Simulation of cellular irradiation with the CENBG microbeam line using GEANT4

Light-ion microbeams provide a unique opportunity to irradiate biological samples at the cellular level and to investigate radiobiological effects at low doses of high LET ionising radiation. Since 1998 a single-ion irradiation facility has been developed on the focused horizontal microbeam line of the CENBG 3.5 MV Van de Graaff accelerator. This setup delivers in air single protons and alpha particles of a few MeV onto cultured cells, with a spatial resolution of a few microns, allowing subcellular targeting. In this paper, we present results from the use of the GEANT4 toolkit to simulate cellular irradiation with the CENBG microbeam line, from the entrance to the microprobe up to the cellular medium.Comment: 6 pages, 8 figures, presented at the 2003 IEEE-NSS conference, Portland, OR, USA, October 20-24, 200

Tributação da energia : aspectos tributários da integração energética na América do Sul

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Direito, Curso de Pós-Graduação em Direito, 2017.O trabalho discorre sobre os óbices tributários à integração energética da América do Sul e propõe soluções no âmbito da legislação brasileira para superar esses problemas. A pesquisa tem por objetivos gerais analisar as diferentes modalidades de tributação da energia nos sistemas tributários selecionados da América do Sul e propor alterações legislativas no sistema tributário brasileiro que promovam a harmonização do mesmo com os demais sistemas tributários da região. São objetivos específicos do trabalho detectar as discrepâncias entre os sistemas tributários selecionados que constituem óbice à integração em matéria de energia; analisar peculiaridades do mercado de geração, transmissão e distribuição de energia que afetem o processo de harmonização tributária entre os Estados selecionados; indicar métodos de harmonização adequados às etapas e peculiaridades do mercado de geração e fornecimento de energia; analisar a aplicação dos critérios de destino e origem na tributação da energia de modo a equilibrar equidade e eficiência; propor alterações legislativas no sistema brasileiro de modo a garantir a neutralidade fiscal sobre a energia elétrica e o intercâmbio energético eficiente entre países da região. Como marco teórico, utiliza a literatura tributária em matéria de tributação do consumo, integração econômica regional e harmonização legislativa em matéria tributária. Conclui pela necessidade de unificação e centralização da tributação geral sobre o consumo no Brasil e pela manutenção, no caso da tributação de produtos de energia, do critério de destino como definidor de competência na tributação de operações internacionais.The dissertation discusses the tax obstacles to South American energy integration and proposes solutions under Brazilian legislation to overcome these problems. The general objectives of the research are to analyze the different models of energy taxation in the selected tax systems of South America and to propose legislative changes in the Brazilian tax system that could promote it’s the harmonization in relation to the other tax systems of the region. The specific objectives of the dissertation are to detect the discrepancies between the selected tax systems that are an obstacle to energy integration; analyze peculiarities of the generation, transmission and distribution market that affect the process of tax harmonization between the selected States; indicate appropriate methods of harmonization to the stages and peculiarities of the energy generation and supply market; check the application of destination and origin criteria in energy taxation in order to balance justice and efficiency; propose legislative changes in the Brazilian system in order to guarantee fiscal neutrality on energy and efficient energy exchange between countries of the region. As a theoretical framework, it uses the tax literature on taxation of consumption, regional economic integration and legislative harmonization in tax matters. It concludes by the need to unify and centralize the general taxation on consumption in Brazil and by maintaining, in the case of energy products taxation, the criterion of destination as a competence element in the taxation of international operations

Quantification of the Time Course of CYP3A Inhibition, Activation, and Induction Using a Population Pharmacokinetic Model of Microdosed Midazolam Continuous Infusion

Background Cytochrome P450 (CYP) 3A contributes to the metabolism of many approved drugs. CYP3A perpetrator drugs can profoundly alter the exposure of CYP3A substrates. However, effects of such drug-drug interactions are usually reported as maximum effects rather than studied as time-dependent processes. Identification of the time course of CYP3A modulation can provide insight into when significant changes to CYP3A activity occurs, help better design drug-drug interaction studies, and manage drug-drug interactions in clinical practice. Objective We aimed to quantify the time course and extent of the in vivo modulation of different CYP3A perpetrator drugs on hepatic CYP3A activity and distinguish different modulatory mechanisms by their time of onset, using pharmacologically inactive intravenous microgram doses of the CYP3A-specific substrate midazolam, as a marker of CYP3A activity. Methods Twenty-four healthy individuals received an intravenous midazolam bolus followed by a continuous infusion for 10 or 36 h. Individuals were randomized into four arms: within each arm, two individuals served as a placebo control and, 2 h after start of the midazolam infusion, four individuals received the CYP3A perpetrator drug: voriconazole (inhibitor, orally or intravenously), rifampicin (inducer, orally), or efavirenz (activator, orally). After midazolam bolus administration, blood samples were taken every hour (rifampicin arm) or every 15 min (remaining study arms) until the end of midazolam infusion. A total of 1858 concentrations were equally divided between midazolam and its metabolite, 1’-hydroxymidazolam. A nonlinear mixed-effects population pharmacokinetic model of both compounds was developed using NONMEM®. CYP3A activity modulation was quantified over time, as the relative change of midazolam clearance encountered by the perpetrator drug, compared to the corresponding clearance value in the placebo arm. Results Time course of CYP3A modulation and magnitude of maximum effect were identified for each perpetrator drug. While efavirenz CYP3A activation was relatively fast and short, reaching a maximum after approximately 2–3 h, the induction effect of rifampicin could only be observed after 22 h, with a maximum after approximately 28–30 h followed by a steep drop to almost baseline within 1–2 h. In contrast, the inhibitory impact of both oral and intravenous voriconazole was prolonged with a steady inhibition of CYP3A activity followed by a gradual increase in the inhibitory effect until the end of sampling at 8 h. Relative maximum clearance changes were +59.1%, +46.7%, −70.6%, and −61.1% for efavirenz, rifampicin, oral voriconazole, and intravenous voriconazole, respectively. Conclusions We could distinguish between different mechanisms of CYP3A modulation by the time of onset. Identification of the time at which clearance significantly changes, per perpetrator drug, can guide the design of an optimal sampling schedule for future drug-drug interaction studies. The impact of a short-term combination of different perpetrator drugs on the paradigm CYP3A substrate midazolam was characterized and can define combination intervals in which no relevant interaction is to be expected. Clinical Trial Registration The trial was registered at the European Union Drug Regulating Authorities for Clinical Trials (EudraCT-No. 2013-004869-14)

Simulation-Based Assessment of the Impact of Non-Adherence on Endoxifen Target Attainment in Different Tamoxifen Dosing Strategies

Tamoxifen is widely used in breast cancer treatment and minimum steady-state concentrations of its active metabolite endoxifen (CSS,min ENDX) above 5.97 ng/mL have been associated with favourable disease outcome. Yet, about 20% of patients do not reach target CSS,min ENDX applying conventional tamoxifen dosing. Moreover, 4–75% of patients are non-adherent, resulting in worse disease outcomes. Assuming complete adherence, we previously showed model-informed precision dosing (MIPD) to be superior to conventional and CYP2D6-guided dosing in minimising the proportion of patients with subtarget CSS,min ENDX. Given the high non-adherence rate in long-term tamoxifen therapy, this study investigated the impact of non-adherence on CSS,min ENDX target attainment in different dosing strategies. We show that MIPD allows to account for the expected level of non-adherence (here: up to 2 missed doses/week): increasing the MIPD target threshold from 5.97 ng/mL to 9 ng/mL (the lowest reported CSS,min ENDX in CYP2D6 normal metabolisers) as a safeguard resulted in the lowest interindividual variability and proportion of patients with subtarget CSS,min ENDX even in non-adherent patients. This is a significant improvement to conventional and CYP2D6-guided dosing. Adding a fixed increment to the originally selected dose is not recommended, since it inflates interindividual variability

Spin states of asteroids in the Eos collisional family

Eos family was created during a catastrophic impact about 1.3 Gyr ago. Rotation states of individual family members contain information about the history of the whole population. We aim to increase the number of asteroid shape models and rotation states within the Eos collision family, as well as to revise previously published shape models from the literature. Such results can be used to constrain theoretical collisional and evolution models of the family, or to estimate other physical parameters by a thermophysical modeling of the thermal infrared data. We use all available disk-integrated optical data (i.e., classical dense-in-time photometry obtained from public databases and through a large collaboration network as well as sparse-in-time individual measurements from a few sky surveys) as input for the convex inversion method, and derive 3D shape models of asteroids together with their rotation periods and orientations of rotation axes. We present updated shape models for 15 asteroids and new shape model determinations for 16 asteroids. Together with the already published models from the publicly available DAMIT database, we compiled a sample of 56 Eos family members with known shape models that we used in our analysis of physical properties within the family. Rotation states of asteroids smaller than ~20 km are heavily influenced by the YORP effect, whilst the large objects more or less retained their rotation state properties since the family creation. Moreover, we also present a shape model and bulk density of asteroid (423) Diotima, an interloper in the Eos family, based on the disk-resolved data obtained by the Near InfraRed Camera (Nirc2) mounted on the W.M. Keck II telescope.Comment: Accepted for publication in ICARUS Special Issue - Asteroids: Origin, Evolution & Characterizatio

High-throughput screening of tick-borne pathogens in Europe

Due to increased travel, climatic, and environmental changes, the incidence of tick-borne disease in both humans and animals is increasing throughout Europe. Therefore, extended surveillance tools are desirable. To accurately screen tick-borne pathogens (TBPs), a large scale epidemiological study was conducted on 7050 Ixodes ricinus nymphs collected from France, Denmark, and the Netherlands using a powerful new high-throughput approach. This advanced methodology permitted the simultaneous detection of 25 bacterial, and 12 parasitic species (including; Borrelia, Anaplasma, Ehrlichia, Rickettsia, Bartonella, Candidatus Neoehrlichia, Coxiella, Francisella, Babesia, and Theileria genus) across 94 samples. We successfully determined the prevalence of expected (Borrelia burgdorferi sensu lato, Anaplasma phagocytophilum, Rickettsia helvetica, Candidatus Neoehrlichia mikurensis, Babesia divergens, Babesia venatorum), unexpected (Borrelia miyamotoi), and rare (Bartonella henselae) pathogens in the three European countries. Moreover we detected Borrelia spielmanii, Borrelia miyamotoi, Babesia divergens, and Babesia venatorum for the first time in Danish ticks. This surveillance method represents a major improvement in epidemiological studies, able to facilitate comprehensive testing of TBPs, and which can also be customized to monitor emerging diseases

The field high-amplitude SX Phe variable BL Cam: results from a multisite photometric campaign. II. Evidence of a binary - possibly triple - system

Short-period high-amplitude pulsating stars of Population I ($\delta$ Sct stars) and II (SX Phe variables) exist in the lower part of the classical (Cepheid) instability strip. Most of them have very simple pulsational behaviours, only one or two radial modes being excited. Nevertheless, BL Cam is a unique object among them, being an extreme metal-deficient field high-amplitude SX Phe variable with a large number of frequencies. Based on a frequency analysis, a pulsational interpretation was previously given. aims heading (mandatory) We attempt to interpret the long-term behaviour of the residuals that were not taken into account in the previous Observed-Calculated (O-C) short-term analyses. methods heading (mandatory) An investigation of the O-C times has been carried out, using a data set based on the previous published times of light maxima, largely enriched by those obtained during an intensive multisite photometric campaign of BL Cam lasting several months. results heading (mandatory) In addition to a positive (161 $\pm$ 3) x 10$^{-9}$ yr$^{-1}$ secular relative increase in the main pulsation period of BL Cam, we detected in the O-C data short- (144.2 d) and long-term ($\sim$ 3400 d) variations, both incompatible with a scenario of stellar evolution. conclusions heading (mandatory) Interpreted as a light travel-time effect, the short-term O-C variation is indicative of a massive stellar component (0.46 to 1 M_{\sun}) with a short period orbit (144.2 d), within a distance of 0.7 AU from the primary. More observations are needed to confirm the long-term O-C variations: if they were also to be caused by a light travel-time effect, they could be interpreted in terms of a third component, in this case probably a brown dwarf star ($\geq$ 0.03 \ M_{\sun}), orbiting in $\sim$ 3400 d at a distance of 4.5 AU from the primary.Comment: 7 pages, 5 figures, accepted for publication in A&