GC-selective DNA-binding antibiotic, Mithramycin A, reveals multiple points of control in the regulation of Hdm2 protein synthesis

The primary role of the Hdm2/Mdm2 oncoprotein is to regulate the levels and activity of the transcription factor p53. Hdm2 synthesis is itself tightly controlled and, as demonstrated by a recently described SNP (SNP309) in the hdm2-P2 promoter, minor variations in Hdm2 expression have phenotypic consequences on radiation sensitivity and cancer predisposition. To further define mechanisms regulating Hdm2 expression, we have investigated the effects of the GC-selective DNA-binding drug, Mithramycin A (MA) on hdm2 mRNA transcription, trafficking, and translation. Firstly we show that the constitutive hdm2-P1 promoter is inhibited by MA. We define, for the first time, the minimal sequence elements that are required for P1-promoter activity and identify those which confer MA sensitivity. Secondly, MA induces p53-dependent transcription from the hdm2-P2 promoter. Thirdly, and critically, MA also inhibits Hdm2 synthesis at the post-transcriptional level, with negative effects on hdm2 mRNA nuclear export and translation. This study highlights the complex interplay between the pathways that regulate Hdm2 protein synthesis in cancer cells, and furthermore emphasizes the export of hdm2 mRNA from the nucleus to the cytoplasm as a key point of control in this process.<br/><br/

Opportunistic accountability: state–society bargaining over shared interests

Conflicting preferences between the state and society underpin most accountability mechanisms by providing a credible way for society to impose costs on the state. Adapting a classic bargaining framework, we argue that broader conditions can support state–society bargaining. Policies that both the state and society value can also enhance society’s negotiating power, provided society has a relatively lower valuation and is more patient than the state. By threatening to sabotage their own interests but hurt the impatient state even more, citizens can compel the state to deliver broader policy benefits. We illustrate this logic with the case of polio vaccination in northern Nigeria, where entire communities have resisted the vaccine as a strategy to bargain for more desired services. To resolve and preempt noncompliance, the Nigerian government has enhanced service delivery in other areas, demonstrating the opportunity for improved accountability in the presence of shared-interest policies.Institutions, Decisions and Collective Behaviou

A Solvable Model of a Glass

An analytically tractable model is introduced which exhibits both, a glass--like freezing transition, and a collection of double--well configurations in its zero--temperature potential energy landscape. The latter are generally believed to be responsible for the anomalous low--temperature properties of glass-like and amorphous systems via a tunneling mechanism that allows particles to move back and forth between adjacent potential energy minima. Using mean--field and replica methods, we are able to compute the distribution of asymmetries and barrier--heights of the double--well configurations {\em analytically}, and thereby check various assumptions of the standard tunneling model. We find, in particular, strong correlations between asymmetries and barrier--heights as well as a collection of single--well configurations in the potential energy landscape of the glass--forming system --- in contrast to the assumptions of the standard model. Nevertheless, the specific heat scales linearly with temperature over a wide range of low temperatures.Comment: 11 pages, latex, including 5 figures, talk presented at the XIV Sitges Conferenc

Relationship between dynamical heterogeneities and stretched exponential relaxation

We identify the dynamical heterogeneities as an essential prerequisite for stretched exponential relaxation in dynamically frustrated systems. This heterogeneity takes the form of ordered domains of finite but diverging lifetime for particles in atomic or molecular systems, or spin states in magnetic materials. At the onset of the dynamical heterogeneity, the distribution of time intervals spent in such domains or traps becomes stretched exponential at long time. We rigorously show that once this is the case, the autocorrelation function of the renewal process formed by these time intervals is also stretched exponential at long time.Comment: 8 pages, 4 figures, submitted to PR

A 31-day time to surgery compliant exercise training programme improves aerobic health in the elderly

Background: Over 41,000 people were diagnosed with colorectal cancer (CRC) in the UK in 2011. The incidence of CRC increases with age. Many elderly patients undergo surgery for CRC, the only curative treatment. Such patients are exposed to risks, which increase with age and reduced physical fitness. Endurance-based exercise training programmes can improve physical fitness, but such programmes do not comply with the UK, National Cancer Action Team 31-day time-to-treatment target. High-intensity interval training (HIT) can improve physical performance within 2–4 weeks, but few studies have shown HIT to be effective in elderly individuals, and those who do employ programmes longer than 31 days. Therefore, we investigated whether HIT could improve cardiorespiratory fitness in elderly volunteers, age-matched to a CRC population, within 31 days. Methods: This observational cohort study recruited 21 healthy elderly participants (8 male and 13 female; age 67 years (range 62–73 years)) who undertook cardiopulmonary exercise testing before and after completing 12 sessions of HIT within a 31-day period. Results: Peak oxygen consumption (VO2 peak) (23.9 ± 4.7 vs. 26.2 ± 5.4 ml/kg/min, p = 0.0014) and oxygen consumption at anaerobic threshold (17.86 ± 4.45 vs. 20.21 ± 4.11 ml/kg/min, p = 0.008) increased after HIT. Conclusions: It is possible to improve cardiorespiratory fitness in 31 days in individuals of comparable age to those presenting for CRC surgery

Electronic structure, phase stability and chemical bonding in Th2_2Al and Th2_2AlH4_4

We present the results of theoretical investigation on the electronic structure, bonding nature and ground state properties of Th$_2$Al and Th$_2$AlH$_4$ using generalized-gradient-corrected first-principles full-potential density-functional calculations. Th$_2$AlH$_4$ has been reported to violate the "2 \AA rule" of H-H separation in hydrides. From our total energy as well as force-minimization calculations, we found a shortest H-H separation of 1.95 {\AA} in accordance with recent high resolution powder neutron diffraction experiments. When the Th$_2$Al matrix is hydrogenated, the volume expansion is highly anisotropic, which is quite opposite to other hydrides having the same crystal structure. The bonding nature of these materials are analyzed from the density of states, crystal-orbital Hamiltonian population and valence-charge-density analyses. Our calculation predicts different nature of bonding for the H atoms along $a$ and $c$. The strongest bonding in Th$_2$AlH$_4$ is between Th and H along $c$ which form dumb-bell shaped H-Th-H subunits. Due to this strong covalent interaction there is very small amount of electrons present between H atoms along $c$ which makes repulsive interaction between the H atoms smaller and this is the precise reason why the 2 {\AA} rule is violated. The large difference in the interatomic distances between the interstitial region where one can accommodate H in the $ac$ and $ab$ planes along with the strong covalent interaction between Th and H are the main reasons for highly anisotropic volume expansion on hydrogenation of Th$_2$Al.Comment: 14 pages, 9 figure

Evaporative cooling of trapped fermionic atoms

We propose an efficient mechanism for the evaporative cooling of trapped fermions directly into quantum degeneracy. Our idea is based on an electric field induced elastic interaction between trapped atoms in spin symmetric states. We discuss some novel general features of fermionic evaporative cooling and present numerical studies demonstrating the feasibility for the cooling of alkali metal fermionic species $^6$Li, $^{40}$K, and $^{82,84,86}$Rb. We also discuss the sympathetic cooling of fermionic hyperfine spin mixtures, including the effects of anisotropic interactions.Comment: to be publishe

Transformation of in-plane ρ(T)\rho (T) in YBa2Cu3O7−δYBa_{2}Cu_{3}O_{7-\delta} at fixed oxygen content

This paper reveals the origin of variation in the magnitude and temperature dependence of the normal state resistivity frequently observed in different YBCO single crystal or thin film samples with the same $T_{c}$. We investigated temperature dependence of resistivity in $YBa_{2}Cu_{3}O_{7-\delta}$ thin films with 7- $\delta = 6.95$ and 6.90, which were subjected to annealing in argon at 400-420 K ($120-140^{o}C$). Before annealing these films exhibited a non-linear $\rho_{ab}(T)$, with a flattening below 230 K, similar to $\rho_{b}(T)$ and $\rho_{ab}(T)$ observed in untwinned and twinned YBCO crystals, respectively. For all films the annealing causes an increase of resistivity and a transformation of $\rho_{ab}(T)$ from a non-linear dependence towards a more linear one (less flattening). In films with 7- $\delta = 6.90$ the increase of resistivity is also associated with an increase in $T_{c}$. We proposed the model that provides an explanation of these phenomena in terms of thermally activated redistribution of residual O(5) oxygens in the chain-layer of YBCO. Good agreement between the experimental data for $\rho_{ab}(t,T)$, where t is the annealing time, and numerical calculations was obtained.Comment: 8 pages, 9 figures, submitted to PR

Low-light-level nonlinear optics with slow light

Electromagnetically induced transparency in an optically thick, cold medium creates a unique system where pulse-propagation velocities may be orders of magnitude less than $c$ and optical nonlinearities become exceedingly large. As a result, nonlinear processes may be efficient at low-light levels. Using an atomic system with three, independent channels, we demonstrate a quantum interference switch where a laser pulse with an energy density of $\sim23$ photons per $\lambda^2/(2\pi)$ causes a 1/e absorption of a second pulse.Comment: to be published in PR