In human basophils, IL-3 selectively induces RANKL expression that is modulated by IgER-dependent and IgER-independent stimuli

BACKGROUND Receptor activator of NF-κB ligand (RANKL) is expressed as either surface (hRANKL1, hRANKL2) or soluble (hRANKL3) form. RANKL is involved in multifaceted processes of immunoregulation and bone resorption such as they occur in rheumatoid arthritis (RA). Interestingly, activated basophils, which are effector cells in allergic inflammation, contribute to the progress of collagen-induced arthritis (CIA), a mouse model for RA. Here, we investigate under which conditions human basophils express RANKL. METHODS Among other stimuli, basophils were cultured with IL-3 alone. Alternatively, as a secondary stimulus, IgER-dependent or IgER-independent agents were added simultaneously either with IL-3 or after prolonged IL-3 culturing. Expression of RANKL protein and mRNA was analyzed by flow cytometry, ELISA, and real-time PCR. A coculture system was applied to investigate biological activity of basophil-derived RANKL. RESULTS We show that in human basophils, IL-3 but no other stimulus induces de novo expression of soluble and surface RANKL, of which the latter enhances survival of MoDC. Upon simultaneous stimulation, IgER cross-linking reduces surface RANKL expression, while IgER-independent stimuli have no effect. This is in contrast to consecutive stimulation, as triggering with both IgER-dependent and IgER-independent stimuli enhances RANKL expression, particularly in its soluble form. Real-time PCR analysis shows that RANKL expression is mainly regulated at the mRNA level. CONCLUSION This study identifies IL-3 as a potent inducer of RANKL expression in human basophils, suggesting them to interact with bone physiology and activation of immune cells. IgER-dependent and IgER-independent stimuli modulate the IL-3-mediated RANKL expression in a time- and stimulus-dependent fashion.

Works Councils: An Agency Perspective

This paper investigates the role of works councils in a simple agency framework in whichworks councils are supposed to monitor manager's information on behalf of the workforce,but they are independent agents who might pursue their private interest. First, we considerthat workers can incentivize works councils through contingent monetary payments. In orderto deter collusion, workers must pay higher compensations in states of nature where they canbe expropriated by potential coalitions among works councils and management. Collusionmakes contingent payments costly and reduces workers' payoffs. Second, when elections areused to align works councils' interest only well compensated representatives would face aninter-temporal trade-off between accepting management's transfers at first period and losingrents at the second period. Elections increase the cost of entering on collusive behaviour withmanagement and works councils will try to behave on the employees' interest.

Works councils: an agency perspective

This paper investigates the role of works councils in a simple agency framework in which works councils are supposed to monitor manager’s information on behalf of the workforce, but they are independent agents who might pursue their private interest. First, we consider that workers can incentivize works councils through contingent monetary payments. In order to deter collusion, workers must pay higher compensations in states of nature where they can be expropriated by potential coalitions among works councils and management. Collusion makes contingent payments costly and reduces workers’ payoffs. Second, when elections are the exclusive mechanisms to align works councils’ interest, only well compensated representatives would face an intertemporal tradeoff between accepting management’s transfers at first period and losing rents at the second period. Elections increase the cost of entering on collusive behavior with management and works councils will try to behave on the employees’ interest.

High-fat diet associated with obesity induces impairment of mouse corpus cavernosum responses

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

A multi-agent system with a percolation approach to simulate the driving pattern of Plug-In ELectric Vehicles

A multi-agent system with a percolation approach to simulate the driving pattern of Plug-In Electric Vehicle (PEV), especially suited to simulate the PEVs behavior on any distribution systems, is presented. This tool intends to complement information about the driving patterns database on systems where that kind of information is not available. So, this paper aims to provide a framework that is able to work with any kind of technology and load generated of PEVs. The service zone is divided into several sub-zones, each subzone is considered as an independent agent identified with corresponding load level, and their relationships with the neighboring zones are represented as network probabilities. A percolation approach is used to characterize the autonomy of the battery of the PVEs to move through the city. The methodology is tested with data from a mid-size city real distribution system. The result shows the sub-area where the battery of PEVs will need to be recharge and gives the planners of distribution systems the necessary input for a medium to long term network planning in a smart grid environment. © 2012 IEEE.

Baiuka: jogos de lendas amazônicas para avaliação de inteligências múltiplas

BAIUKA é um jogo educativo voltado para despertar a consciência ecológica baseado em lendas amazônicas. Este trabalho teve como objetivo central construir um jogo educativo infantil baseado nas Inteligências Múltiplas, voltado para a cultura amazônica, gerando automaticamente avaliações sobre o comportamento do jogador, a partir de agentes autônomos, auxiliando o professor em sala de aula. Teve como objetivos específicos oferecer um instrumento de motivação da aprendizagem a partir do uso de jogos educativos na web, além de desenvolver um modelo para avaliar jogos educacionais. A caminhada metodológica teve como principal base de análise a metodologia qualitativa e envolveu, além de pesquisas documentais e bibliográficas, a pesquisa de campo na Escola Ipiranga, com aplicação de um checklist a professores devidamente selecionados, assim como especialistas que, de alguma forma, atuam nessa realidade. Os resultados da pesquisa indicam a boa aceitação por parte dos professores de proporcionar momentos de atividade lúdica para as crianças. Infelizmente, também constatamos a dificuldade em se criar um jogo educacional que seja interessante ao jovem, aliando metodologias pedagógicas ao poder dos jogos computacionais. Porém, não obstante essa triste constatação, a pesquisa aponta com esperança que os jogos computadorizados possam ser considerados o estado da arte para o desenvolvimento de ambientes de aprendizagem motivadores. A produção desta nova geração de jogos didáticos requer times interdisciplinares, criativos e capazes de trabalharem cooperativamente.

Neural Approach in Multi-Agent Routing for Static Telecommunication Networks

The problem of multi-agent routing in static telecommunication networks with fixed configuration is considered. The problem is formulated in two ways: for centralized routing schema with the coordinator-agent (global routing) and for distributed routing schema with independent agents (local routing). For both schemas appropriate Hopfield neural networks (HNN) are constructed.

How to map the diversity of the audiovisual industry in the digital era. A Methodological Proposition

This article presents a methodological proposition to map the diversity of the audiovisual industry in the digital scenario by portraying the most important interactions between those who create, produce, distribute and disseminate audiovisual productions on line, paying special attention to powerful intermediaries and to small and medium independent agents. Taking as a point of departure a flexible understanding of social network analysis, the aim is to understand the structure of the audiovisual industry on the internet so that, taking into consideration a given sector, agents, their relations and the networks they give place to – as well as the structural conditions under which they operate – are studied. The aim is to answer questions such as: what is mapping, what is of interesting to map, how can it be done and what advantages and disadvantages the results will present.

ATG5 is induced by DNA-damaging agents and promotes mitotic catastrophe independent of autophagy

Anticancer drug therapy activates both molecular cell death and autophagy pathways. Here we show that even sublethal concentrations of DNA-damaging drugs, such as etoposide and cisplatin, induce the expression of autophagy-related protein 5 (ATG5), which is both necessary and sufficient for the subsequent induction of mitotic catastrophe. We demonstrate that ATG5 translocates to the nucleus, where it physically interacts with survivin in response to DNA-damaging agents both in vitro and in carcinoma tissues obtained from patients who had undergone radiotherapy and/or chemotherapy. As a consequence, elements of the chromosomal passenger complex are displaced during mitosis, resulting in chromosome misalignment and segregation defects. Pharmacological inhibition of autophagy does not prevent ATG5-dependent mitotic catastrophe, but shifts the balance to an early caspase-dependent cell death. Our data suggest a dual role for ATG5 in response to drug-induced DNA damage, where it acts in two signalling pathways in two distinct cellular compartments, the cytosol and the nucleus.

MODELING SCIENTIFIC AGENTS FOR A BETTER SCIENCE

Science is a fundamental human activity and we trust its results because it has several error-correcting mechanisms. It is subject to experimental tests that are replicated by independent parts. Given the huge amount of information available and the information asymetry between producers and users of knowledge, scientists have to rely on the reports of others. This makes it possible for social effects to influence the scientific community. Here, an Opinion Dynamics agent model is proposed to describe this situation. The influence of Nature through experiments is described as an external field that acts on the experimental agents. We will see that the retirement of old scientists can be fundamental in the acceptance of a new theory. We will also investigate the interplay between social influence and observations. This will allow us to gain insight in the problem of when social effects can have negligible effects in the conclusions of a scientific community and when we should worry about them.

3D-Pharmacophore mapping of thymidine-based inhibitors of TMPK as potential antituberculosis agents

Tuberculosis (TB) is the primary cause of mortality among infectious diseases. Mycobacterium tuberculosis monophosphate kinase (TMPKmt) is essential to DNA replication. Thus, this enzyme represents a promising target for developing new drugs against TB. In the present study, the receptor-independent, RI, 4D-QSAR method has been used to develop QSAR models and corresponding 3D-pharmacophores for a set of 81 thymidine analogues, and two corresponding subsets, reported as inhibitors of TMPKmt. The resulting optimized models are not only statistically significant with r (2) ranging from 0.83 to 0.92 and q (2) from 0.78 to 0.88, but also are robustly predictive based on test set predictions. The most and the least potent inhibitors in their respective postulated active conformations, derived from each of the models, were docked in the active site of the TMPKmt crystal structure. There is a solid consistency between the 3D-pharmacophore sites defined by the QSAR models and interactions with binding site residues. Moreover, the QSAR models provide insights regarding a probable mechanism of action of the analogues.

Stimulation of protein kinase C-dependent and -independent signaling pathways by bistratene A in intestinal epithelial cells

The marine toxin bistratene A (BisA) potently induces cytostasis and differentiation in a variety of systems. Evidence that BisA is a selective activator of protein kinase C (PKC) delta implicates PKC delta signaling in the negative growth-regulatory effects of this agent. The current study further investigates the signaling pathways activated by BisA by comparing its effects with those of the PKC agonist phorbol 12-myristate 13-acetate (PMA) in the IEC-18 intestinal crypt cell line. Both BisA and PMA induced cell cycle arrest in these cells, albeit with different kinetics. While BisA produced sustained cell cycle arrest in G(o)/G(1) and G(2)/M, the effects of PMA were transient and involved mainly a G(o)/G(1), blockade. BisA also produced apoptosis in a proportion of the population, an effect not seen with PMA. Both agents induced membrane translocation/activation of PKC, with BisA translocating only PKC delta and PMA translocating PKC alpha, delta, and epsilon in these cells. Notably, while depletion of PKC alpha, delta, and epsilon abrogated the cell cycle-specific effects of PMA in IEC-18 cells, the absence of these PKC isozymes failed to inhibit BisA-induced G(o)/G(1), and G(2)/M arrest or apoptosis. The cell cycle inhibitory and apoptotic effects of BisA, therefore, appear to be PKC-independent in IEG-18 cells. On the other hand, BisA and PMA both promoted PKC-dependent activation of Erk 1 and 2 in this system. Thus, intestinal epithelial cells respond to BisA through activation of at least two signaling pathways: a PKC delta -dependent pathway, which leads to activation of mitogen-activated protein kinase and possibly cytostasis in the appropriate context, and a PKC-independent pathway, which induces both cell cycle arrest in G(o)/G(1) and G(2)/M and apoptosis through as yet unknown mechanisms. (C) 2001 Elsevier Science Inc. All rights reserved.

Software development for estimation of optical clearing agent’s diffusion coefficients in biological tissues

The study of chemical diffusion in biological tissues is a research field of high importance and with application in many clinical, research and industrial areas. The evaluation of diffusion and viscosity properties of chemicals in tissues is necessary to characterize treatments or inclusion of preservatives in tissues or organs for low temperature conservation. Recently, we have demonstrated experimentally that the diffusion properties and dynamic viscosity of sugars and alcohols can be evaluated from optical measurements. Our studies were performed in skeletal muscle, but our results have revealed that the same methodology can be used with other tissues and different chemicals. Considering the significant number of studies that can be made with this method, it becomes necessary to turn data processing and calculation easier. With this objective, we have developed a software application that integrates all processing and calculations, turning the researcher work easier and faster. Using the same experimental data that previously was used to estimate the diffusion and viscosity of glucose in skeletal muscle, we have repeated the calculations with the new application. Comparing between the results obtained with the new application and with previous independent routines we have demonstrated great similarity and consequently validated the application. This new tool is now available to be used in similar research to obtain the diffusion properties of other chemicals in different tissues or organs.

Beta-adrenergic blocking agents in heart failure

Cardiac dysfunction in heart failure is widely recognized as a progressive process, regardless of the clinical signs and symptoms. An increase in cardiac sympathetic drive is one of the earliest neurohormonal responses occurring in patients with heart failure and may be one of the major causes of the progressive remodeling leading to the decline in myocardial function, and responsible for the poor prognosis of patients with heart failure. Therefore, recent data provided by several appropriately designed clinical trials clearly indicate the benefits of beta-adrenoceptor blocking agents, combined with diuretics, ACE inhibitors, and digoxin in chronic heart failure class II to IV due to systolic ventricular dysfunction. The benefits are related to symptoms, functional capacity, remodeling, and improvement in left ventricular function, reduction in cardiovascular hospitalization, a decrease in the overall and sudden cardiac death rate, and are similar in patients with ischemic or nonischemic cardiomyopathy, independent of age, gender, or functional class. In this review we describe the cardiovascular effects of the increase in sympathetic drive, the pharmacological properties of the beta-blockers most evaluated in heart failure therapy (metoprolol, bisoprolol, and carvedilol), the major clinical trials related to these agents in heart failure, the recommendations for their appropriate use in clinical practice, the precautions to be adopted, and how to handle the more common adverse reactions.

CD4+ T cell count recovery in HIV type 1-infected patients is independent of class of antiretroviral therapy.

BACKGROUND: In recent years, treatment options for human immunodeficiency virus type 1 (HIV-1) infection have changed from nonboosted protease inhibitors (PIs) to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) and boosted PI-based antiretroviral drug regimens, but the impact on immunological recovery remains uncertain. METHODS: During January 1996 through December 2004 [corrected] all patients in the Swiss HIV Cohort were included if they received the first combination antiretroviral therapy (cART) and had known baseline CD4(+) T cell counts and HIV-1 RNA values (n = 3293). For follow-up, we used the Swiss HIV Cohort Study database update of May 2007 [corrected] The mean (+/-SD) duration of follow-up was 26.8 +/- 20.5 months. The follow-up time was limited to the duration of the first cART. CD4(+) T cell recovery was analyzed in 3 different treatment groups: nonboosted PI, NNRTI, or boosted PI. The end point was the absolute increase of CD4(+) T cell count in the 3 treatment groups after the initiation of cART. RESULTS: Two thousand five hundred ninety individuals (78.7%) initiated a nonboosted-PI regimen, 452 (13.7%) initiated an NNRTI regimen, and 251 (7.6%) initiated a boosted-PI regimen. Absolute CD4(+) T cell count increases at 48 months were as follows: in the nonboosted-PI group, from 210 to 520 cells/muL; in the NNRTI group, from 220 to 475 cells/muL; and in the boosted-PI group, from 168 to 511 cells/muL. In a multivariate analysis, the treatment group did not affect the response of CD4(+) T cells; however, increased age, pretreatment with nucleoside reverse-transcriptase inhibitors, serological tests positive for hepatitis C virus, Centers for Disease Control and Prevention stage C infection, lower baseline CD4(+) T cell count, and lower baseline HIV-1 RNA level were risk factors for smaller increases in CD4(+) T cell count. CONCLUSION: CD4(+) T cell recovery was similar in patients receiving nonboosted PI-, NNRTI-, and boosted PI-based cART.