NFAT transcription factors: from cell cycle to tumor development

The nuclear factor of activated T cells (NFAT) family of transcription factors has been primarily identified in immune cells; however, these proteins have been recently found to be functionally active in several other non-immune cell types. NFAT proteins are activated upon different stimuli that lead to increased intracellular calcium levels. Regardless of their widely known cytokine gene expression properties, NFATs have been shown to regulate other genes related to cell cycle progression, cell differentiation and apoptosis, revealing a broader role for these proteins in normal cell physiology. Several reports have addressed the participation of NFATs in many aspects of malignant cell transformation and tumorigenic processes. In this review, we will discuss the involvement of the different NFAT family members in the regulation of cell cycling, differentiation and tumor formation, and also its implications on oncogenesis. Better understanding the mechanisms by which NFATs regulate cell cycle and tumor-related events should be relevant for the development of rational anti-cancer therapies.

Thermodynamic evaluation and modeling of proton and water exchange associated with benzamidine and berenil binding to ß-trypsin

Serine-proteases are involved in vital processes in virtually all species. They are important targets for researchers studying the relationships between protein structure and activity, for the rational design of new pharmaceuticals. Trypsin was used as a model to assess a possible differential contribution of hydration water to the binding of two synthetic inhibitors. Thermodynamic parameters for the association of bovine ß-trypsin (homogeneous material, observed 23,294.4 ± 0.2 Da, theoretical 23,292.5 Da) with the inhibitors benzamidine and berenil at pH 8.0, 25ºC and with 25 mM CaCl2, were determined using isothermal titration calorimetry and the osmotic stress method. The association constant for berenil was about 12 times higher compared to the one for benzamidine (binding constants are K = 596,599 ± 25,057 and 49,513 ± 2,732 M-1, respectively; the number of binding sites is the same for both ligands, N = 0.99 ± 0.05). Apparently the driving force responsible for this large difference of affinity is not due to hydrophobic interactions because the variation in heat capacity (DCp), a characteristic signature of these interactions, was similar in both systems tested (-464.7 ± 23.9 and -477.1 ± 86.8 J K-1 mol-1 for berenil and benzamidine, respectively). The results also indicated that the enzyme has a net gain of about 21 water molecules regardless of the inhibitor tested. It was shown that the difference in affinity could be due to a larger number of interactions between berenil and the enzyme based on computational modeling. The data support the view that pharmaceuticals derived from benzamidine that enable hydrogen bond formation outside the catalytic binding pocket of ß-trypsin may result in more effective inhibitors.

Streptozotocin-induced mechanical hypernociception is not dependent on hyperglycemia

Since streptozotocin (STZ)-induced diabetes is a widely used model of painful diabetic neuropathy, the aim of the present study was to design a rational protocol to investigate whether the development of mechanical hypernociception induced by STZ depends exclusively on hyperglycemia. Male Wistar rats (180-200 g; N = 6-7 per group) received a single intravenous injection of STZ at three different doses (10, 20, or 40 mg/kg). Only the higher dose (40 mg/kg) induced a significant increase in blood glucose levels, glucose tolerance and deficiency in weight gain. However, all STZ-treated rats (hyperglycemic or not) developed persistent (for at least 20 days) and indistinguishable bilateral mechanical hypernociception that was not prevented by daily insulin treatment (2 IU twice a day, sc). Systemic morphine (2 mg/kg) but not local (intraplantar) morphine treatment (8 µg/paw) significantly inhibited the mechanical hypernociception induced by STZ (10 or 40 mg/kg). In addition, intraplantar injection of STZ at doses that did not cause hyperglycemia (30, 100 or 300 µg/paw) induced ipsilateral mechanical hypernociception for at least 8 h that was inhibited by local and systemic morphine treatment (8 µg/paw or 2 mg/kg, respectively), but not by dexamethasone (1 mg/kg, sc). The results of this study demonstrate that systemic administration of STZ induces mechanical hypernociception that does not depend on hyperglycemia and intraplantar STZ induces mechanical sensitization of primary sensory neurons responsive to local morphine treatment.

Trends in adjuvant development for vaccines: DAMPs and PAMPs as potential new adjuvants

Aluminum salts have been widely used in vaccine formulations and, after their introduction more than 80 years ago, only few vaccine formulations using new adjuvants were developed in the last two decades. Recent advances in the understanding of how innate mechanisms influence the adaptive immunity opened up the possibility for the development of new adjuvants in a more rational design. The purpose of this review is to discuss the recent advances in this field regarding the attempts to determine the molecular basis and the general mechanisms underlying the development of new adjuvants, with particular emphasis on the activation of receptors of innate immune recognition. One can anticipate that the use of these novel adjuvants will also provide a window of opportunities for the development of new vaccines.

Origanum vulgare L. essential oil as inhibitor of potentially toxigenic Aspergilli

Origanum vulgare L. essential oil has been known as an interesting source of antimicrobial compounds to be applied in food conservation. In this study, the effect of O. vulgare essential on the growth of A. flavus, A. parasiticus, A. fumigatus, A. terreus and A. ochraceus was assessed. The essential oil had a significant inhibitory effect on all assayed fungi. MIC was 0.6 µL.mL-1 for all fungi, while MFC was in the range of 1.25-2.5 µL.mL-1. The radial mycelial growth of A. flavus and A. parasiticus was strongly inhibited over 14 days at 0.6, 1.25 and 2.5 µL.mL-1 of oil in solid medium. The mycelial mass of all fungi was inhibited over 90% at 0.6 and 0.3 µL.mL-1 in liquid medium, while it was 100% at 1.25 µL.mL-1. The oil in a range of concentrations (0.6 to 2.5 µL.mL-1) was effective in inhibiting the viability and spores germination in a short time of exposure. The main morphological changes caused by the essential oil in A. parasiticus observed under light microscopy were absence of conidiation, leakage of cytoplasm, loss of pigmentation, and disrupted cell structure. These results demonstrated that O. vulgare essential oil produced a significant fungitoxic effect supporting its possible rational use as anti-mould compound in food conservation.

Value Creation Through Sustainability Within The Housing Industry - A Company’s View

The economy, under the condition of scarcity is meanwhile aiming at more rational economic activities that are efficient and effective. Companies need to know how to make use of new possibilities towards a more sustainable business. The right balance between risk and opportunity implies a sustainable growth and competitive advantage. Managers need to navigate companies across the globalization, as the global economy is constantly in motion. Further, companies have to face trends since the business world is changing radically. In order to keep up with those changes, companies have to recognize new trends early and respond quickly, efficiently and smart. To gain a competitive edge is without a doubt a critical aspect of a comprehensive value creation economy that withstands the demand for value capture and sustainability. Expectations towards a responsible economy are growing steadily. Therefore, companies have increasingly an obligation to economize more sustainable and to communicate their social and environmental commitment externally. Sustainability can live through the entire structure of value creation of a company. By reducing environmental and social risks companies can create values. This value creation thus represents a proper performance of a company and the accomplished added value through companies’ activities.

Qual o valor do auto-interesse?

The article critically reviews past and current justifications for the theoretical use of the behavioral assumption of self-interest, explanatory, normative, representational and critical, focusing on the critical function. This latter emerges from an incursion into the modern history of ideas and may be shown still to fertilize a number of contemporary economic approaches.

Korkokattosäännöksen vaikutukset pikalainamarkkinoihin

Lyhytaikaisista, pienehköistä ja vakuudettomista pikalainoista on muodostunut nopeasti osa suomalaisia kuluttajaluottomarkkinoita. Samalla pikalainatoimintaa koskevaa lainsäädäntöä on uudistettu useaan kertaan. Tämän kandidaatintutkielman tavoitteena on ollut selvittää, miten korkokattosäännös on vaikuttanut pikalainayhtiöiden tarjoamiin tuotteisiin ja alalla toimivan yritysjoukon kokoon. Tutkimus on toteutettu laadullisin menetelmin. Aineistona on käytetty Etelä-Suomen aluehallintoviraston ylläpitämän luotonantajarekisterin tietoja, Tilastokeskuksen tilastotietoja, keskeisiä oikeustapauksia sekä erikseen tutkielmaa varten kerättyjä pikalainayhtiöiden tuotetietoja. Tutkimuksessa havaittiin korkokattosäännöksen voimaantulon vähentäneen pikalainayritysten määrää huomattavasti. Yleisin tuote toimialalla on niin sanottu limiittiluotto joustavalla lainamäärällä ja takaisinmaksulla, minkä lisäksi yhtiöt tarjoavat lyhyitä ja pitkiä kertaluottoja. Korkokattosäännöksen tultua voimaan keskimääräinen luottosumma on kasvanut ja takaisinmaksuaika pidentynyt merkittävästi. Samalla luotoista maksettavien kulujen suhde lainamäärään on pienentynyt ja lainoja on myönnetty niin euro- kuin kappalemääräisesti selvästi aiempaa vähemmän. Tulosten perusteella voidaan sanoa, että lakimuutoksella on ollut selkeitä vaikutuksia pikalaina-alaan. Luotonannon kiristyttyä laskeneet luottokustannukset hyödyttävät kuitenkin vain osaa luotonhakijoista. Muuttuneiden tuotteiden myötä pikalainatoiminta on siirtynyt lähemmäs muuta kuluttajaluottotoimintaa.

The death and resurrection of 'economics with psychology': remarks from a methodological standpoint

One of the merits of contemporary economic analysis is its capacity to offer accounts of choice behavior that dispense with details of the complex decision machinery. The starting point of this paper is the concern with the important methodological debate about whether economics might offer accurate predictions and explanations of actual behavior without any reference to psychological presuppositions. Inspired by an exercise of rational reconstruction of ideas, I aim to offer an interpretation of the process of freeing economic analysis from psychology at the end of the 19th century and the contemporary resurrection of behavioral approaches in the late 1980s.

A teoria da perspectiva e as mudanças de preferência no mainstream: um prospecto Lakatoseano

The theory of the perspective and the changes of preference in the mainstream: a Lakatosean prospect. For many decades over the 20th Century, the mainstream of economics adopted a normative and axiomatic theory of individual behavior in which maximizing procedures were carried out by rationally unbounded agents. This status has been challenged on many grounds and alternative views from fields like psychology have found a way into the core of economics research frontier. Prospect theory, developed by psychologists Daniel Kahneman and Amos Tversky since the 1970s, has provided a more empirical, inductive and descriptive theory of decision making. It has made significant inroads into mainstream microeconomics, shaking the habits of some of its practitioners. This paper first takes stock of its main developments and then uses a Lakatosian framework to draw out its negative and positive heuristics. In what follows, its heuristics are compared to those of traditional rational decision-making theories. The differences between them are highlighted, pointing to changes in the mainstream of the profession and to new opportunities for research.

Herbert A. Simon and the concept of rationality: boundaries and procedures

This paper discusses Herbert A. Simon's conception of rationality in two of its principal general definitions: bounded rationality and procedural rationality. It argues that the latter is the one that better synthesizes the author's view about rational behavior and that the former fills mainly a critical function. They are complementarily used by Simon in this sense. In spite of that, it is argued that it is the low degree of specificity of the concept of bounded rationality one of the reasons for its relatively greater success.

Leigos, expertos e formação de expectativa

Laypeople, experts and expectation formation. This article is a critical discussion, under the light of expectation formation, of the relation that interposes between economic science as body of knowledge and its agents.

Freedom of choice and bounded rationality: a brief appraisal of behavioral economists' plea for light paternalism

Behavioral economics has addressed interesting positive and normative questions underlying the standard rational choice theory. More recently, it suggests that, in a real world of boundedly rational agents, economists could help people to improve the quality of their choices without any harm to autonomy and freedom of choice. This paper aims to scrutinize available arguments for and against current proposals of light paternalistic interventions mainly in the domain of intertemporal choice. It argues that incorporating the notion of bounded rationality in economic analysis and empirical findings of cognitive biases and self-control problems cannot make an indisputable case for paternalism.

Democracia e eficiência: a difícil relação entre política e economia no debate contemporâneo

Democracy and efficiency: hard relations between politics and economy. Many economists see politics as an irrational activity. They also think state action usually generates market inefficiencies and democratic institutions, such as elections, often work as obstacles to sound economic measures. Showing that vision has been embedded into the main currents of economic thought since the last century, we also argue those ideas are exported to great part of contemporary political science, including the area of public policies. Examining the literature, we show that rational choice political scientists, as the economists, claim governability and effective decisions will be guaranteed mainly through concentrated arenas or through insulated arrangements able to protect policy makers from political interference. In other words, governability depends on the reduction of the political arenas. On the contrary, we reject this technocratic solution of splitting politics from economy. With the support of classical pluralist thinkers, we stand another conception, arguing politics is the privileged social space for building interests and values in an institutionalized way. The difficulties to surpass current international crises since 2008 reveal this is a crucial problem: reducing politics would prevent societies from improving institutional solutions which are the only ones able to give space to emerging conflicts and, then, reach eventual consensus around them.

Public-private partnership investments in dry ports – Russian logistics markets and risks

The investments have always been considered as an essential backbone and so-called ‘locomotive’ for the competitive economies. However, in various countries, the state has been put under tight budget constraints for the investments in capital intensive projects. In response to this situation, the cooperation between public and private sector has grown based on public-private mechanism. The promotion of favorable arrangement for collaboration between public and private sectors for the provision of policies, services, and infrastructure in Russia can help to address the problems of dry ports development that neither municipalities nor the private sector can solve alone. Especially, the stimulation of public-private collaboration is significant under the exposure to externalities that affect the magnitude of the risks during all phases of project realization. In these circumstances, the risk in the projects also is becoming increasingly a part of joint research and risk management practice, which is viewed as a key approach, aiming to take active actions on existing global and specific factors of uncertainties. Meanwhile, a relatively little progress has been made on the inclusion of the resilience aspects into the planning process of a dry ports construction that would instruct the capacity planner, on how to mitigate the occurrence of disruptions that may lead to million dollars of losses due to the deviation of the future cash flows from the expected financial flows on the project. The current experience shows that the existing methodological base is developed fragmentary within separate steps of supply chain risk management (SCRM) processes: risk identification, risk evaluation, risk mitigation, risk monitoring and control phases. The lack of the systematic approach hinders the solution of the problem of risk management processes of dry port implementation. Therefore, management of various risks during the investments phases of dry port projects still presents a considerable challenge from the practical and theoretical points of view. In this regard, the given research became a logical continuation of fundamental research, existing in the financial models and theories (e.g., capital asset pricing model and real option theory), as well as provided a complementation for the portfolio theory. The goal of the current study is in the design of methods and models for the facilitation of dry port implementation through the mechanism of public-private partnership on the national market that implies the necessity to mitigate, first and foremost, the shortage of the investments and consequences of risks. The problem of the research was formulated on the ground of the identified contradictions. They rose as a continuation of the trade-off between the opportunities that the investors can gain from the development of terminal business in Russia (i.e. dry port implementation) and risks. As a rule, the higher the investment risk, the greater should be their expected return. However, investors have a different tolerance for the risks. That is why it would be advisable to find an optimum investment. In the given study, the optimum relates to the search for the efficient portfolio, which can provide satisfaction to the investor, depending on its degree of risk aversion. There are many theories and methods in finance, concerning investment choices. Nevertheless, the appropriateness and effectiveness of particular methods should be considered with the allowance of the specifics of the investment projects. For example, the investments in dry ports imply not only the lump sum of financial inflows, but also the long-term payback periods. As a result, capital intensity and longevity of their construction determine the necessity from investors to ensure the return on investment (profitability), along with the rapid return on investment (liquidity), without precluding the fact that the stochastic nature of the project environment is hardly described by the formula-based approach. The current theoretical base for the economic appraisals of the dry port projects more often perceives net present value (NPV) as a technique superior to other decision-making criteria. For example, the portfolio theory, which considers different risk preference of an investor and structures of utility, defines net present value as a better criterion of project appraisal than discounted payback period (DPP). Meanwhile, in business practice, the DPP is more popular. Knowing that the NPV is based on the assumptions of certainty of project life, it cannot be an accurate appraisal approach alone to determine whether or not the project should be accepted for the approval in the environment that is not without of uncertainties. In order to reflect the period or the project’s useful life that is exposed to risks due to changes in political, operational, and financial factors, the second capital budgeting criterion – discounted payback period is profoundly important, particularly for the Russian environment. Those statements represent contradictions that exist in the theory and practice of the applied science. Therefore, it would be desirable to relax the assumptions of portfolio theory and regard DPP as not fewer relevant appraisal approach for the assessment of the investment and risk measure. At the same time, the rationality of the use of both project performance criteria depends on the methods and models, with the help of which these appraisal approaches are calculated in feasibility studies. The deterministic methods cannot ensure the required precision of the results, while the stochastic models guarantee the sufficient level of the accuracy and reliability of the obtained results, providing that the risks are properly identified, evaluated, and mitigated. Otherwise, the project performance indicators may not be confirmed during the phase of project realization. For instance, the economic and political instability can result in the undoing of hard-earned gains, leading to the need for the attraction of the additional finances for the project. The sources of the alternative investments, as well as supportive mitigation strategies, can be studied during the initial phases of project development. During this period, the effectiveness of the investments undertakings can also be improved by the inclusion of the various investors, e.g. Russian Railways’ enterprises and other private companies in the dry port projects. However, the evaluation of the effectiveness of the participation of different investors in the project lack the methods and models that would permit doing the particular feasibility study, foreseeing the quantitative characteristics of risks and their mitigation strategies, which can meet the tolerance of the investors to the risks. For this reason, the research proposes a combination of Monte Carlo method, discounted cash flow technique, the theory of real options, and portfolio theory via a system dynamics simulation approach. The use of this methodology allows for comprehensive risk management process of dry port development to cover all aspects of risk identification, risk evaluation, risk mitigation, risk monitoring, and control phases. A designed system dynamics model can be recommended for the decision-makers on the dry port projects that are financed via a public-private partnership. It permits investors to make a decision appraisal based on random variables of net present value and discounted payback period, depending on different risks factors, e.g. revenue risks, land acquisition risks, traffic volume risks, construction hazards, and political risks. In this case, the statistical mean is used for the explication of the expected value of the DPP and NPV; the standard deviation is proposed as a characteristic of risks, while the elasticity coefficient is applied for rating of risks. Additionally, the risk of failure of project investments and guaranteed recoupment of capital investment can be considered with the help of the model. On the whole, the application of these modern methods of simulation creates preconditions for the controlling of the process of dry port development, i.e. making managerial changes and identifying the most stable parameters that contribute to the optimal alternative scenarios of the project realization in the uncertain environment. System dynamics model allows analyzing the interactions in the most complex mechanism of risk management process of the dry ports development and making proposals for the improvement of the effectiveness of the investments via an estimation of different risk management strategies. For the comparison and ranking of these alternatives in their order of preference to the investor, the proposed indicators of the efficiency of the investments, concerning the NPV, DPP, and coefficient of variation, can be used. Thus, rational investors, who averse to taking increased risks unless they are compensated by the commensurate increase in the expected utility of a risky prospect of dry port development, can be guided by the deduced marginal utility of investments. It is computed on the ground of the results from the system dynamics model. In conclusion, the outlined theoretical and practical implications for the management of risks, which are the key characteristics of public-private partnerships, can help analysts and planning managers in budget decision-making, substantially alleviating the effect from various risks and avoiding unnecessary cost overruns in dry port projects.