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The pathway of molybdenum cofactor biosynthesis has been studied in detail by using proteins from Mycobacterium species, which contain several homologs associated with the first steps of Moco biosynthesis. While all Mycobacteria species contain a MoeZR, only some strains have acquired an additional homolog, MoeBR, by horizontal gene transfer. The role of MoeBR and MoeZR was studied in detail for the interaction with the two MoaD-homologs involved in Moco biosynthesis, MoaD1 and MoaD2, in addition to the CysO protein involved in cysteine biosynthesis. We show that both proteins have a role in Moco biosynthesis, while only MoeZR, but not MoeBR, has an additional role in cysteine biosynthesis. MoeZR and MoeBR were able to complement an E. coli moeB mutant strain, but only in conjunction with the Mycobacterial MoaD1 or MoaD2 proteins. Both proteins were able to sulfurate MoaD1 and MoaD2 in vivo, while only MoeZR additionally transferred the sulfur to CysO. Our in vivo studies show that Mycobacteria have acquired several homologs to maintain Moco biosynthesis. MoeZR has a dual role in Moco- and cysteine biosynthesis and is involved in the sulfuration of MoaD and CysO, whereas MoeBR only has a role in Moco biosynthesis, which is not an essential function for Mycobacteria.
Subcellular compartmentation of primary carbon metabolism in mesophyll cells of Arabidopsis thaliana
(2011)
Metabolism in plant cells is highly compartmented, with many pathways involving reactions in more than one compartment. For example, during photosynthesis in leaf mesophyll cells, primary carbon fixation and starch synthesis take place in the chloroplast, whereas sucrose is synthesized in the cytosol and stored in the vacuole. These reactions are tightly regulated to keep a fine balance between the carbon pools of the different compartments and to fulfil the energy needs of the organelles. I applied a technique which fractionates the cells under non-aqueous conditions, whereby the metabolic state is frozen at the time of harvest and held in stasis throughout the fractionation procedure. With the combination of non-aqueous fractionation and mass spectrometry based metabolite measurements (LC-MS/MS, GC-MS) it was possible to investigate the intracellular distributions of the intermediates of photosynthetic carbon metabolism and its products in subsequent metabolic reactions. With the knowledge about the in vivo concentrations of these metabolites under steady state photosynthesis conditions it was possible to calculate the mass action ratio and change in Gibbs free energy in vivo for each reaction in the pathway, to determine which reactions are near equilibrium and which are far removed from equilibrium. The Km value and concentration of each enzyme were compared with the concentrations of its substrates in vivo to assess which reactions are substrate limited and so sensitive to changes in substrate concentration. Several intermediates of the Calvin-Benson cycle are substrates for other pathways, including dihydroxyacetone-phosphate (DHAP,sucrose synthesis), fructose 6-phosphate (Fru6P, starch synthesis), erythrose 4-phosphate (E4P,shikimate pathway) and ribose 5-phosphate (R5P, nucleotide synthesis). Several of the enzymes that metabolise these intermediates, and so lie at branch points in the pathway, are triose-phosphate isomerase (DHAP), transketolase (E4P, Fru6P), sedoheptulose-1,7-bisphosphate aldolase (E4P) and ribose-5-phosphate isomerase (R5P) are not saturated with their respective substrate as the metabolite concentration is lower than the respective Km value. In terms of metabolic control these are the steps that are most sensitive to changes in substrate availability, while the regulated irreversible reactions of fructose-1,6-bisphosphatase and sedoheptulose-1,7-bisphosphatase are relatively insensitive to changes in the concentrations of their substrates. In the pathway of sucrose synthesis it was shown that the concentration of the catalytic binding site of the cytosolic aldolase is lower than the substrate concentration of DHAP, and that the concentration of Suc6P is lower than the Km of sucrose-phosphatase for this substrate. Both the sucrose-phosphate synthase and sucrose-phosphatase reactions are far removed from equilibrium in vivo. In wild type A. thaliana Columbia-0 leaves, all of the ADPGlc was found to be localised in the chloroplasts. ADPglucose pyrophosphorylase is localised to the chloroplast and synthesises ADPGlc from ATP and Glc1P. This distribution argues strongly against the hypothesis proposed by Pozueta-Romero and colleagues that ADPGlc for starch synthesis is produced in the cytosol via ADP-mediated cleavage of sucrose by sucrose synthase. Based on this observation and other published data it was concluded that the generally accepted pathway of starch synthesis from ADPGlc produced by ADPglucose pyrophosphorylase in the chloroplasts is correct, and that the alternative pathway is untenable. Within the pathway of starch synthesis the concentration of ADPGlc was found to be well below the Km value of starch synthase for ADPGlc, indicating that the enzyme is substrate limited. A general finding in the comparison of the Calvin-Benson cycle with the synthesis pathways of sucrose and starch is that many enzymes in the Calvin Benson cycle have active binding site concentrations that are close to the metabolite concentrations, while for nearly all enzymes in the synthesis pathways the active binding site concentrations are much lower than the metabolite concentrations.
The human immunodeficiency virus (HIV) can be suppressed by highly active anti-retroviral therapy (HAART) in the majority of infected patients. Nevertheless, treatment interruptions inevitably result in viral rebounds from persistent, latently infected cells, necessitating lifelong treatment. Virological failure due to resistance development is a frequent event and the major threat to treatment success. Currently, it is recommended to change treatment after the confirmation of virological failure. However, at the moment virological failure is detected, drug resistant mutants already replicate in great numbers. They infect numerous cells, many of which will turn into latently infected cells. This pool of cells represents an archive of resistance, which has the potential of limiting future treatment options. The objective of this study was to design a treatment strategy for treatment-naive patients that decreases the likelihood of early treatment failure and preserves future treatment options. We propose to apply a single, pro-active treatment switch, following a period of treatment with an induction regimen. The main goal of the induction regimen is to decrease the abundance of randomly generated mutants that confer resistance to the maintenance regimen, thereby increasing subsequent treatment success. Treatment is switched before the overgrowth and archiving of mutant strains that carry resistance against the induction regimen and would limit its future re-use. In silico modelling shows that an optimal trade-off is achieved by switching treatment at & 80 days after the initiation of antiviral therapy. Evaluation of the proposed treatment strategy demonstrated significant improvements in terms of resistance archiving and virological response, as compared to conventional HAART. While continuous pro-active treatment alternation improved the clinical outcome in a randomized trial, our results indicate that a similar improvement might also be reached after a single pro-active treatment switch. The clinical validity of this finding, however, remains to be shown by a corresponding trial.
Zenralamerika
(2011)
Zentralamerika
(2011)
Which repair strategy does the language system deploy when it gets garden-pathed, and what can regressive eye movements in reading tell us about reanalysis strategies? Several influential eye-tracking studies on syntactic reanalysis (Frazier & Rayner, 1982; Meseguer, Carreiras, & Clifton, 2002; Mitchell, Shen, Green, & Hodgson, 2008) have addressed this question by examining scanpaths, i.e., sequential patterns of eye fixations. However, in the absence of a suitable method for analyzing scanpaths, these studies relied on simplified dependent measures that are arguably ambiguous and hard to interpret. We address the theoretical question of repair strategy by developing a new method that quantifies scanpath similarity. Our method reveals several distinct fixation strategies associated with reanalysis that went undetected in a previously published data set (Meseguer et al., 2002). One prevalent pattern suggests re-parsing of the sentence, a strategy that has been discussed in the literature (Frazier & Rayner, 1982); however, readers differed tremendously in how they orchestrated the various fixation strategies. Our results suggest that the human parsing system non-deterministically adopts different strategies when confronted with the disambiguating material in garden-path sentences.
The late mediaeval prose epic Loher und Muller constantly challenges a naive interpretation of what constitutes justice by confronting it over and over again with extreme cases. Generally speaking, 'poetic justice' succeeds in establishing coherence and propel the narrative forward. The constituents of societal norms and of laws are nevertheless relentlessly questioned - to such an extent that the narrative inquiry occasionally departs from the common understanding of justice. With its focus on morality, especially the presence or absence of faith, Loher und Muller is primarily concerned with the potential for conflict inherent in medieval constructions of legality and justice. In doing so, the epic opens up a narrative playground unencumbered by legal constraints as - after all - literature need not comply with medieval jurisdiction and its claims to the validity and scope of its writings. It is literature's privilege to facilitate unfamiliar ways of looking. The playful - but by no means inconsequential - casuistry played out in Loher und Maller gives rise to a 'probable' world tangential to historical reality and its understanding of justice and the law.
Work-related behavior and experience patterns of entrepreneurs compared to teachers and physicians
(2011)
Purpose This study examined the status of health-related behavior and experience patterns of entrepreneurs in comparison with teachers and physicians to identify specific health risks and resources.
Methods Entrepreneurs (n = 632), teachers (n = 5,196), and physicians (n = 549) were surveyed in a cross-sectional design. The questionnaire Work-related Behavior and Experience Patterns (AVEM) was used for all professions and, in addition, two scales (health prevention and self-confidence) from the Checklist for Entrepreneurs in the sample of entrepreneurs.
Results The largest proportion of the entrepreneurs (45%) presented with a healthy pattern (compared with 18.4% teachers and 18.3% physicians). Thirty-eight percent of entrepreneurs showed a risk pattern of overexertion and stress, followed by teachers (28.9%) and physicians (20.6%). Unambitious or burnout patterns were seen in only 9.3/8.2% of entrepreneurs, respectively, and 25.3/27.3% of teachers, and 39.6/21.5% of physicians. While the distribution of patterns in teachers and physicians differed significantly between genders, a gender difference was not found among entrepreneurs. Entrepreneurs with the risk pattern of overexertion scored significantly (P < 0.01) lower in self-confidence and health care than those with the healthy pattern.
Conclusions The development of a successful enterprise depends, in part, on the health of the entrepreneur. The large proportion of entrepreneurs with the healthy pattern irrespective of gender may support the notion that self-selection effects of healthy individuals in this special career might be important. At the same time, a large proportion was at risk for overexertion and might benefit from measures to cope with professional demands and stress and promote a healthy behavior pattern.