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JAK2V617F mediates resistance to DNA damage-induced apoptosis by modulating FOXO3A localization and Bcl-xL deamidation.
The JAK2V617F mutation is found in most patients with a myeloproliferative neoplasm (MPN). This gain-of-function mutation dysregulates cytokine signaling and is associated with increased accumulation of DNA damage, a process likely to drive disease evolution. JAK2V617F inhibits NHE-1 upregulation in response to DNA damage and consequently represses Bcl-xL deamidation and apoptosis, thus giving rise to inappropriate cell survival. However, the mechanism whereby NHE-1 expression is inhibited by JAK2V617F is unknown. In this study, we demonstrate that the accumulation of reactive oxygen species (ROS) in cells expressing JAK2V617F compromises the NHE-1/Bcl-xL deamidation pathway by repressing NHE-1 upregulation in response to DNA damage. In JAK2V617F-positive cells, increased ROS levels results from aberrant PI3K signaling, which decreases nuclear localization of FOXO3A and decreases catalase expression. Furthermore, when compared with autologous control erythroblasts, clonally derived JAK2V617F-positive erythroblasts from MPN patients displayed increased ROS levels and reduced nuclear FOXO3A. However, in hematopoietic stem cells (HSCs), FOXO3A is largely localized within the nuclei despite the presence of JAK2V617F mutation, suggesting that JAK2-FOXO signaling has a different effect on progenitors compared with stem cells. Inactivation of FOXO proteins and elevation of intracellular ROS are characteristics common to many cancers, and hence these findings are likely to be of relevance beyond the MPN field.Work in the Green lab is supported by Leukemia and Lymphoma
Research, Cancer Research UK, the Kay Kendall Leukaemia Fund, the NIHR
Cambridge Biomedical Research Centre, the Cambridge Experimental Cancer
Medicine Centre, and the Leukemia & Lymphoma Society of America. DGK was
supported by a postdoctoral fellowship from the Canadian Institutes of Health
Research (Ottawa, ON), and a Lady Tata Memorial Trust International Award for
Research in Leukaemia (London, UK). HJP was supported by a postdoctoral
fellowship from the Human Frontier Science Program.This is the accepted manuscript. The final version is available at http://www.nature.com/onc/journal/vaop/ncurrent/full/onc2015285a.html
Rapid generation of chromosome-specific alphoid DNA probes using the polymerase chain reaction
Non-isotopic in situ hybridization of chromosome-specific alphoid DNA probes has become a potent tool in the study of numerical aberrations of specific human chromosomes at all stages of the cell cycle. In this paper, we describe approaches for the rapid generation of such probes using the polymerase chain reaction (PCR), and demonstrate their chromosome specificity by fluorescence in situ hybridization to normal human metaphase spreads and interphase nuclei. Oligonucleotide primers for conserved regions of the alpha satellite monomer were used to generate chromosome-specific DNA probes from somatic hybrid cells containing various human chromosomes, and from DNA libraries from sorted human chromosomes. Oligonucleotide primers for chromosome-specific regions of the alpha satellite monomer were used to generate specific DNA probes for the pericentromeric heterochromatin of human chromosomes 1, 6, 7, 17 and X directly from human genomic DNA
Evaluation of two interaction techniques for visualization of dynamic graphs
Several techniques for visualization of dynamic graphs are based on different
spatial arrangements of a temporal sequence of node-link diagrams. Many studies
in the literature have investigated the importance of maintaining the user's
mental map across this temporal sequence, but usually each layout is considered
as a static graph drawing and the effect of user interaction is disregarded. We
conducted a task-based controlled experiment to assess the effectiveness of two
basic interaction techniques: the adjustment of the layout stability and the
highlighting of adjacent nodes and edges. We found that generally both
interaction techniques increase accuracy, sometimes at the cost of longer
completion times, and that the highlighting outclasses the stability adjustment
for many tasks except the most complex ones.Comment: Appears in the Proceedings of the 24th International Symposium on
Graph Drawing and Network Visualization (GD 2016
30 inch Roll-Based Production of High-Quality Graphene Films for Flexible Transparent Electrodes
We report that 30-inch scale multiple roll-to-roll transfer and wet chemical
doping considerably enhance the electrical properties of the graphene films
grown on roll-type Cu substrates by chemical vapor deposition. The resulting
graphene films shows a sheet resistance as low as ~30 Ohm/sq at ~90 %
transparency which is superior to commercial transparent electrodes such as
indium tin oxides (ITO). The monolayer of graphene shows sheet resistances as
low as ~125 Ohm/sq with 97.4% optical transmittance and half-integer quantum
Hall effect, indicating the high-quality of these graphene films. As a
practical application, we also fabricated a touch screen panel device based on
the graphene transparent electrodes, showing extraordinary mechanical and
electrical performances
A Novel Role of Three Dimensional Graphene Foam to Prevent Heater Failure during Boiling
We report a novel boiling heat transfer (NBHT) in reduced graphene oxide (RGO) suspended in water (RGO colloid) near critical heat flux (CHF), which is traditionally the dangerous limitation of nucleate boiling heat transfer because of heater failure. When the heat flux reaches the maximum value (CHF) in RGO colloid pool boiling, the wall temperature increases gradually and slowly with an almost constant heat flux, contrary to the rapid wall temperature increase found during water pool boiling. The gained time by NBHT would provide the safer margin of the heat transfer and the amazing impact on the thermal system as the first report of graphene application. In addition, the CHF and boiling heat transfer performance also increase. This novel boiling phenomenon can effectively prevent heater failure because of the role played by the self-assembled three-dimensional foam-like graphene network (SFG).open2
Comparison of intravascular ultrasound guided versus angiography guided drug eluting stent implantation: a systematic review and meta-analysis
BACKGROUND: Intravascular ultrasound (IVUS) can be a useful tool during drug-eluting stents (DES) implantation as it allows accurate assessment of lesion severity and optimal treatment planning. However, numerous reports have shown that IVUS guided percutaneous coronary intervention is not associated with improved clinical outcomes, especially in non-complex patients and lesions. METHODS: We searched the literature in Medline, the Cochrane Library, and other internet sources to identify studies that compare clinical outcomes between IVUS-guided and angiography-guided DES implantation. Random-effects model was used to assess treatment effect. RESULTS: Twenty eligible studies with a total of 29,068 patients were included in this meta-analysis. The use of IVUS was associated with significant reductions in major adverse cardiovascular events (MACE, odds ratios [OR] 0.77, 95 % confidence intervals [CI] 0.71-0.83, P < 0.001), death (OR 0.62, 95 % CI 0.54-0.71, p < 0.001), and stent thrombosis (OR 0.59, 95 % CI: 0.47-0.73, P < 0.001). The benefit was also seen in the repeated analysis of matched and randomized studies. In stratified analysis, IVUS guidance appeared to be beneficial not only in patients with complex lesions or acute coronary syndromes (ACS) but also patients with mixed lesions or presentations (MACE: OR 0.69, 95 % CI: 0.60-0.79, p < 0.001, OR 0.81, 95 % CI 0.74-0.90, p < 0.001, respectively). By employing meta-regression analysis, the benefit of IVUS is significantly pronounced in patients with complex lesions or ACS with respect to death (p = 0.048). CONCLUSIONS: IVUS guidance was associated with improved clinical outcomes, especially in patients with complex lesions admitted with ACS. Large, randomized clinical trials are warranted to identify populations and lesion characteristics where IVUS guidance would be associated with better outcomes
Molecular Valves for Controlling Gas Phase Transport Made from Discrete Angstrom-Sized Pores in Graphene
An ability to precisely regulate the quantity and location of molecular flux
is of value in applications such as nanoscale 3D printing, catalysis, and
sensor design. Barrier materials containing pores with molecular dimensions
have previously been used to manipulate molecular compositions in the gas
phase, but have so far been unable to offer controlled gas transport through
individual pores. Here, we show that gas flux through discrete angstrom-sized
pores in monolayer graphene can be detected and then controlled using
nanometer-sized gold clusters, which are formed on the surface of the graphene
and can migrate and partially block a pore. In samples without gold clusters,
we observe stochastic switching of the magnitude of the gas permeance, which we
attribute to molecular rearrangements of the pore. Our molecular valves could
be used, for example, to develop unique approaches to molecular synthesis that
are based on the controllable switching of a molecular gas flux, reminiscent of
ion channels in biological cell membranes and solid state nanopores.Comment: to appear in Nature Nanotechnolog
Electronic correlations in the iron pnictides
In correlated metals derived from Mott insulators, the motion of an electron
is impeded by Coulomb repulsion due to other electrons. This phenomenon causes
a substantial reduction in the electron's kinetic energy leading to remarkable
experimental manifestations in optical spectroscopy. The high-Tc
superconducting cuprates are perhaps the most studied examples of such
correlated metals. The occurrence of high-Tc superconductivity in the iron
pnictides puts a spotlight on the relevance of correlation effects in these
materials. Here we present an infrared and optical study on single crystals of
the iron pnictide superconductor LaFePO. We find clear evidence of electronic
correlations in metallic LaFePO with the kinetic energy of the electrons
reduced to half of that predicted by band theory of nearly free electrons.
Hallmarks of strong electronic many-body effects reported here are important
because the iron pnictides expose a new pathway towards a correlated electron
state that does not explicitly involve the Mott transition.Comment: 10 page
Cooperation and Contagion in Web-Based, Networked Public Goods Experiments
A longstanding idea in the literature on human cooperation is that
cooperation should be reinforced when conditional cooperators are more likely
to interact. In the context of social networks, this idea implies that
cooperation should fare better in highly clustered networks such as cliques
than in networks with low clustering such as random networks. To test this
hypothesis, we conducted a series of web-based experiments, in which 24
individuals played a local public goods game arranged on one of five network
topologies that varied between disconnected cliques and a random regular graph.
In contrast with previous theoretical work, we found that network topology had
no significant effect on average contributions. This result implies either that
individuals are not conditional cooperators, or else that cooperation does not
benefit from positive reinforcement between connected neighbors. We then tested
both of these possibilities in two subsequent series of experiments in which
artificial seed players were introduced, making either full or zero
contributions. First, we found that although players did generally behave like
conditional cooperators, they were as likely to decrease their contributions in
response to low contributing neighbors as they were to increase their
contributions in response to high contributing neighbors. Second, we found that
positive effects of cooperation were contagious only to direct neighbors in the
network. In total we report on 113 human subjects experiments, highlighting the
speed, flexibility, and cost-effectiveness of web-based experiments over those
conducted in physical labs
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