High-Resolution Three-Dimensional NMR Structure Of The KRAS Proto-Oncogene Promoter Reveals Key Features Of A G-Quadruplex Involved In Transcriptional Regulation

Non-canonical base pairing within guanine-rich DNA and RNA sequences can produce G-quartets, whose stacking leads to the formation of a G-quadruplex (G4). G4s can coexist with canonical duplex DNA in the human genome and have been suggested to suppress gene transcription, and much attention has therefore focused on studying G4s in promotor regions of disease-related genes. For example, the human KRAS proto-oncogene contains a nuclease-hypersensitive element located upstream of the major transcription start site. The KRAS nuclease-hypersensitive element (NHE) region contains a G-rich element (22RT; 5′-AGGGCGGTGTGGGAATAGGGAA-3′) and encompasses a Myc-associated zinc finger-binding site that regulates KRAS transcription. The NEH region therefore has been proposed as a target for new drugs that control KRAS transcription, which requires detailed knowledge of the NHE structure. In this study, we report a high-resolution NMR structure of the G-rich element within the KRAS NHE. We found that the G-rich element forms a parallel structure with three G-quartets connected by a four-nucleotide loop and two short one-nucleotide double-chain reversal loops. In addition, a thymine bulge is found between G8 and G9. The loops of different lengths and the presence of a bulge between the G-quartets are structural elements that potentially can be targeted by small chemical ligands that would further stabilize the structure and interfere or block transcriptional regulators such as Myc-associated zinc finger from accessing their binding sites on the KRAS promoter. In conclusion, our work suggests a possible new route for the development of anticancer agents that could suppress KRAS expression

Quadrupole moments of rotating neutron stars

Numerical models of rotating neutron stars are constructed for four equations of state using the computer code RNS written by Stergioulas. For five selected values of the star's gravitational mass (in the interval between 1.0 and 1.8 solar masses) and for each equation of state, the star's angular momentum is varied from J=0 to the Keplerian limit J=J_{max}. For each neutron-star configuration we compute Q, the quadrupole moment of the mass distribution. We show that for given values of M and J, |Q| increases with the stiffness of the equation of state. For fixed mass and equation of state, the dependence on J is well reproduced with a simple quadratic fit, Q \simeq - aJ^2/M c^2, where c is the speed of light, and a is a parameter of order unity depending on the mass and the equation of state.Comment: ReVTeX, 7 pages, 5 figures, additional material, and references adde

First science results from SOFIA/FORCAST: The mid-infrared view of the compact HII region W3A

The massive star forming region W3 was observed with the faint object infrared camera for the SOFIA telescope (FORCAST) as part of the Short Science program. The 6.4, 6.6, 7.7, 19.7, 24.2, 31.5 and 37.1 \um bandpasses were used to observe the emission of Polycyclic Aromatic Hydrocarbon (PAH) molecules, Very Small Grains and Big Grains. Optical depth and color temperature maps of W3A show that IRS2 has blown a bubble devoid of gas and dust of $\sim$0.05 pc radius. It is embedded in a dusty shell of ionized gas that contributes 40% of the total 24 \um emission of W3A. This dust component is mostly heated by far ultraviolet, rather than trapped Ly$\alpha$ photons. This shell is itself surrounded by a thin ($\sim$0.01 pc) photodissociation region where PAHs show intense emission. The infrared spectral energy distribution (SED) of three different zones located at 8, 20 and 25\arcsec from IRS2, show that the peak of the SED shifts towards longer wavelengths, when moving away from the star. Adopting the stellar radiation field for these three positions, DUSTEM model fits to these SEDs yield a dust-to-gas mass ratio in the ionized gas similar to that in the diffuse ISM. However, the ratio of the IR-to-UV opacity of the dust in the ionized shell is increased by a factor $\simeq$3 compared to the diffuse ISM.Comment: Accepted for publication in ApJ letters; 13 pages, 3 figures 1 tabl

Supergravity with cosmological constant and the AdS group

It is shown that the supersymmetric extension of the Stelle-West formalism permits the construction of an action for $(3+1)$-dimensional N=1 supergravity with cosmological constant genuinely invariant under the $OSp(4/1).$ Since the action is invariant under the supersymmetric extension of the $AdS$ group, the supersymmetry algebra closes off shell without the need for auxiliary fields. The limit case $m\to 0$, i.e.$(3+1)$ -dimensional N=1 supergravity invariant under the Poincar\'{e} supergroup is also discussed.Comment: 10 page

Galactic periodicity and the oscillating G model

We consider the model involving the oscillation of the effective gravitational constant that has been put forward in an attempt to reconcile the observed periodicity in the galaxy number distribution with the standard cosmological models. This model involves a highly nonlinear dynamics which we analyze numerically. We carry out a detailed study of the bound that nucleosynthesis imposes on this model. The analysis shows that for any assumed value for $\Omega$ (the total energy density) one can fix the value of $\Omega_{\rm bar}$ (the baryonic energy density) in such a way as to accommodate the observational constraints coming from the $^4{\rm He}$ primordial abundance. In particular, if we impose the inflationary value $\Omega=1$ the resulting baryonic energy density turns out to be $\Omega_{\rm bar}\sim 0.021$. This result lies in the very narrow range $0.016 \leq \Omega_{\rm bar} \leq 0.026$ allowed by the observed values of the primordial abundances of the other light elements. The remaining fraction of $\Omega$ corresponds to dark matter represented by a scalar field.Comment: Latex file 29 pages with no figures. Please contact M.Salgado for figures. A more careful study of the model appears in gr-qc/960603

Dimensions of professional competences for interventions towards sustainability

This paper investigates sustainability competences through the eyes of professional practitioners in the field of sustainability and presents empirical data that have been created using an action research approach. The design of the study consists of two workshops, in which professional practitioners in interaction with each other and the facilitators are invited to explore and reflect on the specific knowledge, skills, attitudes and behaviours necessary to conduct change processes successfully towards sustainability in a variety of business and professional contexts. The research focuses on the competences associated with these change processes to devise, propose and conduct appropriate interventions that address sustainability issues. Labelled ‘intervention competence’, this ability comprises an interlocking set of knowledge, skills, attitudes and behaviours that include: appreciating the importance of (trying to) reaching decisions or interventions; being able to learn from lived experience of practice and to connect such learning to one’s own scientific knowledge; being able to engage in political-strategic thinking, deliberations and actions, related to different perspectives; the ability for showing goal-oriented, adequate action; adopting and communicating ethical practices during the intervention process; being able to cope with the degree of complexity, and finally being able to translate stakeholder diversity into collectively produced interventions (actions) towards sustainability. Moreover, this competence has to be practised in contexts of competing values, non-technical interests and power relations. The article concludes with recommendations for future research and practice

Symmetries and conservation laws in the Gunther k-symplectic formalism of field theory

This paper is devoted to studying symmetries of k-symplectic Hamiltonian and Lagrangian first-order classical field theories. In particular, we define symmetries and Cartan symmetries and study the problem of associating conservation laws to these symmetries, stating and proving Noether's theorem in different situations for the Hamiltonian and Lagrangian cases. We also characterize equivalent Lagrangians, which lead to an introduction of Lagrangian gauge symmetries, as well as analyzing their relation with Cartan symmetries.Comment: 29 page