Homeobox gene expression in acute myeloid leukemia is linked to typical underlying molecular aberrations

__Background:__ Although distinct patterns of homeobox (HOX) gene expression have been described in defined cytogenetic and molecular subsets of patients with acute myeloid leukemia (AML), it is unknown whether these patterns are the direct result of transcriptional alterations or rather represent the differentiation stage of the leukemic cell. __Method:__ To address this question, we used qPCR to analyze mRNA expression of HOXA and HOXB genes in bone marrow (BM) samples of 46 patients with AML and sorted subpopulations of healthy BM cells. These various stages of myeloid differentiation represent matched counterparts of morphological subgroups of AML. To further study the transcriptional alterations of HOX genes in hematopoiesis, we also analyzed gene expression of epigenetic modifiers in the subpopluations of healthy BM and leukemic cells. __Results:__ Unsupervised hierarchical clustering divided the AMLs into five clusters characterized by the presence of prevalent molecular genetic aberrations. Notably, the impact of genotype on HOX gene expression was significantly more pronounced than that of the differentiation stage of the blasts. This driving role of molecular aberrations was best exemplified by the repressive effect of the PML-RARa fusion gene on HOX gene expression, regardless of the presence of the FLT3/ITD mutation. Furthermore, HOX gene expression was positively correlated with mRNA levels of histone demethylases (JMJD3 and UTX) and negatively correlated with gene expression of DNA methyltranferases. No such relationships were observed in subpopulations of healthy BM cells. __Conclusion:__ Our results demonstrate that specific molecular genetic aberrations, rather than differentiation per se, underlie the observed differences in HOX gene expression in AML. Moreover, the observed correlations between epigenetic modifiers and HOX ex pression that are specific to malignant hematopoiesis, suggest their potential causal relationships

Time-aging time-stress superposition in soft glass under tensile deformation field

We have studied the tensile deformation behaviour of thin films of aging aqueous suspension of Laponite, a model soft glassy material, when subjected to a creep flow field generated by a constant engineering normal stress. Aqueous suspension of Laponite demonstrates aging behaviour wherein it undergoes time dependent enhancement of its elastic modulus as well as its characteristic relaxation time. However, under application of the normal stress, the rate of aging decreases and in the limit of high stress, the aging stops with the suspension now undergoing a plastic deformation. Overall, it is observed that the aging that occurs over short creep times at small normal stresses is same as the aging that occurs over long creep times at large normal stresses. This observation allows us to suggest an aging time - process time - normal stress superposition principle, which can predict rheological behaviour at longer times by carrying out short time tests.Comment: 26 pages, 7 figures, To appear in Rheologica Act

SARS Coronavirus 3b Accessory Protein Modulates Transcriptional Activity of RUNX1b

BACKGROUND: The causative agent of severe acute respiratory syndrome, SARS coronavirus (SARS-CoV) genome encodes several unique group specific accessory proteins with unknown functions. Among them, accessory protein 3b (also known as ORF4) was lately identified as one of the viral interferon antagonist. Recently our lab uncovered a new role for 3b in upregulation of AP-1 transcriptional activity and its downstream genes. Thus, we believe that 3b might play an important role in SARS-CoV pathogenesis and therefore is of considerable interest. The current study aims at identifying novel host cellular interactors of the 3b protein. METHODOLOGY/PRINCIPAL FINDINGS: In this study, using yeast two-hybrid and co-immunoprecipitation techniques, we have identified a host transcription factor RUNX1b (Runt related transcription factor, isoform b) as a novel interacting partner for SARS-CoV 3b protein. Chromatin immunoprecipitaion (ChIP) and reporter gene assays in 3b expressing jurkat cells showed recruitment of 3b on the RUNX1 binding element that led to an increase in RUNX1b transactivation potential on the IL2 promoter. Kinase assay and pharmacological inhibitor treatment implied that 3b also affect RUNX1b transcriptional activity by regulating its ERK dependent phosphorylation levels. Additionally, mRNA levels of MIP-1α, a RUNX1b target gene upregulated in SARS-CoV infected monocyte-derived dendritic cells, were found to be elevated in 3b expressing U937 monocyte cells. CONCLUSIONS/SIGNIFICANCE: These results unveil a novel interaction of SARS-CoV 3b with the host factor, RUNX1b, and speculate its physiological relevance in upregulating cytokines and chemokine levels in state of SARS virus infection

Directional Sensitivity of the NEWSdm Experiment to Cosmic Ray Boosted Dark Matter

We present a study of a directional search for Dark Matter boosted forward when scattered by cosmic-ray nuclei, using a module of the NEWSdm experiment. The boosted Dark Matter flux at the edge of the Earth's atmosphere is expected to be pointing to the Galactic Center, with a flux 15 to 20 times larger than in the transverse direction. The module of the NEWSdm experiment consists of a 10 kg stack of Nano Imaging Trackers, i.e.~newly developed nuclear emulsions with AgBr crystal sizes down to a few tens of nanometers. The module is installed on an equatorial telescope. The relatively long recoil tracks induced by boosted Dark Matter, combined with the nanometric granularity of the emulsion, result in an extremely low background. This makes an installation at the INFN Gran Sasso laboratory, both on the surface and underground, viable. A comparison between the two locations is made. The angular distribution of nuclear recoils induced by boosted Dark Matter in the emulsion films at the surface laboratory is expected to show an excess with a factor of 3.5 in the direction of the Galactic Center. This excess allows for a Dark Matter search with directional sensitivity. The surface laboratory configuration prevents the deterioration of the signal in the rock overburden and it emerges as the most powerful approach for a directional observation of boosted Dark Matter with high sensitivity. We show that, with this approach, a 10 kg module of the NEWSdm experiment exposed for one year at the Gran Sasso surface laboratory can probe Dark Matter masses between 1 keV/c$^2$ and 1 GeV/c$^2$ and cross-section values down to $10^{-30}$~cm$^2$ with a directional sensitive search.Comment: 15 pages, 14 figures, updated references, clarified discussion in intro section. Submitted to JCA

Interaction between Chromosomal Protein HMGB1 and DNA Studied by DNA-Melting Analysis

Interaction of HMGB1 nonhistone chromosomal protein with DNA was studied using circular dichroism spectroscopy and thermal denaturation of DNA. Melting DNA in the complex was shown to be a biphasic process. The characteristic melting temperatures of unbound DNA and the DNA bound to HMGB1 in 0.25 mM EDTA solutions were found to be TmI=44.0±0.5°C and TmII=62.0±1°C, respectively. It was shown that the binding of the HMGB1 molecule affects the melting of the DNA region approximately 30 b.p. long

Are day hospitals effective for acutely ill psychiatric patients? A European multicenter randomized controlled trial

Check polic