Importance of influx and efflux systems and xenobiotic metabolizing enzymes in intratumoral disposition of anticancer agents.

In this review, intratumoral drug disposition will be integrated into the wide range of resistance mechanisms to anticancer agents with particular emphasis on targeted protein kinase inhibitors. Six rules will be established: 1. There is a high variability of extracellular/intracellular drug level ratios; 2. There are three main systems involved in intratumoral drug disposition that are composed of SLC, ABC and XME enzymes; 3. There is a synergistic interplay between these three systems; 4. In cancer subclones, there is a strong genomic instability that leads to a highly variable expression of SLC, ABC or XME enzymes; 5. Tumor-expressed metabolizing enzymes play a role in tumor-specific ADME and cell survival and 6. These three systems are involved in the appearance of resistance (transient event) or in the resistance itself. In addition, this article will investigate whether the overexpression of some ABC and XME systems in cancer cells is just a random consequence of DNA/chromosomal instability, hypo- or hypermethylation and microRNA deregulation, or a more organized modification induced by transposable elements. Experiments will also have to establish if these tumor-expressed enzymes participate in cell metabolism or in tumor-specific ADME or if they are only markers of clonal evolution and genomic deregulation. Eventually, the review will underline that the fate of anticancer agents in cancer cells should be more thoroughly investigated from drug discovery to clinical studies. Indeed, inhibition of tumor expressed metabolizing enzymes could strongly increase drug disposition, specifically in the target cells resulting in more efficient therapies.

On p-optimal proof systems and logics for PTIME

"Vegeu el resum a l'inici del document del fitxer adjunt"

Schistosomiasis vaccine development: progress and prospects

The undisputed, worldwide success of chemotherapy notwithstanding, schistosomiasis continues to defy control efforts in as much rapid reinfection demands repeated treatment, sometimes as often as once a year. There is thus a need for a complementary tool with effect for the longer term, notably a vaccine. International efforts in this direction have been ongoing for several decades but, until the recombinant DNA techniques were introduced, antigen production remained an unsurmountable bottleneck. Although animal experiments have been highly productive and are still much needed, they probably do not reflect the human situation adequately and real progress can not be expected until more is known about human immune responses to schistosome infection. It is well-known that irradiated cercariae consistently produce high levels of protection in experimental animals but, for various reasons, this proof of principle cannot be directly exploited. Research has instead been focussed on the identification and testing of specific schistosome antigens. This work has been quite successful and is already at the stage where clinical trials are called for. Preliminary results from coordinated in vitro laboratory and field epidemiological studies regarding the protective potential of several antigens support the initiation of such trials. A series of meetings, organized earlier this year in Cairo, Egypt, reviewed recent progress, selecteded suitable vaccine candidates and made firm recommendations for future action including pledging support for large-scale production according to good manufacturing practice (GMP) and Phase I trials. Scientists at the American Centers for Disease Control and Prevention (CDC) have drawn up a detailed research plan. The major financial support will come from USAID, Cairo, which has established a scientific advisory group of Egyptian scientists and representatives from current and previous international donors such as WHO, NIAID, the European Union and the Edna McConnell Clark Foundation.

Review of Department's Operations, Systems and Staffing Needs (Cromien Report)

Review of Department's Operations, Systems and Staffing Needs (Cromien Report). Provided by the Department of Education and Skills, Ireland.

Health at the time of Native-European contact in Southern Patagonia: First steps, results, and prospects

The objective of this paper is to present the first steps into the study of health in southern Patagonia during pre and post Native-European contact. Thus, our work has a double purpose. First, to discuss characteristics and relevance of human bone records of southern Patagonia, in order to study health in a population context. Second, to show some new lines of information, which include paleoparasitology, nutritional paleopathologies, and the study of lifestyles from human remains. In this context, we have started working on the first Spanish settlement "Nombre de Jesus", founded in 1584, and with historical documentation of "La Candelaria" Mission in Rio Grande (1896-1931).

Modelling and Prospects for Audience Measurement of Outdoor Advertising using GPS Devices

The paper describes how to integrate audience measurement and site visibility as the main research approaches in outdoor advertising research in a single concept. Details are portrayed on how GPS is used on a large scale in Switzerland for mobility analysis and audience measurement. Furthermore, the development of a software solution is introduced that allows the integration of all mobility data and poster location information. Finally a model and its results is presented for the calculation of coverage of individual poster campaigns and for the calculation of the number of contacts generated by each billboard.

Relationship of mating systems and metabolic rate with cycle length of spermatogenesis and sperm production rate in shrews

SUMMARY : The shrews are among the most ancient of living eutherian mammals. They represent an interesting comparative model because of their extreme divergent species. The two shrew subfamilies, Soricinae and Crocidurinae are characterized by fundamental differences concerning their metabolic rates, litter size, period of gestation and different mating pattern. In this study we established and compared the sperm characteristics in four species of different genera of shrews (Sorex araneus, Neomys fodiens, Crocidura russula and Suncus murinus) in the context of the sperm competition hypothesis. The sperm competition concerns the competition between ejaculates of different males for fertilization of ova of a female within a single estrus period. As expected, a greater relative testis size (indicating the importance of polyandry) was associated with a higher number of cauda epididymal spermatozoa, higher level of circulating testosterone and a higher percentage of progressive sperm motility. In addition, we investigated if the basal metabolic rate (BMR) and relative testis size (RTS) may be correlated with the cycle length of spermatogenesis. In this purpose, we determined and compared the cycle length of spermatogenesis in six species of shrews belonging to two subfamilies: Soiricinae (Sorex araneus, Sorex coronatus, Sorex minutus, Neomys fodiens) and Crocidurinae (Crocidura russula, Sunctes murinus). Our results indicate that sperm competition and metabolic rate may act independently or together reducing cycle length of spermatogenesis and thus increase sperm production. We finally investigated this correlation across 32 mammalian species. After testing the data for phylogenetic independence, our results showed that BMR explained only 21 % of the variation, while the RTS explained 44% of the variation of the cycle length of spermatogenesis. The level of the sperm competition, indicated by RTS, is thus to our knowledge the most important factor influencing the speed of spermatogenesis in mammals. RESUME : Les musaraignes sont parmi les plus anciens mammifères vivants. Grâce à leurs extrêmes divergences, ils sont souvent utilisés comme modèles dans des études comparatives. Les deux sous-familles Soricinae et Crocidurinae sont caractérisées par des différences fondamentales, notamment en termes d'intensité du métabolisme, des stratégies de reproduction et du comportement social. Dans la première partie de cette étude, nous avons établi et comparé certaines "caractéristiques des spermatozoïdes chez quatre espèces de musaraignes appartenant à des genres différents (Sorex araneus, Neomys fodiens, Crocidura russula et Suncus murinus). Les résultats ont été interprétés dans le contexte de la théorie de la compétition spermatique, c'est-à-dire la compétition entre le sperme de deux ou plusieurs mâles pour féconder un maximum d'ovules de la même femelle. Cette compétition spermatique peut amener à certaines adaptations biologiques afin de produire plus de sperme. Comme attendu, une grande taille relative des testicules est associée à un nombre élevé de spermatozoïdes, dont la majorité présente une mobilité progressive. Un taux élévé de testostérone a également été observé. De plus, nous avons étudié l'influence du métabolisme basal ainsi que l'intensité de la compétition spermatique sur la durée du cycle de la spermatogenèse. Dans ce but, nous avons déterminé et comparé les durées de la spermatogenèse chez six espèces de musaraignes appartenant à deux sous-familles : Soricinae (Sorex araneus, Sorex coronatus, Sorex minutus, Neomys fodiens) et Crocidurinae (Crocidura russula, Suncus murinus). Les résultats obtenus indiquent que ces deux facteurs (l'intensité du métabolisme basal et de la compétition spermatique) agissent d'une manière dépendante ou indépendante dans le même sens. La conséquence de ces actions est une diminution de la durée de la spermatogenèse entraînant une augmentation de la production de spermatozoïdes. Nous avons finalement étudié ce phénomène dans l'ensemble des mammifères. Après avoir testé l'indépendance phylogénétique, nos résultats montrent que l'intensité de la compétition spermatique indiquée par le RTS est mieux corrélée avec la régulation de la durée de la spermatogenèse qu'avec l'intensité du métabolisme.

The investigation of deaths in custody: a qualitative analysis of problems and prospects.

The right to be treated humanely when detained is universally recognized. Deficiencies in detention conditions and violence, however, subvert this right. When this occurs, proper medico-legal investigations are critical irrespective of the nature of death. Unfortunately, the very context of custody raises serious concerns over the effectiveness and fairness of medico-legal examinations. The aim of this manuscript is to identify and discuss the practical and ethical difficulties encountered in the medico-legal investigation following deaths in custody. Data for this manuscript come from a larger project on Death in Custody that examined the causes of deaths in custody and the conditions under which these deaths should be investigated and prevented. A total of 33 stakeholders from forensic medicine, law, prison administration or national human rights administration were interviewed. Data obtained were analyzed qualitatively. Forensic experts are an essential part of the criminal justice process as they offer evidence for subsequent indictment and eventual punishment of perpetrators. Their independence when investigating a death in custody was deemed critical and lack thereof, problematic. When experts were not independent, concerns arose in relation to conflicts of interest, biased perspectives, and low-quality forensic reports. The solutions to ensure independent forensic investigations of deaths in custody must be structural and simple: setting binding standards of practice rather than detailed procedures and relying on preexisting national practices as opposed to encouraging new practices that are unattainable for countries with limited resources.

On the origins of electoral systems and political parties. The role of elections in multi-member districts

The old, understudied electoral system composed of multi-member districts, open ballot and plurality rule is presented as the most remote scene of the origin of both political parties and new electoral systems. A survey of the uses of this set of electoral rules in different parts of the world during remote and recent periods shows its wide spread. A model of voting by this electoral system demonstrates that, while it can produce varied and pluralistic representation, it also provides incentives to form factional or partisan candidacies. Famous negative reactions to the emergence of factions and political parties during the 18th and 19th centuries are reinterpreted in this context. Many electoral rules and procedures invented since the second half of the 19th century, including the Australian ballot, single-member districts, limited and cumulative ballots, and proportional representation rules, derived from the search to reduce the effects of the originating multi-member district system in favor of a single party sweep. The general relations between political parties and electoral systems are restated to account for the foundational stage here discussed.

Ecological assembly rules in plant communities--approaches, patterns and prospects.

Understanding how communities of living organisms assemble has been a central question in ecology since the early days of the discipline. Disentangling the different processes involved in community assembly is not only interesting in itself but also crucial for an understanding of how communities will behave under future environmental scenarios. The traditional concept of assembly rules reflects the notion that species do not co-occur randomly but are restricted in their co-occurrence by interspecific competition. This concept can be redefined in a more general framework where the co-occurrence of species is a product of chance, historical patterns of speciation and migration, dispersal, abiotic environmental factors, and biotic interactions, with none of these processes being mutually exclusive. Here we present a survey and meta-analyses of 59 papers that compare observed patterns in plant communities with null models simulating random patterns of species assembly. According to the type of data under study and the different methods that are applied to detect community assembly, we distinguish four main types of approach in the published literature: species co-occurrence, niche limitation, guild proportionality and limiting similarity. Results from our meta-analyses suggest that non-random co-occurrence of plant species is not a widespread phenomenon. However, whether this finding reflects the individualistic nature of plant communities or is caused by methodological shortcomings associated with the studies considered cannot be discerned from the available metadata. We advocate that more thorough surveys be conducted using a set of standardized methods to test for the existence of assembly rules in data sets spanning larger biological and geographical scales than have been considered until now. We underpin this general advice with guidelines that should be considered in future assembly rules research. This will enable us to draw more accurate and general conclusions about the non-random aspect of assembly in plant communities.

Short and long-term effects of tillage systems and nutrient sources on soil physical properties of a Southern Brazilian Hapludox

Soil tillage promotes changes in soil structure. The magnitude of the changes varies with the nature of the soil, tillage system and soil water content and decreases over time after tillage. The objective of this study was to evaluate short-term (one year period) and long-term (nine year period) effects of soil tillage and nutrient sources on some physical properties of a very clayey Hapludox. Five tillage systems were evaluated: no-till (NT), chisel plow + one secondary disking (CP), primary + two (secondary) diskings (CT), CT with burning of crop residues (CTb), and CT with removal of crop residues from the field (CTr), in combination with five nutrient sources: control without nutrient application (C); mineral fertilizers, according to technical recommendations for each crop (MF); 5 Mg ha-1 yr-1 of poultry litter (wetmatter) (PL); 60 m³ ha-1 yr-1 of cattle slurry (CS) and; 40 m³ ha-1 yr-1 of swine slurry (SS). Bulk density (BD), total porosity (TP), and parameters related to the water retention curve (macroporosity, mesoporosity and microporosity) were determined after nine years and at five sampling dates during the tenth year of the experiment. Soil physical properties were tillage and time-dependent. Tilled treatments increased total porosity and macroporosity, and reduced bulk density in the surface layer (0.00-0.05 m), but this effect decreased over time after tillage operations due to natural soil reconsolidation, since no external stress was applied in this period. Changes in pore size distribution were more pronounced in larger and medium pore diameter classes. The bulk density was greatest in intermediate layers in all tillage treatments (0.05-0.10 and 0.12-0.17 m) and decreased down to the deepest layer (0.27-0.32 m), indicating a more compacted layer around 0.05-0.20 m. Nutrient sources did not significantly affect soil physical and hydraulic properties studied.

Aggregate stability as affected by short and long-term tillage systems and nutrient sources of a hapludox in southern Brazil

The ability of a soil to keep its structure under the erosive action of water is usually high in natural conditions and decreases under frequent and intensive cultivation. The effect of five tillage systems (NT = no-till; CP = chisel plowing and one secondary disking; CT = primary and two secondary distings; CTb = CT with crop residue burning; and CTr = CT with removal of crop residues from the field), combined with five nutrient sources (C = control, no nutrient application; MF = mineral fertilizers according to technical recommendations for each crop; PL = 5 Mg ha-1 y-1 fresh matter of poultry litter; CM = 60 m³ ha-1 y-1 slurry cattle manure; and SM = 40 m³ ha-1 y-1 slurry swine manure) on wet-aggregate stability was determined after nine years (four sampled soil layers) and on five sampling dates in the 10th year (two sampled soil layers) of the experiment. The size distribution of the air-dried aggregates was strongly affected by soil bulk density, and greater values of geometric mean diameter (GMD AD) found in some soil tillage or layer may be partly due to the higher compaction degree. After nine years, the GMD AD on the surface was greater in NT and CP compared to conventional tillage systems (CT, CTb and CTr), due to the higher organic matter content, as well as less soil mobilization. Aggregate stability in water, on the other hand, was affected by the low variation in previous gravimetric moisture of aggregates, which contributed to a high coefficient of variation of this attribute. The geometric mean diameter of water-stable aggregates (GMD WS) was highest in the 0.00-0.05 m layer in the NT system, in the layers 0.05-0.10 and 0.12-0.17 m in the CT, and values were intermediate in CP. The stability index (SI) in the surface layers was greater in treatments where crop residues were kept in the field (NT, CP and CT), which is associated with soil organic matter content. No differences were found in the layer 0.27-0.32 m. The effect of nutrient sources on GMD AD and GMD WS was small and did not affect SI.

Phosphorus and root distribution and corn growth as related to long-term tillage systems and fertilizer placement

Soil and fertilizer management during cultivation can affect crop productivity and profitability. Long-term experiments are therefore necessary to determine the dynamics of nutrient and root distribution as related to soil profile, as well as the effects on nutrient uptake and crop growth. An 18-year experiment was conducted at the Federal University of Rio Grande do Sul State (UFRGS), in Eldorado do Sul, Brazil, on Rhodic Paleudult soil. Black oat and vetch were planted in the winter and corn in the summer. The soil management methods were conventional, involving no-tillage and strip tillage techniques and broadcast, row-and strip-applied fertilizer placement (triple superphosphate). Available P (Mehlich-1) and root distribution were determined in soil monoliths during the corn grain filling period. Corn shoot dry matter production and P accumulation during the 2006/2007 growing season were determined and the efficiency of P utilization calculated. Regardless of the degree of soil mobilization, P and roots were accumulated in the fertilized zone with time, mainly in the surface layer (0-10 cm). Root distribution followed P distribution for all tillage systems and fertilizer treatments. Under no-tillage, independent of the fertilizer placement, the corn plants developed more roots than in the other tillage systems. Although soil tillage systems and fertilizer treatments affected P and root distribution throughout the soil profile, as well as P absorption and corn growth, the efficiency of P utilization was not affected.

Labile and stable fractions of soil organic matter under management systems and native cerrado

Soil organic matter can be analyzed on the basis of the different fractions. Changes in the levels of organic matter, caused by land use, can be better understood by alterations in the different compartments. The aim of this study was to evaluate the effect of different management systems on the labile and stable organic matter of a dystrophic Red Latosol (Oxisol). The following properties were determined: total organic C and total N (TOC and TN), particulate organic C and particulate N (POC and PN), organic C and N mineral-associated (MOC and NM) and particulate organic C associated with aggregate classes (POCA). Eight treatments were used: seven with soil management systems and one with native Cerrado as a reference. The experiment was designed to study the dynamics of systems of tillage and crop rotation, alternating in time and space. The experimental design was a randomized block design with three replications. The soil samples were collected from five depths: 0-5, 5-10, 10-20, 20-30 and 30-40 cm. Changes in organic C by land use occurred mainly in the fraction of particulate organic matter (> 53 mm). Proper management of grazing promoted increased levels of particulate organic matter by association with larger aggregates (2-8 mm), demonstrating the importance of the formation of this aggregate class for C protection in pasture.