Open source drug discovery- A new paradigm of collaborative research in tuberculosis drug development

It is being realized that the traditional closed-door and market driven approaches for drug discovery may not be the best suited model for the diseases of the developing world such as tuberculosis and malaria, because most patients suffering from these diseases have poor paying capacity. To ensure that new drugs are created for patients suffering from these diseases, it is necessary to formulate an alternate paradigm of drug discovery process. The current model constrained by limitations for collaboration and for sharing of resources with confidentiality hampers the opportunities for bringing expertise from diverse fields. These limitations hinder the possibilities of lowering the cost of drug discovery. The Open Source Drug Discovery project initiated by Council of Scientific and Industrial Research, India has adopted an open source model to power wide participation across geographical borders. Open Source Drug Discovery emphasizes integrative science through collaboration, open-sharing, taking up multi-faceted approaches and accruing benefits from advances on different fronts of new drug discovery. Because the open source model is based on community participation, it has the potential to self-sustain continuous development by generating a storehouse of alternatives towards continued pursuit for new drug discovery. Since the inventions are community generated, the new chemical entities developed by Open Source Drug Discovery will be taken up for clinical trial in a non-exclusive manner by participation of multiple companies with majority funding from Open Source Drug Discovery. This will ensure availability of drugs through a lower cost community driven drug discovery process for diseases afflicting people with poor paying capacity. Hopefully what LINUX the World Wide Web have done for the information technology, Open Source Drug Discovery will do for drug discovery. (C) 2011 Elsevier Ltd. All rights reserved.

Crowd Sourcing a New Paradigm for Interactome Driven Drug Target Identification in Mycobacterium tuberculosis

A decade since the availability of Mycobacterium tuberculosis (Mtb) genome sequence, no promising drug has seen the light of the day. This not only indicates the challenges in discovering new drugs but also suggests a gap in our current understanding of Mtb biology. We attempt to bridge this gap by carrying out extensive re-annotation and constructing a systems level protein interaction map of Mtb with an objective of finding novel drug target candidates. Towards this, we synergized crowd sourcing and social networking methods through an initiative `Connect to Decode' (C2D) to generate the first and largest manually curated interactome of Mtb termed `3interactome pathway' (IPW), encompassing a total of 1434 proteins connected through 2575 functional relationships. Interactions leading to gene regulation, signal transduction, metabolism, structural complex formation have been catalogued. In the process, we have functionally annotated 87% of the Mtb genome in context of gene products. We further combine IPW with STRING based network to report central proteins, which may be assessed as potential drug targets for development of drugs with least possible side effects. The fact that five of the 17 predicted drug targets are already experimentally validated either genetically or biochemically lends credence to our unique approach.

Salmonella enterica serovars Typhimurium and Typhi as model organisms Revealing paradigm of host-pathogen interactions

The lifestyle of intracellular pathogens has always questioned the skill of a microbiologist in the context of finding the permanent cure to the diseases caused by them. The best tool utilized by these pathogens is their ability to reside inside the host cell, which enables them to easily bypass the humoral immunity of the host, such as the complement system. They further escape from the intracellular immunity, such as lysosome and inflammasome, mostly by forming a protective vacuole-bound niche derived from the host itself. Some of the most dreadful diseases are caused by these vacuolar pathogens, for example, tuberculosis by Mycobacterium or typhoid fever by Salmonella. To deal with such successful pathogens therapeutically, the knowledge of a host-pathogen interaction system becomes primarily essential, which further depends on the use of a model system. A well characterized pathogen, namely Salmonella, suits the role of a model for this purpose, which can infect a wide array of hosts causing a variety of diseases. This review focuses on various such aspects of research on Salmonella which are useful for studying the pathogenesis of other intracellular pathogens.

Phospholipid Mediated Activation of Calcium Dependent Protein Kinase 1 (CaCDPK1) from Chickpea: A New Paradigm of Regulation

Phospholipids, the major structural components of membranes, can also have functions in regulating signaling pathways in plants under biotic and abiotic stress. The effects of adding phospholipids on the activity of stress-induced calcium dependent protein kinase (CaCDPK1) from chickpea are reported here. Both autophosphorylation as well as phosphorylation of the added substrate were enhanced specifically by phosphatidylcholine and to a lesser extent by phosphatidic acid, but not by phosphatidylethanolamine. Diacylgylerol, the neutral lipid known to activate mammalian PKC, stimulated CaCDPK1 but at higher concentrations. Increase in V-max of the enzyme activity by these phospholipids significantly decreased the K-m indicating that phospholipids enhance the affinity towards its substrate. In the absence of calcium, addition of phospholipids had no effect on the negligible activity of the enzyme. Intrinsic fluorescence intensity of the CaCDPK1 protein was quenched on adding PA and PC. Higher binding affinity was found with PC (K-1/2 = 114 nM) compared to PA (K-1/2 = 335 nM). We also found that the concentration of PA increased in chickpea plants under salt stress. The stimulation by PA and PC suggests regulation of CaCDPK1 by these phospholipids during stress response.

Optimal control of grinding mill circuit using model predictive static programming: A new nonlinear MPC paradigm

The recently developed reference-command tracking version of model predictive static programming (MPSP) is successfully applied to a single-stage closed grinding mill circuit. MPSP is an innovative optimal control technique that combines the philosophies of model predictive control (MPC) and approximate dynamic programming. The performance of the proposed MPSP control technique, which can be viewed as a `new paradigm' under the nonlinear MPC philosophy, is compared to the performance of a standard nonlinear MPC technique applied to the same plant for the same conditions. Results show that the MPSP control technique is more than capable of tracking the desired set-point in the presence of model-plant mismatch, disturbances and measurement noise. The performance of MPSP and nonlinear MPC compare very well, with definite advantages offered by MPSP. The computational speed of MPSP is increased through a sequence of innovations such as the conversion of the dynamic optimization problem to a low-dimensional static optimization problem, the recursive computation of sensitivity matrices and using a closed form expression to update the control. To alleviate the burden on the optimization procedure in standard MPC, the control horizon is normally restricted. However, in the MPSP technique the control horizon is extended to the prediction horizon with a minor increase in the computational time. Furthermore, the MPSP technique generally takes only a couple of iterations to converge, even when input constraints are applied. Therefore, MPSP can be regarded as a potential candidate for online applications of the nonlinear MPC philosophy to real-world industrial process plants. (C) 2014 Elsevier Ltd. All rights reserved.

Combination of Cyanine Behaviour and Giant Hyperpolarisability in Novel Merocyanine Dyes: Beyond the Bond Length Alternation (BLA) Paradigm

Merocyanine dyes that exhibit antithetic cyaninelike behaviour and giant first-order hyperpolarisability (beta) values have been designed. These cyanine-type dyes open up an intriguing route towards molecular-based electrooptic materials as well as new second-harmonic generation dyes for imaging.

Lack of Critical Slowing Down Suggests that Financial Meltdowns Are Not Critical Transitions, yet Rising Variability Could Signal Systemic Risk

Complex systems inspired analysis suggests a hypothesis that financial meltdowns are abrupt critical transitions that occur when the system reaches a tipping point. Theoretical and empirical studies on climatic and ecological dynamical systems have shown that approach to tipping points is preceded by a generic phenomenon called critical slowing down, i.e. an increasingly slow response of the system to perturbations. Therefore, it has been suggested that critical slowing down may be used as an early warning signal of imminent critical transitions. Whether financial markets exhibit critical slowing down prior to meltdowns remains unclear. Here, our analysis reveals that three major US (Dow Jones Index, S&P 500 and NASDAQ) and two European markets (DAX and FTSE) did not exhibit critical slowing down prior to major financial crashes over the last century. However, all markets showed strong trends of rising variability, quantified by time series variance and spectral function at low frequencies, prior to crashes. These results suggest that financial crashes are not critical transitions that occur in the vicinity of a tipping point. Using a simple model, we argue that financial crashes are likely to be stochastic transitions which can occur even when the system is far away from the tipping point. Specifically, we show that a gradually increasing strength of stochastic perturbations may have caused to abrupt transitions in the financial markets. Broadly, our results highlight the importance of stochastically driven abrupt transitions in real world scenarios. Our study offers rising variability as a precursor of financial meltdowns albeit with a limitation that they may signal false alarms.

Los dilemas de la acción colectiva global. Un estudio de caso : el movimiento sindical en el MERCOSUR (1991-2012)

Resumen: Este trabajo analiza la acción colectiva sindical postnacional en el MERCOSUR en un período histórico signado por profundas mutaciones políticas, económicas, y productivas sociales (1991-2012) a partir de los relatos y representaciones de sus protagonistas. El trabajo cualitativo intentará explicar la configuración del sindicalismo internacional en la globalización, y describir las estrategias del movimiento obrero mercosureño. La metodología cualitativa ilustra un trabajo de campo a partir de entrevistas en profundidad a 34 sindicalistas del Mercosur, y entrevistas adicionales a tres representantes de la Confederación Sindical de las Américas, dos empresarios del Mercosur, un especialista académico en la dimensión sociolaboral de la integración regional y un representante de la OIT en la región. La metodología de análisis e interpretación de dichas entrevistas ha sido la teoría fundamentada, entendida como la técnica más idónea de aprehender los procesos sociales a través de las voces de los líderes obreros, comprender su realidad, sus representaciones y sistema de valores, sus ideas y su acción colectiva. La literatura de los movimientos sociales en la globalización capitalista ha puesto el énfasis en la emergencia de nuevos colectivos cuyos reclamos se concentran en el reconocimiento (Fraser y Honneth, 2006) de sus identidades que el modelo fordista de producción pareció invisibilizar y soslayar ante la primacía de las prácticas económicas y demandas distributivas. Esta tesis conjuga una perspectiva dualista y demuestra que las estrategias de reconocimiento y las reivindicaciones de redistribución de tipo clasista se resignificaron en el escenario postnacional a través de la Coordinadora de Centrales Sindicales del Cono Sur –CCSCS- (subregional) y, con un desarrollo menor: los Sindicatos Globales (FSI, GUFs) en la acción sectorial [1991-2012]. Para arribar al núcleo configurativo de sus representaciones y su sistema de valores, la investigación transitó por los sentidos y significados del trabajo, las mutaciones productivas y de las condiciones del trabajo, las teorías del fin del trabajo, la precarización y la representación de los trabajadores más frágiles: mujeres, jóvenes y migrantes. En un segundo orden se interpeló sobre la gobernanza mundial, los organismos internacionales, el régimen normativo internacional, la civilización capitalista, para luego abordar el estudio específico del Mercosur y la acción obrera en dicho proceso. El núcleo determinó que para los representantes obreros la acción colectiva sindical debe ser postnacional y su objetivo es limitar la globalización capitalista neoliberal. La CCSCS conformó desde sus inicios un movimiento capaz de elevarse al rango supranacional para representar la voz de los trabajadores del MERCOSUR. La pluralidad configuró su mayor virtud durante sus primeros 20 años, reconociendo una experiencia de aprendizaje de tolerancia y respeto, que ellos definen como la unidad en la diversidad. Esta entidad constituye un patrimonio único como paradigma del sindicalismo postnacional. Los sindicatos del Cono Sur adoptaron diversas modalidades de acción colectiva: a) reactiva (con repertorios de insubordinación, de lucha y resistencia al modelo neoliberal), b) proactiva (con repertorios de incidencia normativa en el MERCOSUR) y c) participativa (con repertorios de producción propositiva de incidencia en la dimensión social del MERCOSUR). Su acción colectiva reactiva, normativa y propositiva fue eficaz a mediano plazo para participar e incidir en el MERCOSUR, crear una dimensión social del bloque y dotar de derechos normativos a los ciudadanos de la región. Su acción tuvo un sentido político de gran poder instituyente, con capacidad movilización y alta exposición pública. Sin embargo, en la segunda década su lógica de construcción quedó subordinada a los procesos nacionales y a los partidos gobernantes, dejó de ser performativa y de creación política, dirimiéndose en la esfera social junto a otros movimientos sociales emergentes, y provocó un ciclo de desmovilización. Simultáneamente, emergió con fuerza otra modalidad de sindicalismo postnacional con la fusión y refundación de los Sindicatos Globales. Su acción sectorial contribuye a restaurar las demandas de distribución que habían quedado soslayadas, pero esta tesis manifiesta que los protagonistas afirman que sus marcos de acción colectiva deberán ser conjuntos para ser exitosa. El sindicalismo postnacional en el MERCOSUR se define a sí mismos como agente de desarrollo, protagonista del modelo socioproductivo, pero también como vehículo partícipe de la democracia y de una matriz sustentable de desarrollo

Some features of the turbulence produced by rising air bubbles in water

Presented in this paper is an experimental study on the characteristics of the turbulence produced by rising air bubbles in water. The measurements of turbulent velocities were made by using visualization technique of particle streak and computer image processing of the flow field. The turbulence features have been examined, showing that the rising bubble-produced turbulence can be approximately modeled by homogeneous turbulence as in the case of grid turbulence in air.

A reflection on the future of the quality management paradigm in the EU

In recent years, the Quality Management Paradigm has successfully taken root in the European Union’s business environment. Quality management besides being a multivariate issue including matters from management and economics till engineering may be called a global knowledge in permanent bubbling. This theoretical article is an eclectic effort to analyse the evolution of the Quality Management Paradigm. More specifically, the article deals with this management Paradigm evolution and change according to the present and future expected business environments.

Using the system dynamics paradigm in teaching and learning technological university subjets

2nd International Conference on Education and New Learning Technologies

Numerical simulation of a single fluid particle rising in non-Newtonian fluids

In this work, a level set method is developed for simulating the motion of a fluid particle rising in non-Newtonian fluids described by generalized Newtonian as well as viscoelastic model fluids. As the shear-thinning model we use a Carreau-Yasuda model, and the viscoelastic effect can be modeled with Oldroyd-B constitutive equations. The control volume formulation with the SIMPLEC algorithm incorporated is used to solve the governing equations on a staggered Eulerian grid. The level set method is implemented to compute the motion of a bubble in a Newtonian fluid as one of typical examples for validation, and the computational results are in good agreement with the reported experimental data．The level set method is also applied for simulating a Newtonian drop rising in Carreau-Yasuda and Oldroyd-B fluids．Numerical results including noticeably negative wake behind the drop and viscosity field are obtained, and compare satisfactorily with the known literature data.