involved in angiogenic processes. Reporter gene
assays revealed a 114 bp transcriptional active region of the human NG2 promoter, whose activity
was decreased after CK2 inhibition. Functional analyses demonstrated that the pharmacological
inhibition of CK2 by CX-4945 suppresses pericyte proliferation, migration, spheroid sprouting and
the stabilization of endothelial tubes. Moreover, aortic rings of NG2â/â mice showed a significantly
reduced vascular sprouting when compared to rings of NG2+/+ mice, indicating that NG2 is an
important regulator of the angiogenic activity of pericytes. In vivo, implanted Matrigel plugs
containing CX-4945-treated pericytes exhibited a lower microvessel density when compared to
controls. These findings demonstrate that CK2 regulates the angiogenic activity of pericytes through
NG2 gene expression. Hence, the inhibition of CK2 represents a promising anti-angiogenic strategy,
because it does not only target endothelial cells, but also vessel-associated pericytes
CK2 Activity Mediates the Aggressive Molecular Signature of Glioblastoma Multiforme by Inducing Nerve/Glial Antigen (NG)2 Expression
Nerve/glial antigen (NG)2 expression crucially determines the aggressiveness of glioblastoma multiforme (GBM). Recent evidence suggests that protein kinase CK2 regulates NG2 expression.
Therefore, we investigated in the present study whether CK2 inhibition suppresses proliferation
and migration of NG2-positive GBM cells. For this purpose, CK2 activity was suppressed in the
NG2-positive cell lines A1207 and U87 by the pharmacological inhibitor CX-4945 and CRISPR/Cas9-
mediated knockout of CK2α. As shown by quantitative real-time PCR, luciferase-reporter assays,
flow cytometry and western blot, this significantly reduced NG2 gene and protein expression when
compared to vehicle-treated and wild type controls. In addition, CK2 inhibition markedly reduced
NG2-dependent A1207 and U87 cell proliferation and migration. The Cancer Genome Atlas (TCGA)-
based data further revealed not only a high expression of both NG2 and CK2 in GBM but also
a positive correlation between the mRNA expression of the two proteins. Finally, we verified a
decreased NG2 expression after CX-4945 treatment in patient-derived GBM cells. These findings
indicate that the inhibition of CK2 represents a promising approach to suppress the aggressive
molecular signature of NG2-positive GBM cells. Therefore, CX-4945 may be a suitable drug for the
future treatment of NG2-positive GBM
Improvement of islet transplantation by the fusion of islet cells with functional blood vessels
Pancreatic islet transplantation still represents a promising therapeutic strategy for curative treatment of type 1 diabetes mellitus. However, a limited number of organ donors and insufficient vascularization with islet engraftment failure restrict the successful transfer of this approach into clinical practice. To overcome these problems, we herein introduce a novel strategy for the generation of prevascularized islet organoids by the fusion of pancreatic islet cells with functional native microvessels. These insulin-secreting organoids exhibit a significantly higher angiogenic activity compared to freshly isolated islets, cultured islets, and non-prevascularized islet organoids. This is caused by paracrine signaling between the ÎČ-cells and the microvessels, mediated by insulin binding to its corresponding receptor on endothelial cells. In vivo, the prevascularized islet organoids are rapidly blood-perfused after transplantation by the interconnection of their autochthonous microvasculature with surrounding blood vessels. As a consequence, a lower number of islet grafts are required to restore normoglycemia in diabetic mice. Thus, prevascularized islet organoids may be used to improve the success rates of clinical islet transplantation
The Origin of T Tauri X-ray Emission: New Insights from the Chandra Orion Ultradeep Project
We use the data of the Chandra Orion Ultradeep Project (COUP) to study the
nearly 600 X-ray sources that can be reliably identified with optically well
characterized T Tauri stars (TTS) in the Orion Nebula Cluster. We detect X-ray
emission from more than 97% of the optically visible late-type (spectral types
F to M) cluster stars. This proofs that there is no ``X-ray quiet'' population
of late-type stars with suppressed magnetic activity. All TTS with known
rotation periods lie in the saturated or super-saturated regime of the relation
between activity and Rossby numbers seen for main-sequence (MS) stars, but the
TTS show a much larger scatter in X-ray activity than seen for the MS stars.
Strong near-linear relations between X-ray luminosities, bolometric
luminosities and mass are present. We also find that the fractional X-ray
luminosity rises slowly with mass over the 0.1 - 2 M_sun range. The plasma
temperatures determined from the X-ray spectra of the TTS are much hotter than
in MS stars, but seem to follow a general solar-stellar correlation between
plasma temperature and activity level. The large scatter about the relations
between X-ray activity and stellar parameters seems to be related to the
influence of accretion on the X-ray emission. While the X-ray activity of the
non-accreting TTS is consistent with that of rapidly rotating MS stars, the
accreting stars are less X-ray active (by a factor of ~2-3 on average) and
produce much less well defined correlations than the non-accretors. We discuss
possible reasons for the suppression of X-ray emission by accretion and the
implications of our findings on long-standing questions related to the origin
of the X-ray emission from young stars.Comment: accepted for ApJS, COUP Special Issu
Editorial Board
Source at http://dx.doi.org/10.1186/s12888-017-1345-8 Background: The duration of untreated psychosis is determined by both patient and service related factors.
Few studies have considered the geographical accessibility of services in relation to treatment delay in early
psychosis. To address this, we investigated whether treatment delay is co-determined by straight-line distance
to hospital based specialist services in a mainly rural mental health context.
Methods: A naturalistic cross-sectional study was conducted among a sample of recent onset psychosis patients
in northern Norway (n = 62). Data on patient and service related determinants were analysed.
Results: Half of the cohort had a treatment delay longer than 4.5 months. In a binary logistic regression model,
straight-line distance was found to make an independent contribution to delay in which we controlled for other
known risk factors.
Conclusions: The determinants of treatment delay are complex. This study adds to previous studies on treatment
delay by showing that the spatial location of services also makes an independent contribution. In addition, it may
be that insidious onset is a more important factor in treatment delay in remote areas, as the logistical implications of
specialist referral are much greater than for urban dwellers. The threshold for making a diagnosis in a remote location
may therefore be higher. Strategies to reduce the duration of untreated psychosis in rural areas would benefit from
improving appropriate referral by crisis services, and the detection of insidious onset of psychosis in community based
specialist services
The regulatory mechanisms of NG2/CSPG4 expression
Neuron-glial antigen 2 (NG2), also known as chondroitin sulphate proteoglycan 4 (CSPG4), is a surface type I transmembrane core proteoglycan that is crucially involved in cell survival, migration and angiogenesis. NG2 is frequently used as a marker for the identification and characterization of certain cell types, but little is known about the mechanisms regulating its expression. In this review, we provide evidence that the regulation of NG2 expression underlies inflammation and hypoxia and is mediated by methyltransferases, transcription factors, including Sp1, paired box (Pax) 3 and Egr-1, and the microRNA miR129-2. These regulatory factors crucially determine NG2-mediated cellular processes such as glial scar formation in the central nervous system (CNS) or tumor growth and metastasis. Therefore, they are potential targets for the establishment of novel NG2-based therapeutic strategies in the treatment of CNS injuries, cancer and other conditions of these types
Metagenomic binning of a marine sponge microbiome reveals unity in defense but metabolic specialization
Marine sponges are ancient metazoans that are populated by distinct and highly diverse microbial communities. In order to obtain deeper insights into the functional gene repertoire of the Mediterranean sponge Aplysina aerophoba, we combined Illumina short-read and PacBio long-read sequencing followed by un-targeted metagenomic binning. We identified a total of 37 high-quality bins representing 11 bacterial phyla and two candidate phyla. Statistical comparison of symbiont genomes with selected reference genomes revealed a significant enrichment of genes related to bacterial defense (restriction-modification systems, toxin-antitoxin systems) as well as genes involved in host colonization and extracellular matrix utilization in sponge symbionts. A within-symbionts genome comparison revealed a nutritional specialization of at least two symbiont guilds, where one appears to metabolize carnitine and the other sulfated polysaccharides, both of which are abundant molecules in the sponge extracellular matrix. A third guild of symbionts may be viewed as nutritional generalists that perform largely the same metabolic pathways but lack such extraordinary numbers of the relevant genes. This study characterizes the genomic repertoire of sponge symbionts at an unprecedented resolution and it provides greater insights into the molecular mechanisms underlying microbial-sponge symbiosis
- âŠ