Transport properties of nitrogen doped p‐gallium selenide single crystals

Nitrogen doped gallium selenide single crystals are studied through Hall effect and photoluminescence measurements in the temperature ranges from 150 to 700 K and from 30 to 45 K, respectively. The doping effect of nitrogen is established and room temperature resistivities as low as 20 Ω cm are measured. The temperature dependence of the hole concentration can be explained through a single acceptor‐single donor model, the acceptor ionization energy being 210 meV, with a very low compensation rate. The high quality of nitrogen doped GaSe single crystals is confirmed by photoluminescence spectra exhibiting only exciton related peaks. Two phonon scattering mechanisms must be considered in order to give quantitative account of the temperature dependence of the hole mobility: scattering by 16.7 meV A′1 homopolar optical phonons with a hole‐phonon coupling constant g2=0.115 and scattering by 31.5 meV LO polar phonon with a hole Fröhlich constant αh⊥[email protected]

Opening a new window to other worlds with spectropolarimetry

A high level of diversity has already been observed among the planets of our own Solar System. As such, one expects extrasolar planets to present a wide range of distinctive features, therefore the characterisation of Earth- and super Earth-like planets is becoming of key importance in scientific research. The SEARCH (Spectropolarimetric Exoplanet AtmospheRe CHaracerisation) mission proposal of this paper represents one possible approach to realising these objectives. The mission goals of SEARCH include the detailed characterisation of a wide variety of exoplanets, ranging from terrestrial planets to gas giants. More specifically, SEARCH will determine atmospheric properties such as cloud coverage, surface pressure and atmospheric composition, and may also be capable of identifying basic surface features. To resolve a planet with a semi major axis of down to 1.4AU and 30pc distant SEARCH will have a mirror system consisting of two segments, with elliptical rim, cut out of a parabolic mirror. This will yield an effective diameter of 9 meters along one axis. A phase mask coronagraph along with an integral spectrograph will be used to overcome the contrast ratio of star to planet light. Such a mission would provide invaluable data on the diversity present in extrasolar planetary systems and much more could be learned from the similarities and differences compared to our own Solar System. This would allow our theories of planetary formation, atmospheric accretion and evolution to be tested, and our understanding of regions such as the outer limit of the Habitable Zone to be further improved.Comment: 23 pages, accepted for publication in Experimental Astronom

Photoswitchable diacylglycerols enable optical control of protein kinase C.

Increased levels of the second messenger lipid diacylglycerol (DAG) induce downstream signaling events including the translocation of C1-domain-containing proteins toward the plasma membrane. Here, we introduce three light-sensitive DAGs, termed PhoDAGs, which feature a photoswitchable acyl chain. The PhoDAGs are inactive in the dark and promote the translocation of proteins that feature C1 domains toward the plasma membrane upon a flash of UV-A light. This effect is quickly reversed after the termination of photostimulation or by irradiation with blue light, permitting the generation of oscillation patterns. Both protein kinase C and Munc13 can thus be put under optical control. PhoDAGs control vesicle release in excitable cells, such as mouse pancreatic islets and hippocampal neurons, and modulate synaptic transmission in Caenorhabditis elegans. As such, the PhoDAGs afford an unprecedented degree of spatiotemporal control and are broadly applicable tools to study DAG signaling

Chemical combination effects predict connectivity in biological systems

Efforts to construct therapeutically useful models of biological systems require large and diverse sets of data on functional connections between their components. Here we show that cellular responses to combinations of chemicals reveal how their biological targets are connected. Simulations of pathways with pairs of inhibitors at varying doses predict distinct response surface shapes that are reproduced in a yeast experiment, with further support from a larger screen using human tumour cells. The response morphology yields detailed connectivity constraints between nearby targets, and synergy profiles across many combinations show relatedness between targets in the whole network. Constraints from chemical combinations complement genetic studies, because they probe different cellular components and can be applied to disease models that are not amenable to mutagenesis. Chemical probes also offer increased flexibility, as they can be continuously dosed, temporally controlled, and readily combined. After extending this initial study to cover a wider range of combination effects and pathway topologies, chemical combinations may be used to refine network models or to identify novel targets. This response surface methodology may even apply to non-biological systems where responses to targeted perturbations can be measured

Axl/Gas6/NFκB signalling in schwannoma pathological proliferation, adhesion and survival.

TAM family receptor tyrosine kinases comprising Tyro3 (Sky), Axl, and Mer are overexpressed in some cancers, correlate with multidrug resistance and contribute to tumourigenesis by regulating invasion, angiogenesis, cell survival and tumour growth. Mutations in the gene coding for a tumour suppressor merlin cause development of multiple tumours of the nervous system such as schwannomas, meningiomas and ependymomas occurring spontaneously or as part of a hereditary disease neurofibromatosis type 2. The benign character of merlin-deficient tumours makes them less responsive to chemotherapy. We previously showed that, amongst other growth factor receptors, TAM family receptors (Tyro3, Axl and Mer) are significantly overexpressed in schwannoma tissues. As Axl is negatively regulated by merlin and positively regulated by E3 ubiquitin ligase CRL4DCAF1, previously shown to be a key regulator in schwannoma growth we hypothesized that Axl is a good target to study in merlin-deficient tumours. Moreover, Axl positively regulates the oncogene Yes-associated protein, which is known to be under merlin regulation in schwannoma and is involved in increased proliferation of merlin-deficient meningioma and mesothelioma. Here, we demonstrated strong overexpression and activation of Axl receptor as well as its ligand Gas6 in human schwannoma primary cells compared to normal Schwann cells. We show that Gas6 is mitogenic and increases schwannoma cell-matrix adhesion and survival acting via Axl in schwannoma cells. Stimulation of the Gas6/Axl signalling pathway recruits Src, focal adhesion kinase (FAK) and NFκB. We showed that NFκB mediates Gas6/Axl-mediated overexpression of survivin, cyclin D1 and FAK, leading to enhanced survival, cell-matrix adhesion and proliferation of schwannoma. We conclude that Axl/FAK/Src/NFκB pathway is relevant in merlin-deficient tumours and is a potential therapeutic target for schwannoma and other merlin-deficient tumours

Relations between C9orf72 expansion size in blood, age at onset, age at collection and transmission across generations in patients and presymptomatic carriers

A (GGGGCC) n repeat expansion in C9orf72 gene is the major cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The relations between the repeats size and the age at disease onset (AO) or the clinical phenotype (FTD vs. ALS) were investigated in 125 FTD, ALS, and presymptomatic carriers. Positive correlations were found between repeats number and the AO (p < 10 e−4 ) but our results suggested that the association was mainly driven by age at collection (p < 10 e−4 ). A weaker association was observed with clinical presentation (p = 0.02), which became nonsignificant after adjustment for the age at collection in each group. Importantly, repeats number variably expanded or contracted over time in carriers with multiple blood samples, as well as through generations in parent-offspring pairs, conversely to what occurs in several expansion diseases with anticipation at the molecular level. Finally, this study establishes that measure of repeats number in lymphocytes is not a reliable biomarker predictive of the AO or disease outcome in C9orf72 long expansion carriers

Facilitation of AMPA Receptor Synaptic Delivery as a Molecular Mechanism for Cognitive Enhancement

A small peptide from a neuronal cell adhesion molecule enhances synaptic plasticity in the hippocampus and results in improved cognitive performance in rats

Similar NF-κB Gene Signatures in TNF-α Treated Human Endothelial Cells and Breast Tumor Biopsies

BACKGROUND: Endothelial dysfunction has been implicated in the pathogenesis of diverse pathologies ranging from vascular and immune diseases to cancer. TNF-α is one of the mediators of endothelial dysfunction through the activation of transcription factors, including NF-κB. While HUVEC (macrovascular cells) have been largely used in the past, here, we documented an NF-κB gene signature in TNFα-stimulated microvascular endothelial cells HMEC often used in tumor angiogenesis studies. METHODOLOGY/PRINCIPAL FINDINGS: We measured mRNA expression of 55 NF-κB related genes using quantitative RT-PCR in HUVEC and HMEC. Our study identified twenty genes markedly up-regulated in response to TNFα, including adhesion molecules, cytokines, chemokines, and apoptosis regulators, some of them being identified as TNF-α-inducible genes for the first time in endothelial cells (two apoptosis regulators, TNFAIP3 and TNFRSF10B/Trail R2 (DR5), the chemokines GM-CSF/CSF2 and MCF/CSF1, and CD40 and TNF-α itself, as well as NF-κB components (RELB, NFKB1 or 50/p105 and NFKB2 or p52/p100). For eight genes, the fold induction was much higher in HMEC, as compared to HUVEC. Most importantly, our study described for the first time a connection between NF-κB activation and the induction of most, if not all, of these genes in HMEC as evaluated by pharmacological inhibition and RelA expression knock-down by RNA interference. Moreover, since TNF-α is highly expressed in tumors, we further applied the NF-κB gene signature documented in TNFα-stimulated endothelial cells to human breast tumors. We found a significant positive correlation between TNF and the majority (85 %) of the identified endothelial TNF-induced genes in a well-defined series of 96 (48 ERα positive and 48 ERα negative) breast tumors. CONCLUSION/SIGNIFICANCE: Taken together these data suggest the potential use of this NF-κB gene signature in analyzing the role of TNF-α in the endothelial dysfunction, as well as in breast tumors independently of the presence of ERα

Protein kinase C activation disrupts epithelial apical junctions via ROCK-II dependent stimulation of actomyosin contractility

<p>Abstract</p> <p>Background</p> <p>Disruption of epithelial cell-cell adhesions represents an early and important stage in tumor metastasis. This process can be modeled <it>in vitro </it>by exposing cells to chemical tumor promoters, phorbol esters and octylindolactam-V (OI-V), known to activate protein kinase C (PKC). However, molecular events mediating PKC-dependent disruption of epithelial cell-cell contact remain poorly understood. In the present study we investigate mechanisms by which PKC activation induces disassembly of tight junctions (TJs) and adherens junctions (AJs) in a model pancreatic epithelium.</p> <p>Results</p> <p>Exposure of HPAF-II human pancreatic adenocarcinoma cell monolayers to either OI-V or 12-O-tetradecanoylphorbol-13-acetate caused rapid disruption and internalization of AJs and TJs. Activity of classical PKC isoenzymes was responsible for the loss of cell-cell contacts which was accompanied by cell rounding, phosphorylation and relocalization of the F-actin motor nonmuscle myosin (NM) II. The OI-V-induced disruption of AJs and TJs was prevented by either pharmacological inhibition of NM II with blebbistatin or by siRNA-mediated downregulation of NM IIA. Furthermore, AJ/TJ disassembly was attenuated by inhibition of Rho-associated kinase (ROCK) II, but was insensitive to blockage of MLCK, calmodulin, ERK1/2, caspases and RhoA GTPase.</p> <p>Conclusion</p> <p>Our data suggest that stimulation of PKC disrupts epithelial apical junctions via ROCK-II dependent activation of NM II, which increases contractility of perijunctional actin filaments. This mechanism is likely to be important for cancer cell dissociation and tumor metastasis.</p