MOLECULAR DOCKING STUDY ON 1H-(3,4d) PYRAZOLO-PYRIMIDINES AS CYCLIN DEPENDANT KINASE (CDK2) INHIBITORS

Objective: CDK2 inhibitors are implicated in several carcinomas viz. Carcinoma of lung, bladder, sarcomas and retinoblastoma. Pyrazolopyrimidines, being purine bioisosters inhibit more than one type of kinase. In this study, we are studying some novel derivatives of 1H-pyrazolo [3,4d] pyrimidines not reported earlier. The objective of the present study is an attempt towards design and development of 1H-[3,4-] pyrazolo-pyrimidines as CDK2 inhibitors through rational drug design.Methods: The present study has been done on CDK2 structure, PDB ID, 3WBL, co-crystallized with ligand PDY from RCSB protein data bank. A series of seventeen 1H-Pyrazolo [3,4-d] pyrimidines feasible for synthesis was docked on the said CDK2 receptor using Auto Dock 4 version, 1.5.6. Outputs were exported to discovery studio 3.5 client for visual inspection of the binding modes and interactions of the compounds with amino acid residues in the active sites.Results: The results of docking studies revealed that the present series of 1H-Pyrazolo[3,4-d] pyrimidines is showing significant binding through hydrogen bonding, hydrophobic, pi and Van der waals interactions, similar to the ligand PDY. Some conserved H-bond interactions comparable to bioisosters and compounds presently under human trials were noted. Ki values predicted in silico also suggest that the series will show promising CDK2 inhibitory activity.Conclusion: The series designed and docked can be further developed by synthesis and in vitro and in vivo activity. The receptor inhibitory activity can also be checked by specific receptor assays

The Price of Anarchy for Selfish Ring Routing is Two

We analyze the network congestion game with atomic players, asymmetric strategies, and the maximum latency among all players as social cost. This important social cost function is much less understood than the average latency. We show that the price of anarchy is at most two, when the network is a ring and the link latencies are linear. Our bound is tight. This is the first sharp bound for the maximum latency objective.Comment: Full version of WINE 2012 paper, 24 page

An explicit model to extract viscoelastic properties of cells from AFM force-indentation curves

Atomic force microscopy (AFM) is widely used for quantifying the mechanical properties of soft materials such as cells. AFM force-indentation curves are conventionally fitted with a Hertzian model to extract elastic properties. These properties solely are, however, insufficient to describe the mechanical properties of cells. Here, we expand the analysis capabilities to describe the viscoelastic behavior while using the same force-indentation curves. Our model gives an explicit relation of force and indentation and extracts physically meaningful mechanical parameters. We first validated the model on simulated force-indentation curves. Then, we applied the fitting model to the force-indentation curves of two hydrogels with different crosslinking mechanisms. Finally, we characterized HeLa cells in two cell cycle phases, interphase and mitosis, and showed that mitotic cells have a higher apparent elasticity and a lower apparent viscosity. Our study provides a simple method, which can be directly integrated into the standard AFM framework for extracting the viscoelastic properties of materials

Efficiency in Multi-objective Games

In a multi-objective game, each agent individually evaluates each overall action-profile on multiple objectives. I generalize the price of anarchy to multi-objective games and provide a polynomial-time algorithm to assess it. This work asserts that policies on tobacco promote a higher economic efficiency

On Linear Congestion Games with Altruistic Social Context

We study the issues of existence and inefficiency of pure Nash equilibria in linear congestion games with altruistic social context, in the spirit of the model recently proposed by de Keijzer {\em et al.} \cite{DSAB13}. In such a framework, given a real matrix $\Gamma=(\gamma_{ij})$ specifying a particular social context, each player $i$ aims at optimizing a linear combination of the payoffs of all the players in the game, where, for each player $j$, the multiplicative coefficient is given by the value $\gamma_{ij}$. We give a broad characterization of the social contexts for which pure Nash equilibria are always guaranteed to exist and provide tight or almost tight bounds on their prices of anarchy and stability. In some of the considered cases, our achievements either improve or extend results previously known in the literature

Extended Smoothed Boundary Method for Solving Partial Differential Equations with General Boundary Conditions on Complex Boundaries

In this article, we describe an approach for solving partial differential equations with general boundary conditions imposed on arbitrarily shaped boundaries. A continuous function, the domain parameter, is used to modify the original differential equations such that the equations are solved in the region where a domain parameter takes a specified value while boundary conditions are imposed on the region where the value of the domain parameter varies smoothly across a short distance. The mathematical derivations are straightforward and generically applicable to a wide variety of partial differential equations. To demonstrate the general applicability of the approach, we provide four examples herein: (1) the diffusion equation with both Neumann and Dirichlet boundary conditions; (2) the diffusion equation with both surface diffusion and reaction; (3) the mechanical equilibrium equation; and (4) the equation for phase transformation with the presence of additional boundaries. The solutions for several of these cases are validated against corresponding analytical and semi-analytical solutions. The potential of the approach is demonstrated with five applications: surface-reaction-diffusion kinetics with a complex geometry, Kirkendall-effect-induced deformation, thermal stress in a complex geometry, phase transformations affected by substrate surfaces, and a self-propelled droplet.Comment: This document is the revised version of arXiv:0912.1288v

Greek diminutives in Gothic

Investigation of the outcomes of Greek diminutive nouns in the Gothic New Testament reveals a variety of translation strategies. The Gothic Version does not automatically carry over a word’s diminutive character. Most cases of Greek diminutives translated with Gothic diminutives are part of a Gothic pattern, centred on children. In other cases, the usual range of Gothic translation decisions are found, ranging from subtle discriminations to elisions of distinction.PostprintPeer reviewe

Malicious Bayesian Congestion Games

In this paper, we introduce malicious Bayesian congestion games as an extension to congestion games where players might act in a malicious way. In such a game each player has two types. Either the player is a rational player seeking to minimize her own delay, or - with a certain probability - the player is malicious in which case her only goal is to disturb the other players as much as possible. We show that such games do in general not possess a Bayesian Nash equilibrium in pure strategies (i.e. a pure Bayesian Nash equilibrium). Moreover, given a game, we show that it is NP-complete to decide whether it admits a pure Bayesian Nash equilibrium. This result even holds when resource latency functions are linear, each player is malicious with the same probability, and all strategy sets consist of singleton sets. For a slightly more restricted class of malicious Bayesian congestion games, we provide easy checkable properties that are necessary and sufficient for the existence of a pure Bayesian Nash equilibrium. In the second part of the paper we study the impact of the malicious types on the overall performance of the system (i.e. the social cost). To measure this impact, we use the Price of Malice. We provide (tight) bounds on the Price of Malice for an interesting class of malicious Bayesian congestion games. Moreover, we show that for certain congestion games the advent of malicious types can also be beneficial to the system in the sense that the social cost of the worst case equilibrium decreases. We provide a tight bound on the maximum factor by which this happens.Comment: 18 pages, submitted to WAOA'0

Nash Social Welfare in Selfish and Online Load Balancing

In load balancing problems there is a set of clients, each wishing to select a resource from a set of permissible ones, in order to execute a certain task. Each resource has a latency function, which depends on its workload, and a client's cost is the completion time of her chosen resource. Two fundamental variants of load balancing problems are {\em selfish load balancing} (aka. {\em load balancing games}), where clients are non-cooperative selfish players aimed at minimizing their own cost solely, and {\em online load balancing}, where clients appear online and have to be irrevocably assigned to a resource without any knowledge about future requests. We revisit both selfish and online load balancing under the objective of minimizing the {\em Nash Social Welfare}, i.e., the geometric mean of the clients' costs. To the best of our knowledge, despite being a celebrated welfare estimator in many social contexts, the Nash Social Welfare has not been considered so far as a benchmarking quality measure in load balancing problems. We provide tight bounds on the price of anarchy of pure Nash equilibria and on the competitive ratio of the greedy algorithm under very general latency functions, including polynomial ones. For this particular class, we also prove that the greedy strategy is optimal as it matches the performance of any possible online algorithm