Modeling Miller, Neil A
Journal of aerosol medicine and pulmonary drug delivery
37, Številka:
1
Journal Article
Recenzirano
Modeling is coming to the fore as it is now widely accepted and indeed expected during drug discovery and development. Modeling integrates knowledge, increases understanding and provides the ability ...to predict an outcome either before it occurs or when it is not possible to measure. This makes modeling an attractive option for inhaled drugs as it is not possible to routinely measure what is occurring to the drug (pharmacokinetics) and what effect the drug is having (pharmacodynamics) at local microscopic sites of such a diverse and complex organ as the lung. Many pieces of information (data and knowledge) exist like the pieces of a jigsaw puzzle and modeling brings the pieces together in a scientific and mechanistically coherent manner to increase understanding of both the efficacy and safety of inhaled drugs.
The Human Cytochrome P450 (CYP) Allele Nomenclature Database, a critical resource for the pharmacogenetics and genomics communities, has transitioned to the Pharmacogene Variation (PharmVar) ...Consortium. In this report we provide a summary of the current database, provide an overview of the PharmVar consortium, and highlight the PharmVar database which will serve as the new home for pharmacogene nomenclature.
Climate change is posing severe challenges in Africa, where resilient crops are urgently needed to withstand drought periods and unreliable rainfall. Multi-purpose legume species, such as lablab ...(Lablab purpureus (L.) Sweet), have been under-utilized yet have the potential to overcome climate challenges. While lablab is native to Africa, there are few characterized varieties and it is under-utilized by smallholder farmers due to a lack of information and access to varieties. Knowledge is especially lacking on the performance of this crop by genotype, management, and environment. We conducted a two-year field study at two sites to evaluate 29 lablab cultivars under sole and maize intercrop management, with 14 cultivars selected for in-depth study. Cultivars were evaluated on vegetative biomass and grain yield production, with N fixation assessed for one site year. Biomass and grain production differed across environments and cultivars, with only biomass affected by intercropping. Average grain yield was substantially reduced to only 37 kg ha-1 in environments with maximum temperatures greater than 33°C, but biomass production yielded comparable amounts across high temperatures and in dry (<500 mm rainfall) environments. Tradeoffs were found between biomass and grain yield across high yielding cultivars, with the top three grain accessions averaging 612 kg ha-1 of grain and 1.97 Mg ha-1 biomass whereas the top three biomass accessions produced 327 kg ha-1 grain and 2.52 Mg ha-1 biomass across all environments. In a comparison of production and N fixation measurements, cultivars were identified which may have high performance in both. Suitability of lablab for grain and biomass production were visualized across Tanzania in a map comparing max temperature thresholds for grain and biomass against average regional livestock populations. This provides a way forward for identifying potential areas for lablab cultivation as a novel means to enhance fodder and pulse production with smallholder farmers.
We performed two experiments to investigate how monocular vision and a monocular generalized reduction in vision (MRV) impact driving performance during racing. A total of 75 visually normal students ...or professional racing drivers, were recruited for the two experiments. Driving performance was evaluated under three visual conditions: normal vision, simulated monocularity and simulated monocular reduction in vision. During the driving scenario, the drivers had to detect and react to the sudden intrusion of an opponent's racing car into their trajectory when entering a turn. Generalized Linear Mixed Models (GLMMs) and ANOVA were then used to explore how monocular vision and monocular reduction in vision affect drivers' performance (crash and reaction time) while confronting them with critical situations. The results show that drivers under monocular condition are from 2.1 (95% CI 1.11-4.11, p = .024) to 6.5 (95% CI 3.91-11.13; p = .0001) times more likely to collide with target vehicles compared with their baseline (binocular) condition, depending on the driving situation. Furthermore, there was an average increase in reaction time from 64 ms (p = .029) to 126 ms (p = .015) under monocular condition, depending on the critical driving situation configuration. This study objectively demonstrates that monocularity has a significant impact on driving performance and safety during car racing, whereas performance under monocular reduction in vision conditions is less affected.
Physiologically based pharmacokinetic modelling is well established in the pharmaceutical industry and is accepted by regulatory agencies for the prediction of drug–drug interactions. However, ...physiologically based pharmacokinetic modelling is valuable to address a much wider range of pharmaceutical applications, and new regulatory impact is expected as its full power is leveraged. As one example, physiologically based pharmacokinetic modelling is already routinely used during drug discovery for in-vitro to in-vivo translation and pharmacokinetic modelling in preclinical species, and this leads to the application of verified models for first-in-human pharmacokinetic predictions. A consistent cross-industry strategy in this application area would increase confidence in the approach and facilitate further learning. With this in mind, this article aims to enhance a previously published first-in-human physiologically based pharmacokinetic model-building strategy. Based on the experience of scientists from multiple companies participating in the GastroPlus™ User Group Steering Committee, new Absorption, Distribution, Metabolism and Excretion knowledge is integrated and decision trees proposed for each essential component of a first-in-human prediction. We have reviewed many relevant scientific publications to identify new findings and highlight gaps that need to be addressed. Finally, four industry case studies for more challenging compounds illustrate and highlight key components of the strategy.
We investigate a population of transiting planets that receive relatively modest stellar insolation, indicating equilibrium temperatures <1000 K, and for which the heating mechanism that inflates hot ...Jupiters does not appear to be significantly active. We use structural evolution models to infer the amount of heavy elements within each of these planets. There is a correlation between the stellar metallicity and the mass of heavy elements in its transiting planet(s). It appears that all giant planets possess a minimum of ~10-15 Earth masses of heavy elements, with planets around metal-rich stars having larger heavy-element masses. There is also an inverse relationship between the mass of the planet and the metal enrichment (Z pl/Z star), which appears to have little dependency on the metallicity of the star. Saturn- and Jupiter-like enrichments above solar composition are a hallmark of all the gas giants in the sample, even planets of several Jupiter masses. These relationships provide an important constraint on planet formation and suggest large amounts of heavy elements within planetary H/He envelopes. We suggest that the observed correlation can soon also be applied to inflated planets, such that the interior heavy-element abundance of these planets could be estimated, yielding better constraints on their interior energy sources. We point to future directions for planetary population synthesis models and suggest future correlations. This appears to be the first evidence that extrasolar giant planets, as a class, are enhanced in heavy elements.
Cyclic electron flow (CEF) around photosystem I is vital to balancing the photosynthetic energy budget of cyanobacteria and other photosynthetic organisms. The coupling of CEF to proton pumping has ...long been hypothesized to occur, providing proton motive force (PMF) for the synthesis of ATP with no net cost to NADPH. This is thought to occur largely through the activity of NDH-1 complexes, of which cyanobacteria have four with different activities. While a much work has been done to understand the steady-state PMF in both the light and dark, and fluorescent probes have been developed to observe these fluxes in vivo, little has been done to understand the kinetics of these fluxes, particularly with regard to NDH-1 complexes. To monitor the kinetics of proton pumping in Synechocystis sp. PCC 6803, the pH sensitive dye Acridine Orange was used alongside a suite of inhibitors in order to observe light-dependent proton pumping. The assay was demonstrated to measure photosynthetically driven proton pumping and used to measure the rates of proton pumping unimpeded by dark ΔpH. Here, the cyanobacterial NDH-1 complexes are shown to pump a sizable portion of proton flux when CEF-driven and LEF-driven proton pumping rates are observed and compared in mutants lacking some or all NDH-1 complexes. It is also demonstrated that PSII and LEF are responsible for the bulk of light induced proton pumping, though CEF and NDH-1 are capable of generating ~40% of the proton pumping rate when LEF is inactivated.
•Light-driven ΔpH formation across cyanobacterial thylakoids observed•Up to 40% of photosynthetic proton-pumping driven by cyclic electron flow•NDH-1 is the major contributor to proton-pumping by cyclic electron flow.
Processes that damage the optic nerve, including elevated intraocular pressure, trauma, ischemia, and compression, often cause visual loss for which there is no current treatment ....
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