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21.
22.
Urs Duthaler Michael Weber Lorenz Hofer Carlos Chaccour Marta Maia Pie Müller Stephan Krhenbühl Felix Hammann 《PLoS pathogens》2021,17(3)
Mosquitoes are vectors of major diseases such as dengue fever and malaria. Mass drug administration of endectocides to humans and livestock is a promising complementary approach to current insecticide-based vector control measures. The aim of this study was to establish an insect model for pharmacokinetic and drug-drug interaction studies to develop sustainable endectocides for vector control. Female Aedes aegypti mosquitoes were fed with human blood containing either ivermectin alone or ivermectin in combination with ketoconazole, rifampicin, ritonavir, or piperonyl butoxide. Drug concentrations were quantified by LC-MS/MS at selected time points post-feeding. Primary pharmacokinetic parameters and extent of drug-drug interactions were calculated by pharmacometric modelling. Lastly, the drug effect of the treatments was examined. The mosquitoes could be dosed with a high precision (%CV: ≤13.4%) over a range of 0.01–1 μg/ml ivermectin without showing saturation (R2: 0.99). The kinetics of ivermectin were characterised by an initial lag phase of 18.5 h (CI90%: 17.0–19.8 h) followed by a slow zero-order elimination rate of 5.5 pg/h (CI90%: 5.1–5.9 pg/h). By contrast, ketoconazole, ritonavir, and piperonyl butoxide were immediately excreted following first order elimination, whereas rifampicin accumulated over days in the mosquitoes. Ritonavir increased the lag phase of ivermectin by 11.4 h (CI90%: 8.7–14.2 h) resulting in an increased exposure (+29%) and an enhanced mosquitocidal effect. In summary, this study shows that the pharmacokinetics of drugs can be investigated and modulated in an Ae. aegypti animal model. This may help in the development of novel vector-control interventions and further our understanding of toxicology in arthropods. 相似文献
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24.
Maia A. Rabaa Chonticha Klungthong In-Kyu Yoon Edward C. Holmes Piyawan Chinnawirotpisan Butsaya Thaisomboonsuk Anon Srikiatkhachorn Alan L. Rothman Darunee Tannitisupawong Jared Aldstadt Ananda Nisalak Mammen P. Mammen Robert V. Gibbons Timothy P. Endy Thanyalak Fansiri Thomas W. Scott Richard G. Jarman 《PLoS neglected tropical diseases》2013,7(1)
Revealing the patterns and determinants of the spread of dengue virus (DENV) at local scales is central to understanding the epidemiology and evolution of this major human pathogen. We performed a phylogenetic analysis of the envelope (E) genes of DENV-1, -2, -3, and -4 isolates (involving 97, 23, 5, and 74 newly collected sequences, respectively) sampled from school-based cohort and village-based cluster studies in Kamphaeng Phet, Thailand, between 2004 and 2007. With these data, we sought to describe the spatial and temporal patterns of DENV spread within a rural population where a future vaccine efficacy trial is planned. Our analysis revealed considerable genetic diversity within the study population, with multiple lineages within each serotype circulating for various lengths of time during the study period. These results suggest that DENV is frequently introduced into both semi-urban and rural areas in Kamphaeng Phet from other populations. In contrast, the persistence of viral lineages across sampling years was observed less frequently. Analysis of phylogenetic clustering indicated that DENV transmission was highly spatially and temporally focal, and that it occurred in homes rather than at school. Overall, the strength of temporal clustering suggests that seasonal bottlenecks in local DENV populations facilitate the invasion and establishment of viruses from outside of the study area, in turn reducing the extent of lineage persistence. 相似文献
25.
Xiangdan Wang Valerie Quarmby Carl Ng Anan Chuntharapai Theresa Shek Charles Eigenbrot Robert F. Kelley Steven Shia Krista M McCutcheon John Lowe Cecilia Leddy Kyle Coachman Gary Cain Felix Chu Isidro Hotzel Mauricio Maia Eric Wakshull Jihong Yang 《MABS-AUSTIN》2013,5(4):540-554
Pharmacokinetic (PK) and immunohistochemistry (IHC) assays are essential to the evaluation of the safety and efficacy of therapeutic monoclonal antibodies (mAb) during drug development. These methods require reagents with a high degree of specificity because low concentrations of therapeutic antibody need to be detected in samples containing high concentrations of endogenous human immunoglobulins. Current assay reagent generation practices are labor-intensive and time-consuming. Moreover, these practices are molecule-specific and so only support one assay for one program at a time. Here, we describe a strategy to generate a unique assay reagent, 10C4, that preferentially recognizes a panel of recombinant human mAbs over endogenous human immunoglobulins. This “panel-specific” feature enables the reagent to be used in PK and IHC assays for multiple structurally-related therapeutic mAbs. Characterization revealed that the 10C4 epitope is conformational, extensive and mainly composed of non-CDR residues. Most key contact residues were conserved among structurally-related therapeutic mAbs, but the combination of these residues exists at low prevalence in endogenous human immunoglobulins. Interestingly, an indirect contact residue on the heavy chain of the therapeutic appears to play a critical role in determining whether or not it can bind to 10C4, but has no affect on target binding. This may allow us to improve the binding of therapeutic mAbs to 10C4 for assay development in the future. Here, for the first time, we present a strategy to develop a panel-specific reagent that can expedite the development of multiple clinical assays for structurally-related therapeutic mAbs. 相似文献
26.
Central giant cell lesion of the jaws: study of CCND1 gene amplification and p16INK4a protein levels
Renato Luiz Maia Nogueira Mário Henrique Girão Faria Rafael Lima Verde Osterne Roberta Barroso Cavalcante Ronaldo Albuquerque Ribeiro Cassiano Francisco Weege Nonaka Silvia Helena Barem Rabenhorst 《Journal of molecular histology》2013,44(5):527-534
Central giant cell lesions (CGCLs) are uncommon benign jaw lesions with uncertain etiology and a variable clinical behavior. In neoplasms, alterations in molecules involved in the G1/S checkpoint are frequently found. Loss of p16INK4a expression or overexpression of cyclin D1 may stimulate cell proliferation. The purpose of this study was to analyze CCND1 gene amplification and the expression of p16INK4a in CGCLs. Structural analysis of the CCND1 was performed using chromogenic in situ hybridization. Immmunohistochemistry was used to identify p16INK4a protein levels. Statistical analysis correlated the two biomarkers with clinical behavior and between each other. Twenty-four lesions were included, being 11 aggressive and 13 non-aggressive. Moderate/high-level CCND1 amplification was found in 12 lesions. Also, immunoreactivity for p16INK4a was present in 12 cases, mainly in mononuclear cells. There was a significantly higher level of p16INK4a expression in mononuclear cells of non-aggressive lesions and lesions with moderate/high-level CCND1 amplification in mononuclear cells. It could be speculated that some CGCLs may develop as a true benign neoplasm. The higher expression of p16INK4a in non-aggressive lesions and in cases with moderate/high-level CCND1 amplification may show that these molecules have a role in CGCLs. 相似文献
27.
Leandro Nolé Eduardo Michael Maia Mincarone Flávia Lucena-Frédou Júlia Rodrigues Martins Gabriel Vinícius Felix Afonso Bárbara Teixeira Villarins Thierry Frédou Alex Souza Lira Arnaud Bertrand 《Zeitschrift fur angewandte Ichthyologie》2020,36(6):845-848
Length-weight relationship parameters were calculated for twelve mesopelagic fish species from the western Tropical Atlantic: Diretmus argenteus, Melamphaes polylepis, Bolinichthys distofax, Diaphus lucidus, Diaphus splendidus, Electrona risso, Hygophum taaningi, Taaningichthys bathyphilus, Melanolagus bericoides, Winteria telescopa, Diplophos taenia, Astronesthes similus. Data was collected off northeastern Brazil from April 9th to May 6th, 2017. Hauls were conducted during day and night at 47 stations by using a micronekton trawl (body mesh: 40 mm, cod-end mesh: 10 mm) from 10 to 1,113 m depth. The material was fixed in a 4% formalin solution for 1 month and then preserved in a 70% alcohol solution for proximally 6 months before processing for length (nearest 0.1 cm of standard length) and weight (nearest 0.01 g of total weight). A new maximum standard length for Winteria telescopa is also provided. 相似文献
28.
Chad M. Eliason Rafael Maia Juan L. Parra Matthew D. Shawkey 《Evolution; international journal of organic evolution》2020,74(2):447-458
Understanding how animal signals are produced is critical for understanding their evolution because complexity and modularity in the underlying morphology can affect evolutionary patterns. Hummingbird feathers show some of the brightest and most iridescent colors in nature. These are produced by optically complex stacks of hollow, platelet-shaped organelles called melanosomes. Neither how these morphologies produce colors nor their evolution has been systematically studied. We first used nanoscale morphological measurements and optical modeling to identify the physical basis of color production in 34 hummingbird species. We found that, in general, the melanosome stacks function as multilayer reflectors, with platelet thickness and air space size explaining variation in hue (color) and saturation (color purity). Additionally, light rays reflected from the outer keratin surface interact with those reflected by small, superficial melanosomes to cause secondary reflectance peaks, primarily in short (blue) wavelengths. We then compared variation of both the morphological components and the colors they produce. The outer keratin cortex evolves independently and is more variable than other morphological traits, possibly due to functional constraints on melanosome packing. Intriguingly, shorter wavelength colors evolve faster than longer wavelength colors, perhaps due to developmental processes that enables greater lability of the shapes of small melanosomes. Together, these data indicate that increased structural complexity of feather tissues is associated with greater variation in morphology and iridescent coloration. 相似文献
29.
Revaz Solomonia Nana Gogichaishvili Maia Nozadze Eka Lepsveridze David Dzneladze Tamar Kiguradze 《Cellular and molecular neurobiology》2013,33(1):119-127
Identification of compounds preventing the biochemical changes that underlie the epileptogenesis process is of great importance. We have previously shown that myo-Inositol (MI) daily treatment prevents certain biochemical changes that are triggered by kainic acid (KA)-induced status epilepticus (SE). The aim of the current work was to study the further influence of MI treatment on the biochemical changes of epileptogenesis and focus on changes in the hippocampus and neocortex of rats for the following GABA-A receptor subunits: α1, α4, γ2, and δ. After SE, one group of rats was treated with saline, while the second group was treated with MI. Control groups that were not treated by the convulsant received either saline or MI administration. 28–30 h after the experiment, a decrease in the amount of the α1 subunit was revealed in the hippocampus and MI had no significant influence on it. On the 28th day of the experiment, the amount of α1 was increased in both the KA? and KA + MI-treated groups. The α4 and γ2 subunits were strongly reduced in the hippocampus of KA-treated animals, but MI significantly halted this reduction. The effects of MI on α4 and γ2 subunit changes were significantly different between hippocampus and neocortex. On the twenty-eighth day after SE, a decrease in the amount of α1 was found in the neocortex, but MI treatment had no effect on it. The obtained results indicate that MI treatment interferes with some of the biochemical processes of epileptogenesis. 相似文献
30.
Rachel S. N. de Pinho Francisco P. da Silva‐Júnior João Paulo C. Bastos Werllen S. Maia Marco Túlio de Mello Veralice M. S. de Bruin 《Chronobiology international》2013,30(5):963-971
Truck drivers are more likely to suffer severe injury and death due to certain truck driving characteristics. Identifying and preventing factors associated with accidents in this population is important to minimize damage and improve road safety. Excessive daytime sleepiness is a major public health problem, leading to impaired cognitive function, reduced alertness, and increased risk of motor vehicle crashes. The aim of this cross‐sectional study was to determine the prevalence and predictors of hypersomnolence (defined as an Epworth Sleepiness Scale score greater than 10) among truck drivers. Three hundred male truck drivers were studied. Quality of sleep was assessed by the Pittsburgh Sleep Quality Index, and the association between demographic, clinical, and occupational data with excessive sleepiness was analyzed. The mean daily sleep duration was 5.6±1.3 h, and poor quality of sleep was found in 46.3% of the individuals. Hypersomnolence was found in 46% of the drivers and was associated with younger age, snoring, and working >10 h without rest. A positive correlation between hypersomnolence and previous accidents was detected (p=0.005). These results show that sleep deprivation and hypersomnolence are frequent among truck drivers. The treatment of sleep‐disordered breathing and the implementation of educational programs, particularly targeting younger drivers and promoting increased awareness of the deleterious effects of sleep loss and work overload, may help to reduce hypersomnolence and accidents among truck drivers. 相似文献