Identification of methotrexate as a heterochromatin-promoting drug.

Heterochromatin is a tightly packed form of DNA involved in gene silencing, chromosome segregation, and protection of genome stability. Heterochromatin is becoming more recognized in tumor suppression and may thus serve as a potential target for cancer therapy. However, to date there are no drugs that are well established to specifically promote heterochromatin formation. Here, we describe a screening method using Drosophila to identify small molecule compounds that promote heterochromatin formation, with the purpose of developing epigenetic cancer therapeutics. We took advantage of a Drosophila strain with a variegated eye color phenotype that is sensitive to heterochromatin levels, and screened a library of 97 FDA approved oncology drugs. This screen identified methotrexate as the most potent small molecule drug, among the 97 oncology drugs screened, in promoting heterochromatin formation. Interestingly, methotrexate has been identified as a JAK/STAT inhibitor in a functional screen, causing reduced phosphorylation of STAT proteins. These findings are in line with our previous observation that unphosphorylated STAT (uSTAT) promotes heterochromatin formation in both Drosophila and human cells and suppresses tumor growth in mouse xenografts. Thus, Drosophila with variegated eye color phenotypes could be an effective tool for screening heterochromatin-promoting compounds that could be candidates as cancer therapeutics

Multichannel cold collisions between metastable Sr atoms

We present a multichannel scattering calculation of elastic and inelastic cold collisions between two low-field seeking, metastable ^{88}Sr [(5s5p) ^3P_2] atoms in the presence of an external magnetic field. The scattering physics is governed by strong anisotropic long-range interactions, which lead to pronounced coupling among the partial waves of relative motion. As a result, nonadiabatic transitions are shown to trigger a high rate of inelastic losses. At relatively high energies, T > 100 mkK, the total inelastic collision rate is comparable with the elastic rate. However, at lower collisional energy, the elastic rate decreases, and at T ~ 1mkK, it becomes substantially smaller than the inelastic rate. Our study suggests that magnetic trapping and evaporative cooling of ^{88}Sr [(5s5p) ^3P_2] atoms, as well as ^{40}Ca [(4s4p) ^3P_2], in low-field seeking states will prove difficult to achieve experimentally.Comment: 4 pages, Latex, Submitte

Coherent spin-current oscillations in transverse magnetic fields

We address the coherence of the dynamics of spin-currents with components transverse to an external magnetic field for the spin-1/2 Heisenberg chain. We study current autocorrelations at finite temperatures and the real-time dynamics of currents at zero temperature. Besides a coherent Larmor oscillation, we find an additional collective oscillation at higher frequencies, emerging as a coherent many-magnon effect at low temperatures. Using numerical and analytical methods, we analyze the oscillation frequency and decay time of this coherent current-mode versus temperature and magnetic field.Comment: 4 pages, 5 figures (and supplemental material: 4 pages, 6 figures

Participatory agro-climate information services: A key component in climate resilient agriculture

The brief promotes participatory agro-climate information services as a key component in achieving climate-smart agriculture. The brief emphasizes that actionable agro-climate information starts with—and responds to—gender-based needs of farmers, integrated at all stages of the value chain. Timely forecasts and accurate agroclimate advisories have been proven to provide farmers with production, adaptation, and mitigation benefits

Does It Make Any Difference How You Feel About Your Job? An Exploratory Study of the Relationship Between Job Satisfaction and Political Orientations

Does job satisfaction - as reported by the jobholder have a bearing on one\u27s political orientations? Findings based upon five sets of political variables suggest that job satisfaction is related to politics, though not always strongly so. Dissatisfied individuals participate less, trust government less, and are more politically alienated than job-satisfied respondents. Job satisfaction cannot be characterized as a surrogate for other job- and personality-related characteristics, but has explanatory power of its own, though this power is affected when controls are introduced to the research design. While job satisfaction has important political implications, none of the relationships examined split satisfied and dissatisfied individuals into opposing majorities. In a relatively alienated, distrustful. and apathetic population, the dissatisfied are somewhat more so. The data base was NORC\u27s General Social Survey Cumulative File 1972-1980

Mixed valence Sn doped (CH3NH3)3Bi2Br9 produced by mechanochemical synthesis

Bismuth halides with formula A3Bi2X9, where A is an inorganic or organic cation, show desirable properties as solar absorbers and luminescent materials. Control of structural and electronic dimensionality of these compounds is important to yield materials with good light absorption and charge transport. Here we report mechanochemical reaction of (CH3NH3)3Bi2Br9 with SnBr2 at room temperature in air, yielding a material with strong absorption across the visible region. We attribute this to mixed valence doping of Sn(II) and Sn(IV) on the Bi site. X-ray diffraction shows no secondary phases, even after heating at 200oC to improve crystallinity. X-ray photoelectron spectroscopy suggests the presence of Sn(II) and Sn(IV) states. A similar approach to dope Sn into the iodide analogue (CH3NH3)3Bi2I9 was unsuccessful

The Ly-6A (Sca-1) GFP transgene is expressed in all adult mouse hematopoietic stem cells

The Sca-1 cell surface glycoprotein is used routinely as a marker of adult hematopoietic stem cells (HSCs), allowing a >100-fold enrichment of these rare cells from the bone marrow of the adult mouse. The Sca-1 protein is encoded by the Ly-6A/E gene, a small 4-exon gene that is tightly controlled in its expression in HSCs and several hematopoietic cell types. For the ability to sort and localize HSCs directly from the mouse, we initiated a transgenic approach in which we created Ly-6A (Sca-1) green fluorescent protein (GFP) transgenic mice. We show here that a 14-kb Ly-6A expression cassette directs the transcription of the GFP marker gene in all functional repopulating HSCs in the adult bone marrow. A >100-fold enrichment of HSCs occurred by sorting for the GFP-expressing cells. Furthermore, as shown by fluorescence-activated cell sorting and histologic analysis of several hematopoietic tissues, the GFP transgene expression pattern generally corresponded to that of Sca-1. Thus, the Ly-6A GFP transgene facilitates the enrichment of HSCs and presents the likelihood of identifying HSCs in situ

ROSY application for selecting R packages that perform ROC analysis

The empirical ROC curve is a powerful statistical tool to evaluate the precision of tests in several fields of study. This is a two-dimensional plot where the horizontal and vertical axis represent false positive and true positive fraction respectively, also referred to as 1-specificity and sensitivity, where precision is evaluated through a summary index, the area under the curve (AUC). Several computer tools are used to perform this analysis one of which is the R environment, this is an open source and free to use environment that allows the creation of different packages designed to perform the same tasks in distinct ways often resulting in different customization and features often providing similar results. There is a need to explore these different packages to provide an experienced user with the simplest and most robust execution of a needed analysis. This work catalogued the different R packages capable of ROC analysis exploring their performance. A shiny web application is presented that serves as a repository allowing for efficient use of all of these packages.This work has been supported by FCT - Fundação para a Ciência e Tecnologia within the RD Units Project Scope: UIDB/00319/2020

The pseudogap in underdoped high Tc superconductors in the framework of the Boson Fermion model

The question of whether the pseudogap in high $T_c$ cuprates is related to super conducting precursor effects or to the existence of extrinsic bosonic massive excitations is investigated on the basis of the Boson-Fermion model. The characteristic three peak structure of the electronic spectral function and the temperature dependent Fermi vector derived here are signatures for a two component scenario which can be tested by ARPES and BIS experiments.Comment: revtex version with 3 eps figures. Revised version to appear in Phys. Rev. B. 4 c programs adde

Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype

A PI3Kα-selective inhibitor has recently been approved for use in breast tumors harboring mutations in PIK3CA, the gene encoding p110α. Preclinical studies have suggested that the PI3K/AKT/mTOR signaling pathway influences stemness, a dedifferentiation-related cellular phenotype associated with aggressive cancer. However, to date, no direct evidence for such a correlation has been demonstrated in human tumors. In two independent human breast cancer cohorts, encompassing nearly 3,000 tumor samples, transcriptional footprint-based analysis uncovered a positive linear association between transcriptionally-inferred PI3K/AKT/mTOR signaling scores and stemness scores. Unexpectedly, stratification of tumors according to PIK3CA genotype revealed a “biphasic” relationship of mutant PIK3CA allele dosage with these scores. Relative to tumor samples without PIK3CA mutations, the presence of a single copy of a hotspot PIK3CA variant was associated with lower PI3K/AKT/mTOR signaling and stemness scores, whereas the presence of multiple copies of PIK3CA hotspot mutations correlated with higher PI3K/AKT/mTOR signaling and stemness scores. This observation was recapitulated in a human cell model of heterozygous and homozygous PIK3CAH1047R expression. Collectively, our analysis (1) provides evidence for a signaling strength-dependent PI3K-stemness relationship in human breast cancer; (2) supports evaluation of the potential benefit of patient stratification based on a combination of conventional PI3K pathway genetic information with transcriptomic indices of PI3K signaling activation