Interferon-γ impacts at multiple points during the progression of autoimmune diabetes

The role of interferon-γ in autoimmune diabetes was assessed by breeding a null mutation of the interferon-γ receptor α chain into the nonobese diabetic mouse strain, as well as into a simplified T cell receptor transgenic model of diabetes. In contrast to a previous report on abrogation of the interferon-γ gene, mutation of the gene encoding its receptor led to drastic effects on disease in both mouse lines. Nonobese diabetic mice showed a marked inhibition of insulitis—both the kinetics and penetrance—and no signs of diabetes; the transgenic model exhibited near-normal insulitis, but this never evolved into diabetes, either spontaneously or after experimental provocation. This failure could not be explained by perturbations in the ratio of T helper cell phenotypes; rather, it reflected a defect in antigen-presenting cells or in the islet β cell targets.

Rational design of a bacterial transcriptional cascade for amplifying gene expression capacity

Cascade regulatory circuits have been described that control numerous cell processes, and may provide models for the design of artificial circuits with novel properties. Here we describe the design of a transcriptional regulatory cascade to amplify the cell response to a given signal. We used the salicylate-responsive activators of Pseudomonas putida NahR of the naphthalene degradation plasmid NAH7 and XylS2, a mutant regulator of the TOL plasmid for catabolism of m-xylene and their respective cognate promoters Psal and Pm. Control of the expression of xylS2 with the nahR/Psal system permitted either their selective activation with specific effectors for each protein or the simultaneous activation of both of them with salicylate. When cells face the common effector of the two regulators, both the increase in XylS2 concentration and the stimulation of its activity act synergistically on the Pm promoter, amplifying the gene expression capacity by at least one order of magnitude with respect to the individual systems. By changing the hierarchy of regulators, we showed that the specific features of the downstream regulator were crucial for the amplification effect. Directed changes in the effector profile of the regulators allowed the extension of the amplifying system to other molecular signals.

Mismatch repair in Xenopus egg extracts: DNA strand breaks act as signals rather than excision points.

In Xenopus egg extracts, DNA strand breaks (nicks) located 3' or 5' to a mismatch cause an overall 3-fold stimulation of the repair of the mismatch in circular heteroduplex DNA molecules. The increase in mismatch repair is almost entirely due to an increase in repair of the nicked strand, which is stimulated 5-fold. Repair synthesis is centered to the mismatch site, decreases symmetrically on both sides, and its position is not significantly altered by the presence of the nick. Therefore, it appears that in the Xenopus germ cells, the mismatch repair system utilizes nicks as signals for the induction and direction of mismatch repair, but not as the start or end point for excision and resynthesis.

Rational interleukin 2 therapy for HIV positive individuals: daily low doses enhance immune function without toxicity.

When administered in high doses to HIV positive (HIV+) individuals, interleukin 2 (IL-2) causes extreme toxicity and markedly increases plasma HIV levels. Integration of the information from the structure-activity relationships of the IL-2 receptor interaction, the cellular distribution of the different classes of IL-2 receptors, and the pharmacokinetics of IL-2 provides for the rationale that low IL-2 doses should circumvent toxicity. Therefore, to identify a nontoxic, but effective and safe IL-2 treatment regimen that does not stimulate viral replication, doses of IL-2 from 62,500 to 250,000 IU/m2/day were administered subcutaneously for 6 months to 16 HIV+ individuals with 200-500 CD4+ T cells/mm3. IL-2 was already detectable in the plasma of most HIV+ individuals even before therapy. Peak plasma IL-2 levels were near saturating for high affinity IL-2 receptors in 10 individuals who received the maximum nontoxic dose, which ranged from 187,500 to 250,000 IU/m2/day. During the 6 months of treatment at this dose range, plasma levels of proinflammatory cytokines remained undetectable, and plasma HIV RNA levels did not change significantly. However, delayed type hypersensitivity responses to common recall antigens were markedly augmented, and there were IL-2 dose-dependent increases in circulating Natural Killer cells, eosinophils, monocytes, and CD4+ T cells. Expanded clinical trials of low dose IL-2 are now warranted, especially in combination with effective antivirals to test for the prevention of immunodeficiency and the emergence of drug-resistant mutants and for the eradication of residual virions.

The oxygen and carbon dioxide compensation points of C3 plants: possible role in regulating atmospheric oxygen.

The O2 and CO2 compensation points (O2 and CO2) of plants in a closed system depend on the ratio of CO2 and O2 concentrations in air and in the chloroplast and the specificities of ribulose bisphosphate carboxylase/oxygenase (Rubisco). The photosynthetic O2 is defined as the atmospheric O2 level, with a given CO2 level and temperature, at which net O2 exchange is zero. In experiments with C3 plants, the O2 with 220 ppm CO2 is 23% O2; O2 increases to 27% with 350 ppm CO2 and to 35% O2 with 700 ppm CO2. At O2 levels below the O2, CO2 uptake and reduction are accompanied by net O2 evolution. At O2 levels above the O2, net O2 uptake occurs with a reduced rate of CO2 fixation, more carbohydrates are oxidized by photorespiration to products of the C2 oxidative photosynthetic carbon cycle, and plants senesce prematurely. The CO2 increases from 50 ppm CO2 with 21% O2 to 220 ppm with 100% O2. At a low CO2/high O2 ratio that inhibits the carboxylase activity of Rubisco, much malate accumulates, which suggests that the oxygen-insensitive phosphoenolpyruvate carboxylase becomes a significant component of the lower CO2 fixation rate. Because of low global levels of CO2 and a Rubisco specificity that favors the carboxylase activity, relatively rapid changes in the atmospheric CO2 level should control the permissive O2 that could lead to slow changes in the immense O2 pool.

Principales puntos de convergencia entre las escuelas hegemónicas de teoría económica y sociológica desde la Ilustración escocesa hasta nuestros días

This research aims to show the main points of convergence between hegemonic schools of economic and sociological theory from the Scottish Enlightenment until today. To this end, on the one hand, we set three basic families of economic thought (the mainstream, the Austrian school and Marxism); and, on the other, we divide the history of sociology in five major generations (pioneers, founders, institutionalizers, compilers and constructivist). Subsequently, we set five historical periods as reference to our respective chapters and compare, within each of them, the theoretical contributions from these two areas. Thus, in the first chapter, called "the liberal parenthesis", we consider the relationship between the classical school of economics and the pioneers and founders of sociology. In the second, entitled "the social question" we analyze, on the one hand, the theoretical consistency of both the neoclassical school, as Austrian, with the principles defended by the institutionalizers of sociology; and, on the other, the influence of Karl Marx, as founder of sociology and classical economist, in the work of Soviet revolutionary theorists. In chapter three, called the "new industrial state", we demonstrate the theoretical proximity between both Keynesianism and the Austrian school of economics, with the doctrine defended by the generation of compilers in sociology. The fourth chapter, entitled "second industrial divide", refers to the similarities between the theoretical contributions of the monetarist Chicago school and the Austrian school with sociological constructivism. Finally, chapter five, the "global market", shows that the two hegemonic schools in economics, "integrated model", and sociology, "analytical sociology", are composed of the same three schools of thought: the rational choice, the neo-institutionalism and network approach. Thus, we can conclude that, if we look at their respective areas of influence, during this historical period occurs an manifest agreement between the theoretical contributions from the economic and sociological fields.

Key points for abolishing Female Genital Mutilation from the perspective of the men involved

Introduction: female Genital Mutilation is internationally considered an affront on human rights and an act of violence against women and young girls. Furthermore, it hierarchises and perpetuates inequality and denies the right to bodily and psychosocial integrity of women and young girls. Aims: to detect the key points for the abolition of Female Genital Mutilation as well as the necessary resources for its eradication. Material and Method: a qualitative methodology with an ethnonursing perspective, via semi-structured interviews, held both individually and in groups, in 21 men familiar with Female Genital Mutilation. Findings: through the voices of men familiar with this tradition, five key points are presented for its gradual eradication: sensitisation and awareness building, team action, abolition-promoting media, focusing action on rural areas and applying educational means before punitive ones. Conclusion and practical implications: awareness-raising via the combined efforts of families, communities and governments, together with the promotion of health education programmes in demonstrating the complications derived from this practice, play a vital part in eradicating Female Genital Mutilation.

Prediction of blackwood wood and pulp quality parameters using NIR-PLS-R spectral modelling : wavenumber ranges and smoothing points

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The Europe barometer points to stormy weather. CEPS Commentary, 15 February 2013

Against the current background of a sharp decline in public support for the EU and an emerging reinforced centre to manage the euro crisis, this commentary finds that the only way Europe’s leaders can hope to keep the fragile equilibrium afloat is to summon up the courage to go forward with concrete proposals for political union.