Synthesis and structure-activity relationship studies of novel anti-infectives for cross screening in tuberculosis and malaria disease models

Includes abstract.Includes bibliographical references (p. 205).Some 12-16 hours after the invasion of the human erythrocyte by the malaria parasite Plasmodium falciparum, there appear in the erythrocyte membrane ‘new permeability pathways’ which mediate an increased permeability of the infected cell to a range of low molecular weight solutes, including anions, cations, amino acids, polyols and nucleosides. There is evidence that the pathways have an important bi-functional role: firstly, that the new permeability pathways are required for the uptake of essential nutrients, and secondly, for the removal of metabolic wastes from the infected cells. Reported screening of 165 analogues of the new permeability pathways inhibitor furosemide, and the related compound bumetanide, for their effect on the malaria parasite-induced choline influx resulted in the identification of 13 effective compounds. Of these, 5 showed inhibitory activity in vitro against the parasite at a concentration of 10 μM. Analysis of the data on all the 165 compounds revealed some preliminary structure-activity relationships. Based on this preliminary structure-activity relationship data, compounds with specific diversity sites were designed for synthesis. Acetolactate synthase (also known as acetohydroxyacid synthase) is the enzyme which catalyzes the first step in the biosynthesis of branched chain amino acids, including valine, leucine and isoleucine. It is a target for several classes of herbicides including sulfonyl ureas and imidazolinones. The complete crystal structure of yeast acetolactate synthase has been shown to share 26% homology with the Mycobacterium tuberculosis enzyme. On this basis, docking studies were initiated, which resulted in the generation of a virtual library of biaryl-based sulfonyl ureas. Exploratory libraries of sulfonyl ureas, imidazolinones, sulfonylcyanoguanidines, acylthioureas and related compounds (phthalimides) with the potential of having antituberculosis activity, presumably targeting acetolactate synthase, were synthesized. Studying the general approaches to the synthesis of sulfonyl ureas, the general procedure is to either react a sulfonamide with an isocyanate in the presence of a weak base, or to react a sulfonyl isocyanate with a primary or secondary amine. Both approaches work well chemically. However, the lack of diverse commercially available (sulfonyl) isocyanates, as well as the instability of isocyanates in general are drawbacks. A method that generates a vast selection of (sulfonyl) isocyanates from a range of commercially available starting materials would, hence, be very useful. A new approach to the synthesis of sulfonyl ureas was envisaged. This strategy involves the use of 1,2,4-dithiazolidine-3,5-dione, which should provide an alternative route to the arylsulfonyl ureas

Strain Localisation, Fracturing and Hydrothermal Mineralisation: Numerical Models of the Mount Isa Copper Deposit, Australia

There is substantial need in mineral exploration to understand the structural controls on ore deposition for these types of deposits in order to predict the localities of new ones. Application of basic principles of rock mechanics, and numerical simulations of deformation and fluid flow processes provide fundamental insights to Proterozoic hydrothermal mineralization atMount Isa, Australia. The rheology of layered meta-sedimentary rocks, and the orientation and position of these layered rocks relative to major fault systems were the key controls on ore deposition...conferenc

Characterization of ore-forming systems - advances and challenges

Economically viable concentrations of mineral resources are uncommon among the predominantly silicate-dominated rocks in Earth's crust. Most ore deposits that were mined in the past or are currently being extracted were found at or near Earth's surface, often serendipitously. To meet the future demand for mineral resources, exploration success hinges on identifying targets at depth, which, on the one hand, requires advances in detection and interpretation techniques for geophysical and geochemical data. On the other hand, however, our knowledge of the chain of events that lead to ore deposit formation is limited. As geoscience embraces an integrated Earth systems approach, considering the geodynamic context of ore deposits can provide a step change in understanding why, how, when and where geological systems become ore-forming systems. Contributions to this volume address the future resources challenge by: (i) applying advanced microscale geochemical detection and characterization methods; (ii) introducing more rigorous 3D Earth models; (iii) exploring critical behaviour and coupled processes; (iv) evaluating the role of geodynamic and tectonic setting; and (v) applying 3D structural models to characterize specific ore-forming systems

Dietary moderately oxidized oil activates the Nrf2 signaling pathway in the liver of pigs

<p>Abstract</p> <p>Background</p> <p>Previous studies have shown that administration of oxidized oils increases gene expression and activities of various enzymes involved in xenobiotic metabolism and stress response in the liver of rats and guinea pigs. As these genes are controlled by nuclear factor erythroid-derived 2-like 2 (Nrf2), we investigated the hypothesis that feeding of oxidized fats causes an activation of that transcription factor in the liver which in turn activates the expression of antioxidant, cytoprotective and detoxifying genes.</p> <p>Methods</p> <p>Twenty four crossbred pigs were allocated to two groups of 12 pigs each and fed nutritionally adequate diets with either fresh rapeseed oil (fresh fat group) or oxidized rapeseed oil prepared by heating at a temperature of 175°C for 72 h (oxidized fat group).</p> <p>Results</p> <p>After 29 days of feeding, pigs of the oxidized fat group had a markedly increased nuclear concentration of the transcription factor Nrf2 and a higher activity of cellular superoxide dismutase and T4-UDP glucuronosyltransferase in liver than the fresh fat group (<it>P </it>< 0.05). In addition, transcript levels of antioxidant and phase II genes in liver, like superoxide dismutase 1, heme oxygenase 1, glutathione peroxidase 1, thioredoxin reductase 1, microsomal glutathione-S-transferase 1, UDP glucuronosyltransferase 1A1 and NAD(P)H:quinone oxidoreductase 1 in the liver were higher in the oxidized fat group than in the fresh fat group (<it>P </it>< 0.05). Moreover, pigs of the oxidized fat group had an increased hepatic nuclear concentration of the transcription factor NF-κB which is also an important transcription factor mediating cellular stress response.</p> <p>Conclusion</p> <p>The present study shows for the first time that administration of an oxidized fat activates the Nrf2 in the liver of pigs which likely reflects an adaptive mechanism to prevent cellular oxidative damage. Activation of the NF-κB pathway might also contribute to this effect of oxidized fat.</p

Up-regulation of endoplasmic reticulum stress induced genes of the unfolded protein response in the liver of periparturient dairy cows

BACKGROUND: In dairy cows, the periparturient phase is a stressful period, which is commonly associated with strong metabolic adaptations and the development of pathophysiologic conditions and disorders. Some of the symptoms occurring in the liver, such as the development of fatty liver, are similar to those observed under the condition of endoplasmic reticulum (ER) stress. Therefore, we hypothesized, that in the liver of dairy cows ER stress is induced during the periparturient phase, which in turn leads to an induction of the unfolded protein response (UPR). In order to investigate this hypothesis, we determined relative mRNA concentrations of 14 genes of the ER stress-induced UPR in liver biopsy samples of 13 dairy cows at 3 wk antepartum and 1, 5 and 14 wk postpartum. RESULTS: We found, that the mRNA concentrations of 13 out of the 14 genes involved in the UPR in the liver were significantly increased (1.9 to 4.0 fold) at 1 wk postpartum compared to 3 wk antepartum. From 1 wk postpartum to later lactation, mRNA concentrations of all the genes considered were declining. Moreover, at 1 wk postpartum, mRNA concentration of the spliced variant of XBP1 was increased in comparison to 3 wk antepartum, indicating that splicing of XBP1 – a hallmark of ER stress - was induced following the onset of lactation. CONCLUSION: The present study reveals, that ER stress might be induced during the periparturient phase in the liver of dairy cows. We assume that the ER stress-induced UPR might contribute to the pathophysiologic conditions commonly observed in the liver of periparturient cows, such as the development of fatty liver, ketosis or inflammation

Application of Photogrammetry in Geology: 3D Investigation of Rock Fracture Distributions

Geology as a science has an important visual component and the knowledge of any geologist is deeply linked to visual experience of rock outcrops, thin sections and analytical images. One of the shortcomings of most geological images such as maps, cross sections and outcrop photographs is that they are 2D, while processes geologists are interested in are typically occurring in 3D space. The 3D geometry of faults, fractures and joints is crucial to quantify geological processes related to fracture mechanics, such as hydrothermal mineralization and ground water flow, but also geotechnical problems such as rock mass stability. A number of studies have shown that some geological structures can be described with a scale invariant, fractal distribution. So far these observations on which these findings are based were restricted to one and two dimensions and has been difficult to obtain a full spatial geometric picture of fracture sets from rock outcrops, because much of the rock is not directly accessible. However, without taking into account the spatial distribution of geological structures the true geometry of joint patterns cannot be fully described and scaling laws, fractal or not, cannot be derived. We present images of joint patterns based on datasets acquired by digital photographs which are processed to three dimensional images using the photogrammetry software Siro3D. This technique allows to obtain a highly accurate 3D picture of the visible outcrop. The spatial pattern of joints in nature is investigated using the software SiroJoint. For the analysis of joint systems a large data set was collected from the Heavitree Quarzite at Ormiston Gorge, near Alice Springs. The Heavitree Quartzite is fragmented by a spectacularly regular three-dimensional joint pattern, which is repeated at different scales and therefore represents a perfect laboratory for our investigations (Hobbs 1993). Siro3D generates a spatially fully referenced 3D image from overlapping digital images, such that each pixel of the image is assigned spatial coordinates. The software SiroJoint routinely constructs planes from the intersection of the rock-face with the linear trace of planar features (Poropat 2001). It provides stereographic plots of structural elements and additionally measures joint persistence, area, and joint spacing. Our measurements allow to analyse geometrical scaling relationships of joint sets with high accuracy and will help explore the character of their 3D complexity. Several hundred joint planes were defined with SiroJoint in an Ormiston Gorge outcrop. Three different joint sets can be distinguished. Joint set one and two are characterized by steeply inclined planes with joint spacings ranging between 2 cm to 40 cm and 2 cm to 10m respectively. Both joints sets depict a power law distribution in joint spacing/frequency plots. The third set is defined by a subhorizontal orientation. It shows a very regular spacing in the meter scale and lacks an exponential distribution. We intend to use the results as a basis to compare observed fracture pattern with those generated by computational methods like Iterated Function Systems. This might help to understand how physical rock properties influence the spatial complexity of fracture systems and develop constitutive scaling relationships for certain rock types.conferenc

Prozeß-produzierte Daten in der Rechtssoziologie: Erfahrungen aus einer Untersuchung der Praxis des Insolvenzrechts

Die Tatsache, daß Entscheidungen und Prozesse im modernen Rechtssystem nur zu verstehen, zu erklären und zu kritisieren sind, wenn die "Welt der Akten" ausdrückliche Beachtung findet, ist bislang in der Rechtssoziologie nicht in ausreichender Weise berücksichtigt worden. Mit den konventionellen Beobachtungs- und Befragungsmethoden kann die Rechtssoziologie ihrem Gegenstand nicht gerecht werden. Aktenanalyse soll diese Methoden zwar nicht ersetzen, muß sie aber notwendigerweise ergänzen. Akten, Dokumente oder andere Aufzeichnungen bieten nicht nur Informationen über Abläufe, sondern auch über die jeweilige Struktur des Verfahrens. Um die Bedeutung der großangelegten Aktenanalyse im Rechtssystem der Bundesrepublik zu exemplifizieren, stellen die Verf. ein Insolvenzprojekt vor, das 1975-1977 am Max-Planck-Institut für ausländisches und internationales Privatrecht durchgeführt worden ist. Die entsprechenden Konkursakten enthalten nicht nur die Kennziffern des Insolvenzverfahrens, sondern sie bieten zudem zahlreiche Informationen über die Rechtsstruktur insgesamt, ihre Stellung zu wirtschaftlichen Abläufen, zu sozialen Abläufen und zur gesellschaftlichen Organisation von Recht und Wirtschaft. Der Beitrag beschreibt im einzelnen das methodische Vorgehen (schriftliche Befragungen und Aktenanalysen), wobei insbesondere die Probleme bei der Datenerhebung aus Akten präsentiert werden (Erstellen der Auswertungsbögen, Zugangsprobleme, Qualität der Daten, Verarbeitung der Daten). Die Verf. weisen abschließend nochmals auf die Bedeutung prozeß-produzierter Daten hin, auf deren Berücksichtigung und systematische Analyse gerade die Rechtssoziologie nicht verzichten kann. (JL

Treatment of lactating sows with clofibrate as a synthetic agonist of PPARalpha does not influence milk fat content and gains of litters

BACKGROUND: In rats, it has been observed that treatment with activators of peroxisome proliferator-activated receptor a (PPARalpha) disturbs metabolic adaptations during lactation, which in turn lead to a reduction of milk fat content and gains of litters during the suckling period. It has not yet been investigated whether agonists of PPARalpha are impairing milk production of lactating sows in a similar manner as in rats. Therefore, the present study aimed to investigate the effect of treatment with clofibrate, a strong synthetic agonist of PPARalpha, on milk composition and litter gains in lactating sows. RESULTS: Twenty lactating sows received either a basal diet (control group) or the same diet with supplementation of 2 g of clofibrate per kg of diet (clofibrate group). In the clofibrate group, mRNA concentrations of various PPARalpha target genes involved in fatty acid utilization in liver and skeletal muscle were moderately up-regulated. Fat and energy content of the milk and gains of litters during the suckling period were not different between the control group and the clofibrate group. CONCLUSIONS: It is shown that treatment with clofibrate induces only a moderate up-regulation of PPARalpha target genes in liver and muscle of lactating sows and in turn might have limited effect on whole body fatty acid utilization. This may be the reason why clofibrate treatment did not influence milk fat content and gains of litters during the suckling period. Thus, the present study indicates that activation of PPARalpha induced either by native agonists such as dietary polyunsaturated fatty acids or a by negative energy balance might be largely uncritical in lactating sows with respect to milk production and litter gains in lactating sows

Crustal surface-wave velocity structure of the east Albany-Fraser Orogen, Western Australia, from ambient noise recordings

Group and phase velocity maps in the period range 2-20 s for the Proterozoic east Albany-Fraser Orogen, Western Australia, are extracted from ambient seismic noise recorded with the 70-station ALFREX array. This two-year temporary installation provided detailed coverage across the orogen and the edge of the Neoarchean Yilgarn Craton, a region where no passive seismic studies of this scale have occurred to date. The surface wave velocities are rather fast overall (>3 km/s nearly everywhere), as expected for exposed Proterozoic basement rocks. No clear signature of the transition between Yilgarn Craton and Albany-Fraser Orogen is observed, but several strong anomalies corresponding to more local geological features were obtained. A prominent, NE-elongated high-velocity anomaly in the northern part of the array is coincident with a Bouguer gravity high caused by the upper crustal metamorphic rocks of the Fraser Zone. This feature disappears towards longer periods, which hints at an exclusively upper crustal origin for this anomaly. Further east, the limestones of the Cenozoic Eucla Basin are clearly imaged as a pronounced low-velocity zone at short periods, but the prevalence of low velocities to periods of ≥5 s implies that the uppermost basement in this area is likewise slow. At longer periods, slightly above-average surface wave velocities are imaged below the Eucla Basin.The Bouguer gravity anomaly map plotted in Fig. 2 is provided by Geoscience Australia (Bacchin et al. 2008; http://www.ga.gov.au/data-pubs/data -compilations/geophysics). We thank the various field crews who helped with data collection and the ANSIR instrument pool for the recorders and seismometers. C.V. Spaggiari and K. Gessner publish with the permission of the Director of the Geological Survey of Western Australia. Comments from two anonymous reviewers and the editor, Ana Ferreira, helped to considerably improve the manuscript

Greenstone burial–exhumation cycles at the late Archean transition to plate tectonics

Converging lines of evidence suggest that, during the late Archean, Earth completed its transition from a stagnant-lid to a plate tectonics regime,although how and when this transition occurred is debated. The geological record indicates that some form of subduction, a key component of plate tectonics—has operated since the Mesoarchean, even though the tectonic style and timescales of burial and exhumation cycles within ancient convergent margins are poorly constrained.Here, we present a Neoarchean pressure–temperature–time (P–T–t) path from supracrustal rocks of the transpressional Yilgarn orogen (Western Australia), which documents how sea-floor-altered rocks underwent deep burial then exhumation during shortening that was unrelated to the episode of burial. Archean subduction, even if generally short-lived, was capable of producing eclogites along converging lithosphere boundaries, although exhumation processes in those environments were likely less efficient than today, such that return of high-pressure rocks to the surface was rare