Glycogen synthase kinase 3 (GSK3) in the heart: a point of integration in hypertrophic signalling and a therapeutic target? A critical analysis

Glycogen synthase kinase 3 (GSK3, of which there are two isoforms, GSK3alpha and GSK3beta) was originally characterized in the context of regulation of glycogen metabolism, though it is now known to regulate many other cellular processes. Phosphorylation of GSK3alpha(Ser21) and GSK3beta(Ser9) inhibits their activity. In the heart, emphasis has been placed particularly on GSK3beta, rather than GSK3alpha. Importantly, catalytically-active GSK3 generally restrains gene expression and, in the heart, catalytically-active GSK3 has been implicated in anti-hypertrophic signalling. Inhibition of GSK3 results in changes in the activities of transcription and translation factors in the heart and promotes hypertrophic responses, and it is generally assumed that signal transduction from hypertrophic stimuli to GSK3 passes primarily through protein kinase B/Akt (PKB/Akt). However, recent data suggest that the situation is far more complex. We review evidence pertaining to the role of GSK3 in the myocardium and discuss effects of genetic manipulation of GSK3 activity in vivo. We also discuss the signalling pathways potentially regulating GSK3 activity and propose that, depending on the stimulus, phosphorylation of GSK3 is independent of PKB/Akt. Potential GSK3 substrates studied in relation to myocardial hypertrophy include nuclear factors of activated T cells, beta-catenin, GATA4, myocardin, CREB, and eukaryotic initiation factor 2Bvarepsilon. These and other transcription factor substrates putatively important in the heart are considered. We discuss whether cardiac pathologies could be treated by therapeutic intervention at the GSK3 level but conclude that any intervention would be premature without greater understanding of the precise role of GSK3 in cardiac processes.

Transgene organization in rice engineered through direct DNA transfer supports a two-phase integration mechanism mediated by the establishment of integration hot spots

Organization of transgenes in rice transformed through direct DNA transfer strongly suggests a two-phase integration mechanism. In the “preintegration” phase, transforming plasmid molecules (either intact or partial) are spliced together. This gives rise to rearranged transgenic sequences, which upon integration do not contain any interspersed plant genomic sequences. Subsequently, integration of transgenic DNA into the host genome is initiated. Our experiments suggest that the original site of integration acts as a hot spot, facilitating subsequent integration of successive transgenic molecules at the same locus. The resulting transgenic locus may have plant DNA separating the transgenic sequences. Our data indicate that transformation through direct DNA transfer, specifically particle bombardment, generally results in a single transgenic locus as a result of this two-phase integration mechanism. Transgenic plants generated through such processes may, therefore, be more amenable to breeding programs as the single transgenic locus will be easier to characterize genetically. Results from direct DNA transfer experiments suggest that in the absence of protein factors involved in exogenous DNA transfer through Agrobacterium, the qualitative and/or quantitative efficiency of transformation events is not compromised. Our results cast doubt on the role of Agrobacterium vir genes in the integration process.

The Failure of Integration: The CIS and other international organisations in the post-Soviet era, 1991-2006. OSW Study 26/2007

Institutional integration processes in the post-Soviet area have ended in failure. It proved impossible to transform the Commonwealth of Independent States into an instrument of real co-operation, even though Russia, which was the most interested in integrating the post-Soviet space, made repeated efforts to this end. The CIS never managed to accomplish its declared objectives and, from this point of view, it does not exist as an integration organisation and de facto never did.

Evaluation of integration technology approaches in the healthcare supply chain

Healthcare organisations are increasingly being challenged to look at their operations and find opportunities to improve the quality, efficiency and effectiveness of their supply chain services. In light of this situation, there is an apparent need for healthcare organisations to invest in integration technologies and to achieve the integration of supply chain processes, in order to break up the historical structure characterised by numerous interfaces and the segregation of responsibilities. The aim of this paper is to take an independent look at the healthcare supply chain and identify at different levels the core entities, processes, information flows, and system integration challenges which impede supply chain quality improvements to be realised. Moreover, this paper proposes, from an information systems perspective, a framework for the evaluation of different integration technology approaches, which can be used as a potential guideline tool for assessing integration technology alternatives, in order to add value to a healthcare-supply-chain management system. Copyright © 2007 Inderscience Enterprises Ltd.

Scavenging processes of atmospheric particulate matter: a numerical modeling of case studies

Below cloud scavenging processes have been investigated considering a numerical simulation, local atmospheric conditions and particulate matter (PM) concentrations, at different sites in Germany. The below cloud scavenging model has been coupled with bulk particulate matter counter TSI (Trust Portacounter dataset, consisting of the variability prediction of the particulate air concentrations during chosen rain events. The TSI samples and meteorological parameters were obtained during three winter Campaigns: at Deuselbach, March 1994, consisting in three different events; Sylt, April 1994 and; Freiburg, March 1995. The results show a good agreement between modeled and observed air concentrations, emphasizing the quality of the conceptual model used in the below cloud scavenging numerical modeling. The results between modeled and observed data have also presented high square Pearson coefficient correlations over 0.7 and significant, except the Freiburg Campaign event. The differences between numerical simulations and observed dataset are explained by the wind direction changes and, perhaps, the absence of advection mass terms inside the modeling. These results validate previous works based on the same conceptual model.

Do economists ‘compose’ economics? A comparison of the creative processes of artists and economists

This is a draft for a chapter of the book version of my Ph.D thesis. The chapter addresses the following question: Are the creative processes of musical composers and academic economists essentially the same, or are there significant differences? The paper finds that there are deep similarities between the creative processes of theoretical economists and the creative processes of artists. The chapter builds a process oriented lifecycle account of creative activity, drawing on testimonial material from the arts and the sciences, and relates the model to the creative work of economists developing economic theory.

Virtual communities of practice: investigating motivations and constraints in the processes of knowledge creation and transfer

With accelerated market volatility, faster response times and increased globalization, business environments are going through a major transformation and firms have intensified their search for strategies which can give them competitive advantage. This requires that companies continuously innovate, to think of new ideas that can be transformed or implemented as products, processes or services, generating value for the firm. Innovative solutions and processes are usually developed by a group of people, working together. A grouping of people that share and create new knowledge can be considered as a Community of Practice (CoP). CoP’s are places which provide a sound basis for organizational learning and encourage knowledge creation and acquisition. Virtual Communities of Practice (VCoP's) can perform a central role in promoting communication and collaboration between members who are dispersed in both time and space. Nevertheless, it is known that not all CoP's and VCoP's share the same levels of performance or produce the same results. This means that there are factors that enable or constrain the process of knowledge creation. With this in mind, we developed a case study in order to identify both the motivations and the constraints that members of an organization experience when taking part in the knowledge creating processes of VCoP's. Results show that organizational culture and professional and personal development play an important role in these processes. No interviewee referred to direct financial rewards as a motivation factor for participation in VCoPs. Most identified the difficulty in aligning objectives established by the management with justification for the time spent in the VCoP. The interviewees also said that technology is not a constraint.

A web-based tool to evaluate the iterative processes of direct search methods

Constrained and unconstrained Nonlinear Optimization Problems often appear in many engineering areas. In some of these cases it is not possible to use derivative based optimization methods because the objective function is not known or it is too complex or the objective function is non-smooth. In these cases derivative based methods cannot be used and Direct Search Methods might be the most suitable optimization methods. An Application Programming Interface (API) including some of these methods was implemented using Java Technology. This API can be accessed either by applications running in the same computer where it is installed or, it can be remotely accessed through a LAN or the Internet, using webservices. From the engineering point of view, the information needed from the API is the solution for the provided problem. On the other hand, from the optimization methods researchers’ point of view, not only the solution for the problem is needed. Also additional information about the iterative process is useful, such as: the number of iterations; the value of the solution at each iteration; the stopping criteria, etc. In this paper are presented the features added to the API to allow users to access to the iterative process data.

Mass Conservation Enhancement of Free Boundary Mesolevel Flows during LCM Processes of Composites Manufacturing

Undesirable void formation during the injection phase of the liquid composite moulding process can be understood as a consequence of the non-uniformity of the flow front progression, caused by the dual porosity of the fibre perform. Therefore the best examination of the void formation physics can be provided by a mesolevel analysis, where the characteristic dimension is given by the fibre tow diameter. In mesolevel analysis, liquid impregnation along two different scales; inside fibre tows and within the open spaces between them; must be considered and the coupling between these flow regimes must be addressed. In such case, it is extremely important to account correctly for the surface tension effects, which can be modelled as capillary pressure applied at the flow front. Numerical implementation of such boundary conditions leads to ill-posing of the problem, in terms of the weak classical as well as stabilized formulation. As a consequence, there is an error in mass conservation accumulated especially along the free flow front. This contribution presents a numerical procedure, which was formulated and implemented in the existing Free Boundary Program in order to significantly reduce this error.

Application of NMR RDC’s, relaxation and self-diffusion for the study of dynamic processes of small molecules in solution

Spin-lattice Relaxation, self-Diffusion coefficients and Residual Dipolar Couplings (RDC’s) are the basis of well established Nuclear Magnetic Resonance techniques for the physicochemical study of small molecules (typically organic compounds and natural products with MW < 1000 Da), as they proved to be a powerful and complementary source of information about structural dynamic processes in solution. The work developed in this thesis consists in the application of the earlier-mentioned NMR techniques to explore, analyze and systematize patterns of the molecular dynamic behavior of selected small molecules in particular experimental conditions. Two systems were chosen to investigate molecular dynamic behavior by these techniques: the dynamics of ion-pair formation and ion interaction in ionic liquids (IL) and the dynamics of molecular reorientation when molecules are placed in oriented phases (alignment media). The application of NMR spin-lattice relaxation and self-diffusion measurements was applied to study the rotational and translational molecular dynamics of the IL: 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM][BF4]. The study of the cation-anion dynamics in neat and IL-water mixtures was systematically investigated by a combination of multinuclear NMR relaxation techniques with diffusion data (using by H1, C13 and F19 NMR spectroscopy). Spin-lattice relaxation time (T1), self-diffusion coefficients and nuclear Overhauser effect experiments were combined to determine the conditions that favor the formation of long lived [BMIM][BF4] ion-pairs in water. For this purpose and using the self-diffusion coefficients of cation and anion as a probe, different IL-water compositions were screened (from neat IL to infinite dilution) to find the conditions where both cation and anion present equal diffusion coefficients (8% water fraction at 25 ºC). This condition as well as the neat IL and the infinite dilution were then further studied by 13C NMR relaxation in order to determine correlation times (c) for the molecular reorientational motion using a mathematical iterative procedure and experimental data obtained in a temperature range between 273 and 353 K. The behavior of self-diffusion and relaxation data obtained in our experiments point at the combining parameters of molar fraction 8 % and temperature 298 K as the most favorable condition for the formation of long lived ion-pairs. When molecules are subjected to soft anisotropic motion by being placed in some special media, Residual Dipolar Couplings (RDCs), can be measured, because of the partial alignment induced by this media. RDCs are emerging as a powerful routine tool employed in conformational analysis, as it complements and even outperforms the approaches based on the classical NMR NOE or J3 couplings. In this work, three different alignment media have been characterized and evaluated in terms of integrity using 2H and 1H 1D-NMR spectroscopy, namely the stretched and compressed gel PMMA, and the lyotropic liquid crystals CpCl/n-hexanol/brine and cromolyn/water. The influence that different media and degrees of alignment have on the dynamic properties of several molecules was explored. Different sized sugars were used and their self-diffusion was determined as well as conformation features using RDCs. The results obtained indicate that no influence is felt by the small molecules diffusion and conformational features studied within the alignment degree range studied, which was the 3, 5 and 6 % CpCl/n-hexanol/brine for diffusion, and 5 and 7.5 % CpCl/n-hexanol/brine for conformation. It was also possible to determine that the small molecules diffusion verified in the alignment media presented close values to the ones observed in water, reinforcing the idea of no conditioning of molecular properties in such media.

How to improve Sonae's processes of suppliers of services' management?

Sonae is one of the greatest retailers in Portugal. As the business got bigger, it centralized operations. Direcção de Serviços Administrativos processes all invoices sent by suppliers. However, there are many which deliver errors and are not processed automatically. As a result, there are lost invoices and suppliers who are not paid, while the company’s accountability becomes less transparent. Such is due to a lack of proactive attitude towards suppliers as well as to a lack of incentives for employees to perform well. Great savings may be achieved with little effort, if the right things are measured so that the right tools may be applied.

Assessment of integration of the leprosy program into primary health care in Aracaju, state of Sergipe, Brazil

INTRODUCTION: The aim of this study was to assess the epidemiological and operational characteristics of the Leprosy Program before and after its integration into the Primary healthcare Services of the municipality of Aracaju-Sergipe, Brazil. METHODS: Data were drawn from the national database. The study periods were divided into preintegration (1996-2000) and postintegration (2001-2007). Annual rates of epidemiological detection were calculated. Frequency data on clinico-epidemiological variables of cases detected and treated for the two periods were compared using the Chi-squared (χ2) test adopting a 5% level of significance. RESULTS: Rates of detection overall, and in subjects younger than 15 years, were greater for the postintegration period and were higher than rates recorded for Brazil as a whole during the same periods. A total of 780 and 1,469 cases were registered during the preintegration and postintegration periods, respectively. Observations for the postintegration period were as follows: I) a higher proportion of cases with disability grade assessed at diagnosis, with increase of 60.9% to 78.8% (p < 0.001), and at end of treatment, from 41.4% to 44.4% (p < 0.023); II) an increase in proportion of cases detected by contact examination, from 2.1% to 4.1% (p < 0.001); and III) a lower level of treatment default with a decrease from 5.64 to 3.35 (p < 0.008). Only 34% of cases registered from 2001 to 2007 were examined. CONCLUSIONS: The shift observed in rates of detection overall, and in subjects younger than 15 years, during the postintegration period indicate an increased level of health care access. The fall in number of patients abandoning treatment indicates greater adherence to treatment. However, previous shortcomings in key actions, pivotal to attaining the outcomes and impact envisaged for the program, persisted in the postintegration period.