Constrained peptidomimetics reveal detailed geometric requirements of covalent prolyl oligopeptidase inhibitors.

Prolyl oligopeptidases cleave peptides on the carboxy side of internal proline residues and their inhibition has potential in the treatment of human brain disorders. Using our docking program fitted, we have designed a series of constrained covalent inhibitors, built from a series of bicyclic scaffolds, to study the optimal shape required for these small molecules. These structures bear nitrile functional groups that we predicted to covalently bind to the catalytic serine of the enzyme. Synthesis and biological assays using human brain-derived astrocytic cells and endothelial cells and human fibroblasts revealed that these compounds act as selective inhibitors of prolyl oligopeptidase activity compared to prolyl-dipeptidyl-aminopeptidase activity, are able to penetrate the cells and inhibit intracellular activities in intact living cells. This integrated computational and experimental study shed light on the binding mode of inhibitors in the enzyme active site and will guide the design of future drug-like molecules.

Mass and energy balance of the carbonization of babassu nutshell as affected by temperature

The objective of this work was to evaluate the carbonization yield of babassu nutshell as affected by final temperature, as well as the energy losses involved in the process. Three layers constituting the babassu nut, that is, the epicarp, mesocarp and endocarp, were used together. The material was carbonized, considering the following final temperatures: 450, 550, 650, 750, and 850ºC. The following were evaluated: energy and charcoal yields, pyroligneous liquid, non-condensable gases, and fixed carbon. The use of babassu nutshell can be highly feasible for charcoal production. The yield of charcoal from babassu nutshell carbonization was higher than that reported in the literature for Eucalyptus wood carbonization, considering the final temperature of 450ºC. Charcoal and energy yields decreased more sharply at lower temperatures, with a tendency to stabilize at higher temperatures. The energy yields obtained can be considered satisfactory, with losses between 45 and 52% (based on higher heating value) and between 43 and 49% (based on lower heating value) at temperatures ranging from 450 to 850ºC, respectively. Yields in fixed carbon and pyroligneous liquid are not affected by the final carbonization temperature.

c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation.

The activity of adult stem cells is essential to replenish mature cells constantly lost due to normal tissue turnover. By a poorly understood mechanism, stem cells are maintained through self-renewal while concomitantly producing differentiated progeny. Here, we provide genetic evidence for an unexpected function of the c-Myc protein in the homeostasis of hematopoietic stem cells (HSCs). Conditional elimination of c-Myc activity in the bone marrow (BM) results in severe cytopenia and accumulation of HSCs in situ. Mutant HSCs self-renew and accumulate due to their failure to initiate normal stem cell differentiation. Impaired differentiation of c-Myc-deficient HSCs is linked to their localization in the differentiation preventative BM niche environment, and correlates with up-regulation of N-cadherin and a number of adhesion receptors, suggesting that release of HSCs from the stem cell niche requires c-Myc activity. Accordingly, enforced c-Myc expression in HSCs represses N-cadherin and integrins leading to loss of self-renewal activity at the expense of differentiation. Endogenous c-Myc is differentially expressed and induced upon differentiation of long-term HSCs. Collectively, our data indicate that c-Myc controls the balance between stem cell self-renewal and differentiation, presumably by regulating the interaction between HSCs and their niche.

Entre psychanalyse et systémique : est-ce que mon coeur balance ?

Se référant à son propre parcours psychothérapeutique qui l'a conduit de la psychanalyse à la systémique, sans qu'il n'ait dû renier les apports de sa première formation, l'auteur réfléchit sur les connivences possibles entre ces deux approches, et plus largement sur les possibilités d'une pratique psychothérapeutique non uniréférencée. Selon lui, la diversité des méthodes psychothérapeutiques ne doit pas nécessairement conduire à un éclectisme hypertolérant, souvent confusionnant. Il importe pour le psychothérapeute de se savoir ici plutôt que là, tout en maintenant une ouverture aux autres pratiques grâce à l'intégration assimilative de certaines de leurs techniques.

The epithelial sodium channel and the control of sodium balance.

Studies aiming at the elucidation of the genetic basis of rare monogenic forms of hypertension have identified mutations in genes coding for the epithelial sodium channel ENaC, for the mineralocorticoid receptor, or for enzymes crucial for the synthesis of aldosterone. These genetic studies clearly demonstrate the importance of the regulation of Na(+) absorption in the aldosterone-sensitive distal nephron (ASDN), for the maintenance of the extracellular fluid volume and blood pressure. Recent studies aiming at a better understanding of the cellular and molecular basis of ENaC-mediated Na(+) absorption in the distal part of nephron, have essentially focused on the regulation ENaC activity and on the aldosterone-signaling cascade. ENaC is a constitutively open channel, and factors controlling the number of active channels at the cell surface are likely to have profound effects on Na(+) absorption in the ASDN, and in the amount of Na(+) that is excreted in the final urine. A number of membrane-bound proteases, kinases, have recently been identified that increase ENaC activity at the cell surface in heterologous expressions systems. Ubiquitylation is a general process that regulates the stability of a variety of target proteins that include ENaC. Recently, deubiquitylating enzymes have been shown to increase ENaC activity in heterologous expressions systems. These regulatory mechanisms are likely to be nephron specific, since in vivo studies indicate that the adaptation of the renal excretion of Na(+) in response to Na(+) diet occurs predominantly in the early part (the connecting tubule) of the ASDN. An important work is presently done to determine in vivo the physiological relevance of these cellular and molecular mechanisms in regulation of ENaC activity. The contribution of the protease-dependent ENaC regulation in mediating Na(+) absorption in the ASDN is still not clearly understood. The signaling pathway that involves ubiquitylation of ENaC does not seem to be absolutely required for the aldosterone-mediated control of ENaC. These in vivo physiological studies presently constitute a major challenge for our understanding of the regulation of ENaC to maintain the Na(+) balance.

Sodium and potassium balance depends on αENaC expression in connecting tubule.

Mutations in α, β, or γ subunits of the epithelial sodium channel (ENaC) can downregulate ENaC activity and cause a severe salt-losing syndrome with hyperkalemia and metabolic acidosis, designated pseudohypoaldosteronism type 1 in humans. In contrast, mice with selective inactivation of αENaC in the collecting duct (CD) maintain sodium and potassium balance, suggesting that the late distal convoluted tubule (DCT2) and/or the connecting tubule (CNT) participates in sodium homeostasis. To investigate the relative importance of ENaC-mediated sodium absorption in the CNT, we used Cre-lox technology to generate mice lacking αENaC in the aquaporin 2-expressing CNT and CD. Western blot analysis of microdissected cortical CD (CCD) and CNT revealed absence of αENaC in the CCD and weak αENaC expression in the CNT. These mice exhibited a significantly higher urinary sodium excretion, a lower urine osmolality, and an increased urine volume compared with control mice. Furthermore, serum sodium was lower and potassium levels were higher in the genetically modified mice. With dietary sodium restriction, these mice experienced significant weight loss, increased urinary sodium excretion, and hyperkalemia. Plasma aldosterone levels were significantly elevated under both standard and sodium-restricted diets. In summary, αENaC expression within the CNT/CD is crucial for sodium and potassium homeostasis and causes signs and symptoms of pseudohypoaldosteronism type 1 if missing.

The Effect of Tax Revenue Budgeting Errors on Fiscal Balance : Evidence from Swiss cantons

This study is an empirical analysis of the impact of direct tax revenue budgeting errors on fiscal deficits. Using panel data from 26 Swiss cantons between 1980 and 2002, we estimate a single equation model on the fiscal balance, as well as a simultaneous equation model on revenue and expenditure. We use new data on budgeted and actual tax revenue to show that underestimating tax revenue significantly reduces fiscal deficits. Furthermore, we show that this effect is channeled through decreased expenditure. The effects of over and underestimation turn out to be symmetric.

Dynamics of Appropriability - Finding a Balance between Efficiency and Strength in the Appropriability Regime

Building and sustaining competitive advantage through the creation of market imperfections is challenging in a constantly changing business environment - particularly since the sources of such advantages are increasingly knowledge-based. Facilitated by improved networks and communication, knowledge spills over to competitors more easily than before,thus creating an appropriability problem: the inability of an innovating firm to utilize its innovations commercially. Consequently, as the importance of intellectual assets increases, their protection also calls for new approaches. Companies have various means of protection at their disposal, and by taking advantage of them they can make intangibles more non-transferable and prevent, or at leastdelay, imitation of their most crucial intellectual assets. However, creating barriers against imitation has another side to it, and the transfer of knowledge in situations requiring knowledge sharing may be unintentionally obstructed. Theaim of this thesis is to increase understanding of how firms can balance knowledge protection and sharing so as to benefit most from their knowledge assets. Thus, knowledge protection is approached through an examination of the appropriability regime of a firm, i.e., the combination of available and effective means ofprotecting innovations, their profitability, and the increased rents due to R&D. A further aim is to provide a broader understanding of the formation and structure of the appropriability regime. The study consists of two parts. The first part introduces the research topic and the overall results of the study, and the second part consists of six complementary research publications covering various appropriability issues. The thesis contributes to the existing literature in several ways. Although there is a wide range of prior research on appropriability issues, a lot of it is restricted either to the study of individual appropriability mechanisms, or to comparing certain features of them. These approaches are combined, and the relevant theoretical concepts are clarified and developed. In addition, the thesis provides empirical evidence of the formation of the appropriability regime, which is consequently presented as an adaptive process. Thus, a framework is provided that better corresponds to the complex reality of the current business environment.

Un balance del tren de alta velocidad en Francia. Enseñanzas para el caso esapañol

La reivindicación del tren de alta velocidad por parte de un número amplio y creciente de ciudades en España, aconseja una reflexión sobre qué se puede realmente esperar de este servicio para estimular el tejido económico local. Nuestra referencia será el TGV de París a Lyon, el más antiguo en Europa, con sus posteriores ampliaciones al sur. De su estudio se puede deducir que su repercusión ha resultado muy modesta como agente dinamizador de la actividad económica local y regional. En el AVE se apunta efectivamente la misma situación, a tener por tanto muy en cuenta en el diseño del nuevo trazado y en las medidas de acompañamiento para rentabilizarlo.

Identifying the preferred subset of enzymatic profiles in nonlinear kinetic metabolic models via multiobjective global optimization and pareto filters

Optimization models in metabolic engineering and systems biology focus typically on optimizing a unique criterion, usually the synthesis rate of a metabolite of interest or the rate of growth. Connectivity and non-linear regulatory effects, however, make it necessary to consider multiple objectives in order to identify useful strategies that balance out different metabolic issues. This is a fundamental aspect, as optimization of maximum yield in a given condition may involve unrealistic values in other key processes. Due to the difficulties associated with detailed non-linear models, analysis using stoichiometric descriptions and linear optimization methods have become rather popular in systems biology. However, despite being useful, these approaches fail in capturing the intrinsic nonlinear nature of the underlying metabolic systems and the regulatory signals involved. Targeting more complex biological systems requires the application of global optimization methods to non-linear representations. In this work we address the multi-objective global optimization of metabolic networks that are described by a special class of models based on the power-law formalism: the generalized mass action (GMA) representation. Our goal is to develop global optimization methods capable of efficiently dealing with several biological criteria simultaneously. In order to overcome the numerical difficulties of dealing with multiple criteria in the optimization, we propose a heuristic approach based on the epsilon constraint method that reduces the computational burden of generating a set of Pareto optimal alternatives, each achieving a unique combination of objectives values. To facilitate the post-optimal analysis of these solutions and narrow down their number prior to being tested in the laboratory, we explore the use of Pareto filters that identify the preferred subset of enzymatic profiles. We demonstrate the usefulness of our approach by means of a case study that optimizes the ethanol production in the fermentation of Saccharomyces cerevisiae.