Fragment-guided approach to incorporating structural information into a CoMFA study: BACE-1 as an example

Alzheimer`s disease is an ultimately fatal neurodegenerative disease, and BACE-1 has become an attractive validated target for its therapy, with more than a hundred crystal structures deposited in the PDB. In the present study, we present a new methodology that integrates ligand-based methods with structural information derived from the receptor. 128 BACE-1 inhibitors recently disclosed by GlaxoSmithKline R&D were selected specifically because the crystal structures of 9 of these compounds complexed to BACE-1, as well as five closely related analogs, have been made available. A new fragment-guided approach was designed to incorporate this wealth of structural information into a CoMFA study, and the methodology was systematically compared to other popular approaches, such as docking, for generating a molecular alignment. The influence of the partial charges calculation method was also analyzed. Several consistent and predictive models are reported, including one with r (2) = 0.88, q (2) = 0.69 and r (pred) (2) = 0.72. The models obtained with the new methodology performed consistently better than those obtained by other methodologies, particularly in terms of external predictive power. The visual analyses of the contour maps in the context of the enzyme drew attention to a number of possible opportunities for the development of analogs with improved potency. These results suggest that 3D-QSAR studies may benefit from the additional structural information added by the presented methodology.

A Robust, Fully Adaptive Hybrid Level-Set/Front-Tracking Method for Two-Phase Flows with an Accurate Surface Tension Computation

We present a variable time step, fully adaptive in space, hybrid method for the accurate simulation of incompressible two-phase flows in the presence of surface tension in two dimensions. The method is based on the hybrid level set/front-tracking approach proposed in [H. D. Ceniceros and A. M. Roma, J. Comput. Phys., 205, 391400, 2005]. Geometric, interfacial quantities are computed from front-tracking via the immersed-boundary setting while the signed distance (level set) function, which is evaluated fast and to machine precision, is used as a fluid indicator. The surface tension force is obtained by employing the mixed Eulerian/Lagrangian representation introduced in [S. Shin, S. I. Abdel-Khalik, V. Daru and D. Juric, J. Comput. Phys., 203, 493-516, 2005] whose success for greatly reducing parasitic currents has been demonstrated. The use of our accurate fluid indicator together with effective Lagrangian marker control enhance this parasitic current reduction by several orders of magnitude. To resolve accurately and efficiently sharp gradients and salient flow features we employ dynamic, adaptive mesh refinements. This spatial adaption is used in concert with a dynamic control of the distribution of the Lagrangian nodes along the fluid interface and a variable time step, linearly implicit time integration scheme. We present numerical examples designed to test the capabilities and performance of the proposed approach as well as three applications: the long-time evolution of a fluid interface undergoing Rayleigh-Taylor instability, an example of bubble ascending dynamics, and a drop impacting on a free interface whose dynamics we compare with both existing numerical and experimental data.

Triply periodic minimal surfaces which converge to the Hoffman-Wohlgemuth example

We get a continuous one-parameter new family of embedded minimal surfaces, of which the period problems are two-dimensional. Moreover, one proves that it has Scherk`s second surface and Hoffman-Wohlgemuth`s example as limit-members.

Internally Displaced Persons Rights in Human Rights Perspective(Specifically Focused on Pakistani IDPs Example) : “Basic Human Rights of IDPs to Attain Equality in Dignity and Rights”

After the WWII, there was much concern to protect human rights situation all over the world. During the cold wars, huge displacement took place within different countries due to internal arms/ethnic conflicts. Millions of IDPs, who were uprooted by armed conflict or ethnic strife faced human rights violence. In 2002, there were estimated between 20-25 millions IDPs in the world (Phuong, p.1). Internally displacement is a worldwide problem and millions of the people displaced in Africa and Asia. These all Internal displacements of the people are only the result of the conflicts or the violations of the Human Rights but also sometimes it happened because of the natural disasters. “All human beings are born free and equal in dignity and rights..."(Streich, Article 1) This article works as the foundation of human rights which gives every human being an equal rights and opportunity to maintain his/her dignity. Human Rights issues related to human dignity must be taken very seriously and should not be ignored at any level; Many human rights issues are not always visible, issues such as: privacy, security, equality, protection of social and cultural values etc. In this paper I am going to apply theoretical approach of “all human being are equal in dignity and rights” to defend IDPs rights.

Swedbank är ett skräckexempel : Swedbank is a terrible example

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