HoxA9 binds and represses the Cebpa +8 kb enhancer

C/EBPα plays a key role in specifying myeloid lineage development. HoxA9 is expressed in myeloid progenitors, with its level diminishing during myeloid maturation, and HOXA9 is over-expressed in a majority of acute myeloid leukemia cases, including those expressing NUP98-HOXD13. The objective of this study was to determine whether HoxA9 directly represses Cebpa gene expression. We find 4-fold increased HoxA9 and 5-fold reduced Cebpa in marrow common myeloid and LSK progenitors from Vav-NUP98-HOXD13 transgenic mice. Conversely, HoxA9 decreases 5-fold while Cebpa increases during granulocytic differentiation of 32Dcl3 myeloid cells. Activation of exogenous HoxA9-ER in 32Dcl3 cells reduces Cebpa mRNA even in the presence of cycloheximide, suggesting direct repression. Cebpa transcription in murine myeloid cells is regulated by a hematopoietic-specific +37 kb enhancer and by a more widely active +8 kb enhancer. ChIP-Seq analysis of primary myeloid progenitor cells expressing exogenous HoxA9 or HoxA9-ER demonstrates that HoxA9 localizes to both the +8 kb and +37 kb Cebpa enhancers. Gel shift analysis demonstrates HoxA9 binding to three consensus sites in the +8 kb enhancer, but no affinity for the single near-consensus site present in the +37 kb enhancer. Activity of a Cebpa +8 kb enhancer/promoter-luciferase reporter in 32Dcl3 or MOLM14 myeloid cells is increased ~2-fold by mutation of its three HOXA9-binding sites, suggesting that endogenous HoxA9 represses +8 kb Cebpa enhancer activity. In contrast, mutation of five C/EBPα-binding sites in the +8 kb enhancer reduces activity 3-fold. Finally, expression of a +37 kb enhancer/promoter-hCD4 transgene reporter is reduced ~2-fold in marrow common myeloid progenitors when the Vav-NUP98-HOXD13 transgene is introduced. Overall, these data support the conclusion that HoxA9 represses Cebpa expression, at least in part via inhibition of its +8 kb enhancer, potentially allowing normal myeloid progenitors to maintain immaturity and contributing to the pathogenesis of acute myeloid leukemia associated with increased HOXA9

Strange Particles in Dense Matter and Kaon Condensates

We discuss the role of strangeness in dense matter and especially in neutron stars. The early (in density) introduction of hyperons found in many calculations is probably delayed by the decrease in vector mean field acting on the neutron. The decrease results from both conventional many-body rescattering effects and from the movement towards asymptotic freedom at high densities. Subthreshold $K^-$-meson production by the KaoS collaboration at GSI shows that the $K^-$-mass must be substantially lowered, by $\gtrsim$ 200 MeV at $\rho\sim 2\rho_0$. It is shown that explicit chiral symmetry breaking through the kaon mass may be responsible for $\Sigma^-$-nucleon and $\Xi^-$-nucleon scalar attraction being weaker than obtained by simple quark scaling. The normal mode of the strangeness minus, charge $e^-$, excitation is constructed as a linear combination of $K^-$-meson and $\Sigma^-$, neutron-hole state. Except for zero momentum, where the terms are unmixed the "kaesobar" is a linear combination of these two components.Comment: 10 pages, 8 postscript figures, Talk given at the International Conference on Hypernuclear and Strange Particle Physics (HYP97), Brookhaven Nat'l Lab., USA, October 13-18, 1997, to be published in Nucl. Phys.

Pluripotency factors functionally premark cell-type-restricted enhancers in ES cells.

Enhancers for embryonic stem (ES) cell-expressed genes and lineage-determining factors are characterized by conventional marks of enhancer activation in ES cells1-3, but it remains unclear whether enhancers destined to regulate cell-type-restricted transcription units might also have distinct signatures in ES cells. Here we show that cell-type-restricted enhancers are 'premarked' and activated as transcription units by the binding of one or two ES cell transcription factors, although they do not exhibit traditional enhancer epigenetic marks in ES cells, thus uncovering the initial temporal origins of cell-type-restricted enhancers. This premarking is required for future cell-type-restricted enhancer activity in the differentiated cells, with the strength of the ES cell signature being functionally important for the subsequent robustness of cell-type-restricted enhancer activation. We have experimentally validated this model in macrophage-restricted enhancers and neural precursor cell (NPC)-restricted enhancers using ES cell-derived macrophages or NPCs, edited to contain specific ES cell transcription factor motif deletions. DNA hydroxyl-methylation of enhancers in ES cells, determined by ES cell transcription factors, may serve as a potential molecular memory for subsequent enhancer activation in mature macrophages. These findings suggest that the massive repertoire of cell-type-restricted enhancers are essentially hierarchically and obligatorily premarked by binding of a defining ES cell transcription factor in ES cells, dictating the robustness of enhancer activation in mature cells

Paying for Likes? Understanding Facebook like fraud using honeypots

Facebook pages offer an easy way to reach out to a very large audience as they can easily be promoted using Facebook's advertising platform. Recently, the number of likes of a Facebook page has become a measure of its popularity and profitability, and an underground market of services boosting page likes, aka like farms, has emerged. Some reports have suggested that like farms use a network of profiles that also like other pages to elude fraud protection algorithms, however, to the best of our knowledge, there has been no systematic analysis of Facebook pages' promotion methods. This paper presents a comparative measurement study of page likes garnered via Facebook ads and by a few like farms. We deploy a set of honeypot pages, promote them using both methods, and analyze garnered likes based on likers' demographic, temporal, and social characteristics. We highlight a few interesting findings, including that some farms seem to be operated by bots and do not really try to hide the nature of their operations, while others follow a stealthier approach, mimicking regular users' behavior

Explicit solution for vibrating bar with viscous boundaries and internal damper

We investigate longitudinal vibrations of a bar subjected to viscous boundary conditions at each end, and an internal damper at an arbitrary point along the bar's length. The system is described by four independent parameters and exhibits a variety of behaviors including rigid motion, super stability/instability and zero damping. The solution is obtained by applying the Laplace transform to the equation of motion and computing the Green's function of the transformed problem. This leads to an unconventional eigenvalue-like problem with the spectral variable in the boundary conditions. The eigenmodes of the problem are necessarily complex-valued and are not orthogonal in the usual inner product. Nonetheless, in generic cases we obtain an explicit eigenmode expansion for the response of the bar to initial conditions and external force. For some special values of parameters the system of eigenmodes may become incomplete, or no non-trivial eigenmodes may exist at all. We thoroughly analyze physical and mathematical reasons for this behavior and explicitly identify the corresponding parameter values. In particular, when no eigenmodes exist, we obtain closed form solutions. Theoretical analysis is complemented by numerical simulations, and analytic solutions are compared to computations using finite elements.Comment: 29 pages, 6 figure

Impact of metabolic comorbidity on the association between body mass index and heatlh-related quality of life: a Scotland-wide cross-sectional study of 5,608 participants

<p/>Background: The prevalence of obesity is rising in Scotland and globally. Overall, obesity is associated with increased morbidity, mortality and reduced health-related quality of life. Studies suggest that "healthy obesity" (obesity without metabolic comorbidity) may not be associated with morbidity or mortality. Its impact on health-related quality of life is unknown. <p/>Methods: We extracted data from the Scottish Health Survey on self-reported health-related quality of life, body mass index (BMI), demographic information and comorbidity. SF-12 responses were converted into an overall health utility score. Linear regression analyses were used to explore the association between BMI and health utility, stratified by the presence or absence of metabolic comorbidity (diabetes, hypertension, hypercholesterolemia or cardiovascular disease), and adjusted for potential confounders (age, sex and deprivation quintile). <p/>Results: Of the 5,608 individuals, 3,744 (66.8%) were either overweight or obese and 921 (16.4%) had metabolic comorbidity. There was an inverted U-shaped relationship whereby health utility was highest among overweight individuals and fell with increasing BMI. There was a significant interaction with metabolic comorbidity (p = 0.007). Individuals with metabolic comorbidty had lower utility scores and a steeper decline in utility with increasing BMI (morbidly obese, adjusted coefficient: -0.064, 95% CI -0.115, -0.012, p = 0.015 for metabolic comorbidity versus -0.042, 95% CI -0.067, -0.018, p = 0.001 for no metabolic comorbidity). <p/>Conclusions: The adverse impact of obesity on health-related quality of life is greater among individuals with metabolic comorbidity. However, increased BMI is associated with reduced health-related quality of life even in the absence of metabolic comorbidity, casting doubt on the notion of "healthy obesity"

Cost-sensitive Bayesian network learning using sampling

A significant advance in recent years has been the development of cost-sensitive decision tree learners, recognising that real world classification problems need to take account of costs of misclassification and not just focus on accuracy. The literature contains well over 50 cost-sensitive decision tree induction algorithms, each with varying performance profiles. Obtaining good Bayesian networks can be challenging and hence several algorithms have been proposed for learning their structure and parameters from data. However, most of these algorithms focus on learning Bayesian networks that aim to maximise the accuracy of classifications. Hence an obvious question that arises is whether it is possible to develop cost-sensitive Bayesian networks and whether they would perform better than cost-sensitive decision trees for minimising classification cost? This paper explores this question by developing a new Bayesian network learning algorithm based on changing the data distribution to reflect the costs of misclassification. The proposed method is explored by conducting experiments on over 20 data sets. The results show that this approach produces good results in comparison to more complex cost-sensitive decision tree algorithms

Hadron production in non linear relativistic mean field models

By using a parametrization of the non-linear Walecka model which takes into account the binding energy of different hyperons, we present a study of particle production yields measured in central Au-Au collision at RHIC. Two sets of different hyperon-meson coupling constants are employed in obtaining the hadron production and chemical freeze-out parameters. These quantities show a weak dependence on the used hyperon-meson couplings. Results are in good overall accordance with experimental data. We have found that the repulsion among the baryons is quite small and, through a preliminary analysis of the effective mesonic masses, we suggest a way to improve the fittings.Comment: 18 pages, 2 figure

Time-Dependent Hartree-Fock simulation of the expansion of abraded nuclei

A recent interpretation of the caloric curve based on the expansion of the abraded spectator nucleus is re-analysed in the framework of the Time-Dependent Hartree-Fock (TDHF) evolution. It is shown that the TDHF dynamics is more complex than a single monopolar collective motion at moderate energy. The inclusion of other important collective degrees of freedom may lead to the dynamical creation of hollow structure. Then, low density regions could be locally reached after a long time by the creation of these exotic density profiles. In particular the systematic of the minimum density reached during the expansion (the so-called turning points) appears to be different.Comment: 30 Latex pages including 9 figure