Activation of Retinoid X Receptor increases dopamine cell survival in models for Parkinson's disease

<p>Abstract</p> <p>Background</p> <p>Parkinson's disease (PD) is caused by degeneration of dopamine (DA) neurons in the ventral midbrain (vMB) and results in severely disturbed regulation of movement. The disease inflicts considerable suffering for the affected and their families. Today, the opportunities for pharmacological treatment are meager and new technologies are needed. Previous studies have indicated that activation of the nuclear receptor Retinoid X Receptor (RXR) provides trophic support for DA neurons. Detailed investigations of these neurotrophic effects have been hampered by the lack of readily available DA neurons <it>in vitro</it>. The aim of this study was to further describe the potential neurotrophic actions of RXR ligands and, for this and future purposes, develop a suitable <it>in vitro</it>-platform using mouse embryonic stem cells (mESCs).</p> <p>Results</p> <p>We studied the potential neurotrophic effects of the RXR ligand LG100268 (LG268) and the RXR-Nurr1 ligand XCT0139508 (XCT) in neuronal cultures derived from rat primary vMB and mESCs. RXR ligands protect DA neurons from stress, such as that induced by the PD-modeling toxin 6-hydroxy dopamine (6-OHDA) and hypoxia, but not from stress induced by oxidative hydrogen peroxide (H₂O₂) or the excitotoxic agent kainic acid (KA). The neurotrophic effect is selective for DA neurons. DA neurons from rat primary vMB and mESCs behaved similarly, but the mESC-derived cultures contained a much higher fraction of DA cells and thus provided more accessible experimental conditions.</p> <p>Conclusions</p> <p>RXR ligands rescue DA neurons from degeneration caused by the PD simulating 6-OHDA as well as hypoxia. Thus, RXR is a novel promising target for PD research. mESC-derived DA cells provide a valid and accessible <it>in vitro</it>-platform for studying PD inducing toxins and potential trophic agents.</p

Nitric oxide from inflammatory origin impairs neural stem cell proliferation by inhibiting epidermal growth factor receptor signaling

Neuroinflammation is characterized by activation of microglial cells, followed by production of nitric oxide (NO), which may have different outcomes on neurogenesis, favoring or inhibiting this process. In the present study, we investigated how the inflammatory mediator NO can affect proliferation of neural stem cells (NSCs), and explored possible mechanisms underlying this effect. We investigated which mechanisms are involved in the regulation of NSC proliferation following treatment with an inflammatory stimulus (lipopolysaccharide plus IFN-gamma), using a culture system of subventricular zone (SVZ)-derived NSCs mixed with microglia cells obtained from wild-type mice (iNOS(+/+)) or from iNOS knockout mice (iNOS(-/-)). We found an impairment of NSC cell proliferation in iNOS(+/+) mixed cultures, which was not observed in iNOS(-/-) mixed cultures. Furthermore, the increased release of NO by activated iNOS(+/+) microglial cells decreased the activation of the ERK/MAPK signaling pathway, which was concomitant with an enhanced nitration of the EGF receptor. Preventing nitrogen reactive species formation with MnTBAP, a scavenger of peroxynitrite (ONOO-), or using the ONOO- degradation catalyst FeTMPyP cell proliferation and ERK signaling were restored to basal levels in iNOS(+/+) mixed cultures. Moreover, exposure to the NO donor NOC-18 (100 mu M), for 48 h, inhibited SVZ-derived NSC proliferation. Regarding the antiproliferative effect of NO, we found that NOC-18 caused the impairment of signaling through the ERK/MAPK pathway, which may be related to increased nitration of the EGF receptor in NSC. Using MnTBAP nitration was prevented, maintaining ERK signaling, rescuing NSC proliferation. We show that NO from inflammatory origin leads to a decreased function of the EGF receptor, which compromised proliferation of NSC. We also demonstrated that NO-mediated nitration of the EGF receptor caused a decrease in its phosphorylation, thus preventing regular proliferation signaling through the ERK/MAPK pathway.Foundation for Science and Technology, (FCT, Portugal); COMPETE; FEDER [PEst-C/SAU/LA0001/2013-2014, PEst-OE/EQB/LA0023/2013-2014, PTDC/SAU-NEU/102612/2008, PTDC/NEU-OSD/0473/2012]; FCT, Portugal [SERH/BPD/78901/2011, SERH/BD/38127/2007, SFRH/BD/77903/2011, SFRH/BD/79308/2011]info:eu-repo/semantics/publishedVersio

Relationship between cerebrovascular reactivity and age in multiple sclerosis

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Epigenetic Activation of SOX11 in Lymphoid Neoplasms by Histone Modifications

Recent studies have shown aberrant expression of SOX11 in various types of aggressive B-cell neoplasms. To elucidate the molecular mechanisms leading to such deregulation, we performed a comprehensive SOX11 gene expression and epigenetic study in stem cells, normal hematopoietic cells and different lymphoid neoplasms. We observed that SOX11 expression is associated with unmethylated DNA and presence of activating histone marks (H3K9/14Ac and H3K4me3) in embryonic stem cells and some aggressive B-cell neoplasms. In contrast, adult stem cells, normal hematopoietic cells and other lymphoid neoplasms do not express SOX11. Such repression was associated with silencing histone marks H3K9me2 and H3K27me3. The SOX11 promoter of non-malignant cells was consistently unmethylated whereas lymphoid neoplasms with silenced SOX11 tended to acquire DNA hypermethylation. SOX11 silencing in cell lines was reversed by the histone deacetylase inhibitor SAHA but not by the DNA methyltransferase inhibitor AZA. These data indicate that, although DNA hypermethylation of SOX11 is frequent in lymphoid neoplasms, it seems to be functionally inert, as SOX11 is already silenced in the hematopoietic system. In contrast, the pathogenic role of SOX11 is associated with its de novo expression in some aggressive lymphoid malignancies, which is mediated by a shift from inactivating to activating histone modifications

Prox1 Regulates the Notch1-Mediated Inhibition of Neurogenesis

During development of the spinal cord, Prox1 controls the balance between proliferation and differentiation of neural progenitor cells via suppression of Notch1 gene expression

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

From stem cell to neuron : A sox perspective

The differentiation of stem cells into the more than 100 billion neurons that compose the central nervous system (CNS) is one of the most remarkable transformations during vertebrate development. A central problem of this process is how neural lineage selection initially is specified in pluripotent stem cells and maintained during the course of neurogenesis. This thesis focuses on how different Sox transcription factors of the HMG-box family control neural cell-type restricted gene expression from the early lineage specification stages to later stages of neuronal maturation. In the two papers on which this thesis is based, we present a molecular pathway where diverse Sox proteins can act to coordinate neural gene expression as development proceeds, from the early neural lineage specification in pluripotent stem cells to the gene regulatory control operating in maturing postmitotic neurons. We show that, already in pluripotent stem cells, Sox2 binds to inactive neural genes and that, in neural progenitors, Sox3 "takes over" and binds to activated neural genes, but also to silent genes destined to become active in maturing postmitotic neurons. Finally, in postmitotic neurons these genes are bound by Sox11. The binding of Sox3 to silent genes is associated with bivalently marked chromatin domains, containing both trimethylated H3K4 and H3K27, which is resolved to an active state upon Sox11 binding. Proneural basic helix-loop-helix (bHLH) transcription factors have key roles in promoting NPCs to commit to a differentiation program leading to the generation of post-mitotic neurons. It is shown that Sox4 and Sox11 act downstream of proneural bHLH proteins and are of critical importance for the activation of neuronal protein expression but not for cell cycle withdrawal. Together these data reveal a regulatory logic whereby sequentially acting Sox transcription factors preselect transcriptional programs that are destined to be activated at later stages of neural differentiation. Thus, a single family of transcription factors acts to coordinate neural gene expression from the early lineage specification to later stages of neural development

Bikubesong i et identitetsperspektiv

I denne oppgaven har jeg undersøkt hvordan to av karakterene i Bikubesong (1999) av Frode Grytten former og utvikler identitetene sine gjennom sine fortellinger. Som det vil gå fram av oppgaven, formes karakterenes identiteter i et samspill mellom egenrefleksjon, menneskelig respons og samfunnsendringer. Mitt teoretiske grunnlag og leseperspektiv har vært todelt, med et identitetsperspektiv på den ene siden, og stedsperspektiv på den andre. Med identitetsperspektivet har jeg forsøkt å se hvilke faktorer som har utløst endringer i karakterenes identitetsdannelse og selvfortelling. Steds- og samfunnsperspektivet har jeg brukt for å få fram hvordan samfunnet karakterene lever i, og menneskene rundt dem, også påvirker karakterenes identitet og selvfortelling. I tillegg har jeg sett hvordan storsamfunnet utenfor Odda også har vært en viktig ytre faktor i karakterenes identitetsdannelse