Depletion of the chromatin remodeler CHD4 sensitizes AML blasts to genotoxic agents and reduces tumor formation

Chromodomain helicase DNA-binding protein 4 (CHD4) is an ATPase that alters the phasing of nucleosomes on DNA and has recently been implicated in DNA double-stranded break (DSB) repair. Here, we show that depletion of CHD4 in acute myeloid leukemia (AML) blasts induces a global relaxation of chromatin that renders cells more susceptible to DSB formation, while concurrently impeding their repair. Furthermore, CHD4 depletion renders AML blasts more sensitive both in vitro and in vivo to genotoxic agents used in clinical therapy: daunorubicin (DNR) and cytarabine (ara-C). Sensitization to DNR and ara-C is mediated in part by activation of the ataxia-telangiectasia mutated pathway, which is preliminarily activated by a Tip60-dependent mechanism in response to chromatin relaxation and further activated by genotoxic agent–induced DSBs. This sensitization preferentially affects AML cells, as CHD4 depletion in normal CD34+ hematopoietic progenitors does not increase their susceptibility to DNR or ara-C. Unexpectedly, we found that CHD4 is necessary for maintaining the tumor-forming behavior of AML cells, as CHD4 depletion severely restricted the ability of AML cells to form xenografts in mice and colonies in soft agar. Taken together, these results provide evidence for CHD4 as a novel therapeutic target whose inhibition has the potential to enhance the effectiveness of genotoxic agents used in AML therapy

Coulomb effects on the formation of proton halo nuclei

The exotic structures in the 2s_{1/2} states of five pairs of mirror nuclei ^{17}O-^{17}F, ^{26}Na-^{26}P, ^{27}Mg-^{27}P, ^{28}Al-^{28}P and ^{29}Si-^{29}P are investigated with the relativistic mean-field (RMF) theory and the single-particle model (SPM) to explore the role of the Coulomb effects on the proton halo formation. The present RMF calculations show that the exotic structure of the valence proton is more obvious than that of the valence neutron of its mirror nucleus, the difference of exotic size between each mirror nuclei becomes smaller with the increase of mass number A of the mirror nuclei and the ratios of the valence proton and valence neutron root-mean-square (RMS) radius to the matter radius in each pair of mirror nuclei all decrease linearly with the increase of A. In order to interpret these results, we analyze two opposite effects of Coulomb interaction on the exotic structure formation with SPM and find that the contribution of the energy level shift is more important than that of the Coulomb barrier for light nuclei. However, the hindrance of the Coulomb barrier becomes more obvious with the increase of A. When A is larger than 34, Coulomb effects on the exotic structure formation will almost become zero because its two effects counteract with each other.Comment: 9 pages, 6 figures. One colum

Earthquake Forecast via Neutrino Tomography

We discuss the possibility of forecasting earthquakes by means of (anti)neutrino tomography. Antineutrinos emitted from reactors are used as a probe. As the antineutrinos traverse through a region prone to earthquakes, observable variations in the matter effect on the antineutrino oscillation would provide a tomography of the vicinity of the region. In this preliminary work, we adopt a simplified model for the geometrical profile and matter density in a fault zone. We calculate the survival probability of electron antineutrinos for cases without and with an anomalous accumulation of electrons which can be considered as a clear signal of the coming earthquake, at the geological region with a fault zone, and find that the variation may reach as much as 3% for $\bar \nu_e$ emitted from a reactor. The case for a $\nu_e$ beam from a neutrino factory is also investigated, and it is noted that, because of the typically high energy associated with such neutrinos, the oscillation length is too large and the resultant variation is not practically observable. Our conclusion is that with the present reactor facilities and detection techniques, it is still a difficult task to make an earthquake forecast using such a scheme, though it seems to be possible from a theoretical point of view while ignoring some uncertainties. However, with the development of the geology, especially the knowledge about the fault zone, and with the improvement of the detection techniques, etc., there is hope that a medium-term earthquake forecast would be feasible.Comment: 6 pages, 4 figures, 1 tabl

HLA-matched sibling transplantation with G-CSF mobilized PBSCs and BM decreases GVHD in adult patients with severe aplastic anemia

<p>Abstract</p> <p>Background</p> <p>Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for severe aplastic anemia (SAA). However, graft failure and graft-versus-host disease (GVHD) are major causes of the early morbidity in Allo-HSCT.</p> <p>Methods</p> <p>To reduce graft failure and GVHD, we treated fifteen patients with SAA using high- dose of HSCT with both G-CSF mobilized PB and BMSCs from HLA-identical siblings to treat patients with SAA.</p> <p>Results</p> <p>All patients had successful bone marrow engraftment. Only one patient had late rejection. Median time to ANC greater than 0.5 × 10⁹/L and platelet counts greater than 20 × 10⁹/L was 12 and 16.5 days, respectively. No acute GVHD was observed. The incidence of chronic GVHD was 6.67%. The total three-year probability of disease-free survival was 79.8%.</p> <p>Conclusion</p> <p>HSCT with both G-CSF mobilized PB and BMSCs is a promising approach for heavily transfused and/or allo-immunized patients with SAA.</p

Heteroatom Doped High Porosity Carbon Nanomaterials as Electrodes for Energy Storage in Electrochemical Capacitors: A Review

At present it is indispensable to develop and implement new/state-of-the-art carbon nanomaterials as electrodes in electrochemical capacitors, since conventional activated carbon based supercapacitor cells cannot fulfil the growing demand of high energy and power densities of electronic devices of the present era, as a result of the rapid developments in this field. Functionalized carbon nanomaterials symbolize the type of materials with huge potential for their use in energy related applications in general and as an electrode active material for electrochemical capacitors in particular. Nitrogen doping of carbons has shown promising results in the field of energy storage in electrochemical capacitors, gaining attention of researchers to evaluate the performance of new heteroatoms functionalised materials such as sulphur, phosphorus and boron lately. Literature is widely available on nitrogen doped materials research for energy storage applications; however, there has been a limited number of review works on other functional materials beyond nitrogen. This review article thus aims to provide important insights and an up-to-date analysis of the most recent developments, the directions of future research, and the techniques used for the synthesis of these functional materials. A critical review of the electrochemical performance including specific capacitance and energy/power densities is made, when these single doped or co-doped active materials are used as electrodes in electrochemical capacitors

Study of detonation wave contours in EFP warhead

An analytical model for calculating the propagation time of shock wave in a wave shaper is presented in this study. The calculated results show that the contours of three typical detonation waves, such as conical detonation wave, spherical detonation wave, and planar detonation wave, can be formed in the main charge by changing the thickness of wave shaper. The results show that the planar detonation wave do better than the conical detonation and the spherical detonation wave in increasing the length–diameter ratio of explosively-formed projectiles (EFP) and keep the nose of EFP integrated. The detonation wave can increase the length–diameter ratio of EFP when the wave shaper has the suitable thickness

Comparison of the concentration of messenger RNA encoding four muscarinic receptor subtypes in control and Alzheimer brains

We determined the concentration of the messenger RNA species which encode four (m1–m4) of the five cloned muscarinic receptors in brains of Alzheimer's disease patients as compared to age-matched controls. Assays were performed using the quantitative method of DNA-excess solution hybridization in the cerebral cortex (frontal, temporal and occipital), hippocampus, nucleus basalis of Meynert and brainstem. The results suggest a statistically significant decrease in the m1 muscarinic receptor message in the temporal and occipital cortex, with no change in other regions. There was no change in the level of mRNA encoding the m2, m3 or m4 receptors in any of the brain regions studied

Methylation of Promoter Proximal-transcribed Sequences of an Embryonic Globin Gene Inhibits Transcription in Primary Erythroid Cells and Promotes Formation of a Cell Type-specific Methyl Cytosine Binding Complex

The methylation pattern of a 248-base pair proximal transcribed region (ρ248) of the avian embryonic ρ-globin gene was found to correlate inversely with stage-specific expression in avian erythroid cells. In vitro methylation of the ρ248 segment alone (in the absence of promoter methylation) resulted in a 5-fold inhibition of transcription in a transient transfection assay in primary erythroid cells in which the transfected gene is packaged into nucleosomal chromatin. This effect was observed if the ρ248 segment was positioned adjacent to the promoter but not when it was located 2.7 kilobases downstream. Fully methylated but not unmethylated ρ248 formed a novel cell type-specific methylcytosine-binding protein complex (MeCPC) that contained methyl bindingdomain protein-2 (MBD-2) and histone deacetylase 1 proteins but differed from MeCP-1. The histone deacetylase inhibitor trichostatin A failed to relieve methylation-mediated repression of transcription from the ρ-gene promoter, supporting the notion of the dominance of methylation over histone deacetylation in silencing through CpG-rich sequences at this locus. These data demonstrate that site-specific methylation of a vertebrate gene 5′-transcribed region alone at the exact CpGs that are methylated in vivo can suppress transcription in homologous primary cells and facilitate binding to a cell type-specific MeCPC