The EIIIA domain from astrocyte-derived fibronectin mediates proliferation of oligodendrocyte progenitor cells following CNS demyelination.

Central nervous system remyelination by oligodendrocyte progenitor cells (OPCs) ultimately fails in the majority of multiple sclerosis (MS) lesions. Remyelination benefits from transient expression of factors that promote migration and proliferation of OPCs, which may include fibronectin (Fn). Fn is present in demyelinated lesions in two major forms; plasma Fn (pFn), deposited following blood-brain barrier disruption, and cellular Fn, synthesized by resident glial cells and containing alternatively spliced domains EIIIA and EIIIB. Here, we investigated the distinctive roles that astrocyte-derived Fn (aFn) and pFn play in remyelination. We used an inducible Cre-lox recombination strategy to selectively remove pFn, aFn or both from mice, and examined the impact on remyelination of toxin-induced demyelinated lesions of spinal cord white matter. This approach revealed that astrocytes are a major source of Fn in demyelinated lesions. Furthermore, following aFn conditional knockout, the number of OPCs recruited to the demyelinated lesion decreased significantly, whereas OPC numbers were unaltered following pFn conditional knockout. However, remyelination completed normally following conditional knockout of aFn and pFn. Both the EIIIA and EIIIB domains of aFn were expressed following demyelination, and in vitro assays demonstrated that the EIIIA domain of aFn mediates proliferation of OPCs, but not migration. Therefore, although the EIIIA domain from aFn mediates OPC proliferation, aFn is not essential for successful remyelination. Since previous findings indicated that astrocyte-derived Fn aggregates in chronic MS lesions inhibit remyelination, aFn removal may benefit therapeutic strategies to promote remyelination in MS.JMJS is recipient of a Junior Scientific Masterclass MD/PhD fellowship from the University Medical Center Groningen. This work was supported by grants from the Netherlands Organization of Scientific Research (NWO, WB, VIDI and Aspasia), the Dutch MS Research Foundation (‘Stichting MS Research’, WB, JMJS, DH), the UK MS Society (CZ, RJMF), and the Research School of Behavioral and Cognitive Neurosciences (BCN, JMJS). Parts of this study were performed at the UMCG Microscopy and Imaging Center (UMIC), which is supported by NWO grants 40-00506-98-9021 and 175-010-2009-023.This is the final version of the article. It was first published by Wiley at http://dx.doi.org/10.1002/glia.2274

CNV analysis in Chinese children of mental retardation highlights a sex differentiation in parental contribution to de novo and inherited mutational burdens

Rare copy number variations (CNVs) are a known genetic etiology in neurodevelopmental disorders (NDD). Comprehensive CNV analysis was performed in 287 Chinese children with mental retardation and/or development delay (MR/DD) and their unaffected parents. When compared with 5,866 ancestry-matched controls, 11~12% more MR/DD children carried rare and large CNVs. The increased CNV burden in MR/DD was predominantly due to de novo CNVs, the majority of which (62%) arose in the paternal germline. We observed a 2~3 fold increase of large CNV burden in the mothers of affected children. By implementing an evidence-based review approach, pathogenic structural variants were identified in 14.3% patients and 2.4% parents, respectively. Pathogenic CNVs in parents were all carried by mothers. The maternal transmission bias of deleterious CNVs was further replicated in a published dataset. Our study confirms the pathogenic role of rare CNVs in MR/DD, and provides additional evidence to evaluate the dosage sensitivity of some candidate genes. It also supports a population model of MR/DD that spontaneous mutations in males’ germline are major contributor to the de novo mutational burden in offspring, with higher penetrance in male than female; unaffected carriers of causative mutations, mostly females, then contribute to the inherited mutational burden.published_or_final_versio

Changes of Mind in an Attractor Network of Decision-Making

Attractor networks successfully account for psychophysical and neurophysiological data in various decision-making tasks. Especially their ability to model persistent activity, a property of many neurons involved in decision-making, distinguishes them from other approaches. Stable decision attractors are, however, counterintuitive to changes of mind. Here we demonstrate that a biophysically-realistic attractor network with spiking neurons, in its itinerant transients towards the choice attractors, can replicate changes of mind observed recently during a two-alternative random-dot motion (RDM) task. Based on the assumption that the brain continues to evaluate available evidence after the initiation of a decision, the network predicts neural activity during changes of mind and accurately simulates reaction times, performance and percentage of changes dependent on difficulty. Moreover, the model suggests a low decision threshold and high incoming activity that drives the brain region involved in the decision-making process into a dynamical regime close to a bifurcation, which up to now lacked evidence for physiological relevance. Thereby, we further affirmed the general conformance of attractor networks with higher level neural processes and offer experimental predictions to distinguish nonlinear attractor from linear diffusion models

Artesunate induces oncosis-like cell death in vitro and has antitumor activity against pancreatic cancer xenografts in vivo

Pancreatic cancer is highly resistant to the currently available chemotherapeutic agents. Less than 5% of patients diagnosed with this disease could survive beyond 5 years. Thus, there is an urgent need for the development of novel, efficacious drugs that can treat pancreatic cancer. Herein we report the identification of artesunate (ART), a derivative of artemisinin, as a potent and selective antitumor agent against human pancreatic cancer cells in vitro and in vivo. ART exhibits selective cytotoxic activity against Panc-1, BxPC-3 and CFPAC-1 pancreatic cancer cells with IC50 values that are 2.3- to 24-fold less than that of the normal human hepatic cells (HL-7702). The pan caspase inhibitor zVAD-fmk did not inhibit the cytotoxic activity of ART. Electron microscopy of ART-treated cells revealed severe cytoplasmic swelling and vacuolization, swollen and internally disorganized mitochondria, dilation (but not fragmentation) of the nuclei without chromatin condensation, and cell lysis, yielding a morphotype that is typical of oncosis. The ART-treated cells exhibited a loss of mitochondrial membrane potential (ΔΨm) and ART-induced cell death was inhibited in the presence of the reactive oxygen species (ROS) scavenger N-acetyl-cysteine (NAC). Importantly, ART produced a dose-dependent tumor regression in an in vivo pancreatic cancer xenografts model. The in vivo antitumor activity of ART was similar to that of gemcitabine. Taken together, our study suggests that ART exhibits antitumor activity against human pancreatic cancer via a novel form of oncosis-like cell death, and that ART should be considered a potential therapeutic candidate for treating pancreatic cancer

Thermal Contraction of Electrodeposited Bi/BiSb Superlattice Nanowires

The lattice parameter of Bi/BiSb superlattice nanowire (SLNW) has been measured using in situ high-temperature X-ray diffraction method. The single crystalline Bi/BiSb SLNW arrays with different bilayer thicknesses have been fabricated within the porous anodic alumina membranes (AAMs) by a charge-controlled pulse electrodeposition. Different temperature dependences of the lattice parameter and thermal expansion coefficient were found for the SLNWs. It was found that the thermal expansion coefficient of the SLNWs with a large bilayer thickness has weak temperature dependence, and the interface stress and defect are the main factors responsible for the thermal contraction of the SLNWs

Benefits and risks of the hormetic effects of dietary isothiocyanates on cancer prevention

The isothiocyanate (ITC) sulforaphane (SFN) was shown at low levels (1-5 µM) to promote cell proliferation to 120-143% of the controls in a number of human cell lines, whilst at high levels (10-40 µM) it inhibited such cell proliferation. Similar dose responses were observed for cell migration, i.e. SFN at 2.5 µM increased cell migration in bladder cancer T24 cells to 128% whilst high levels inhibited cell migration. This hormetic action was also found in an angiogenesis assay where SFN at 2.5 µM promoted endothelial tube formation (118% of the control), whereas at 10-20 µM it caused significant inhibition. The precise mechanism by which SFN influences promotion of cell growth and migration is not known, but probably involves activation of autophagy since an autophagy inhibitor, 3-methyladenine, abolished the effect of SFN on cell migration. Moreover, low doses of SFN offered a protective effect against free-radical mediated cell death, an effect that was enhanced by co-treatment with selenium. These results suggest that SFN may either prevent or promote tumour cell growth depending on the dose and the nature of the target cells. In normal cells, the promotion of cell growth may be of benefit, but in transformed or cancer cells it may be an undesirable risk factor. In summary, ITCs have a biphasic effect on cell growth and migration. The benefits and risks of ITCs are not only determined by the doses, but are affected by interactions with Se and the measured endpoint

Observation of CR Anisotropy with ARGO-YBJ

The measurement of the anisotropies of cosmic ray arrival direction provides important informations on the propagation mechanisms and on the identification of their sources. In this paper we report the observation of anisotropy regions at different angular scales. In particular, the observation of a possible anisotropy on scales between $\sim$ 10 $^{\circ}$ and $\sim$ 30 $^{\circ}$ suggests the presence of unknown features of the magnetic fields the charged cosmic rays propagate through, as well as potential contributions of nearby sources to the total flux of cosmic rays. Evidence of new weaker few-degree excesses throughout the sky region $195^{\circ}\leq$ R.A. $\leq 315^{\circ}$ is reported for the first time.Comment: Talk given at 12th TAUP Conference 2011, 5-9 September 2011, Munich, German

Involvement of EphB1 Receptors Signalling in Models of Inflammatory and Neuropathic Pain

EphB receptors tyrosine kinases and ephrinB ligands were first identified as guidance molecules involved in the establishment of topographical mapping and connectivity in the nervous system during development. Later in development and into adulthood their primary role would switch from guidance to activity-dependent modulation of synaptic efficacy. In sensory systems, they play a role in both the onset of inflammatory and neuropathic pain, and in the establishment of central sensitisation, an NMDA-mediated form of synaptic plasticity thought to underlie most forms of chronic pain. We studied wild type and EphB1 knockout mice in a range of inflammatory and neuropathic pain models to determine 1), whether EphB1 expression is necessary for the onset and/or maintenance of persistent pain, regardless of origin; 2), whether in these models cellular and molecular changes, e.g. phosphorylation of the NR2B subunit of the NMDA receptor, increased c-fos expression or microglial activation, associated with the onset of pain, are affected by the lack of functional EphB1 receptors. Differences in phenotype were examined behaviourally, anatomically, biochemically and electrophysiologically. Our results establish firstly, that functional EphB1 receptors are not essential for the development of normal nociception, thermal or mechanical sensitivity. Secondly, they demonstrate a widespread involvement of EphB1 receptors in chronic pain. NR2B phosphorylation, c-fos expression and microglial activation are all reduced in EphB1 knockout mice. This last finding is intriguing, since microglial activation is supposedly triggered directly by primary afferents, therefore it was not expected to be affected. Interestingly, in some models of long-term pain (days), mechanical and thermal hyperalgesia develop both in wild type and EphB1 knockout mice, but recovery is faster in the latter, indicating that in particular models these receptors are required for the maintenance, rather than the onset of, thermal and mechanical hypersensitivity. This potentially makes them an attractive target for analgesic strategies

Increased CDC20 expression is associated with pancreatic ductal adenocarcinoma differentiation and progression

<p>Abstract</p> <p>Purpose</p> <p>Cell division cycle 20 (CDC20) homolog is an anaphase-promoting complex activator that is essential for cell division, but whether its expression in pancreatic ductal adenocarcinoma (PDAC) is significant is unknown. In this retrospective study, we determined whether aberrant CDC20 expression can be used as a biomarker in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis and whether its expression reflects clinical progression.</p> <p>Experimental design</p> <p>We compared CDC20 expression levels in normal, cancerous, and inflamed pancreatic tissues from stage II PDAC patients with clinical outcomes and determined CDC20 levels in seven PDAC cell lines. CDC20 was identified using a cDNA microarray database containing gene expression profiles for PDAC tissues and cell lines and chronic pancreatitis and normal pancreas tissues. Its expression was confirmed by real-time quantitative reverse-transcriptase-polymerase chain reaction (qRT-PCR). An immunohistochemical analysis of tissue microarrays from resected PDAC tumors and paired benign pancreatic tissues was done and CDC20 levels were correlated with clinical outcome.</p> <p>Results</p> <p>Fifty-six patients were included in this study. A microarray analysis revealed 5-fold higher CDC20 expression in PDAC tissue than in chronic pancreatitis tissue. A qRT-PCR analysis confirmed a mean 20-fold higher CDC20 level in PDAC tissue than in normal pancreas and pancreatitis tissue. RNA and protein CDC20 expression was detected in several PDAC cell lines. An immunohistochemical analysis revealed higher CDC20 protein expression levels in PDAC tissue than in normal pancreas tissue, and high CDC20 expression was associated with poor differentiation (<it>P </it>= 0.020) and a significantly lower 5-year recurrence-free survival rate (<it>P </it>= 0.039); we also found a trend toward a shorter overall survival duration.</p> <p>Conclusions</p> <p>Aberrant CDC20 expression may play an important role in PDAC tumorigenesis and progression and may thus be useful as a marker of disease progression and prognosis and as a therapeutic target.</p