The 2010 Deepwater Horizon spill remains the largest catastrophic release of oil and gas into the deep sea. The irrupted oil and gas substantially impact a marine ecosystem, cause human injury, and ...have high societal opinions. Therefore, understanding the transport and dispersion of subsurface hydrocarbon provides an imperative substratum for the practical assessment and response of marine oil spill accidents. In this review, we summarize the major advances since the Deepwater Horizon accident, with emphasis on the observation and modeling of the droplet and the formation and dynamics of the plume. Additional complexity including more than the investigation of gas-saturated oil at high-pressure and the effect of Earth’s rotation on near field plume is also outlined. We end with a few outlooks on key priorities for more precisely estimations on future oil spills.
Abstract Studies with laboratory animals have demonstrated fatal neurotoxicity that is associated with administration of artemether (AM) and arteether (AE) intramuscularly or artelinic acid (AL) ...orally. Toxicokinetic studies showed oil-soluble artemisinins form a depot at the intramuscular injection sites, which is associated with fascia inflammation in muscles. Oral administration of AL induces a gastrointestinal toxicity that is linked with delayed gastric emptying. These effects suggest that the exposure time of artemisinins was extended due to drug accumulation in blood, and this in turn resulted in neurotoxicity. In the present report, the drug exposure time with a neurotoxic outcome (neurotoxic exposure time) was evaluated as a predictor of neurotoxicity in vivo . The neurotoxic exposure time represents a total time spent above a lowest observed neurotoxic effect levels (LONEL) in plasma. The dose of AE required to induce minimal neurotoxicity requires a 2–3 fold longer exposure time in rhesus monkeys (179.5 h) than in rats (67.1 h) and dogs (103.7 h) by using a daily dose of 6–12.5 mg/kg for 7–28 days, indicating that the safe dosing duration in monkeys should be longer than 7 days under the exposure. The neurotoxic exposure time of artemisinins could be longer in humans as the comparison of monkeys to humans is likely more relevant than from rodents or dogs. Oral AL required much longer exposure times (8-fold) than intramuscular AE to induce neurotoxicity, suggesting that water-soluble artemisinins appear to be much safer than oil-soluble artemisinins. Due to lower doses (2–4 mg/kg) used with current artemisinins and the more rare use of AE in treating humans the exposure time is much shorter in humans. Therefore, the current regimen of 3–5 days dosing duration should be quite safe. These findings support a recently published WHO guide for malaria treatment with artemisinin regimens, such as artemisinin-based combination therapies and injectable artesunate, to avoid neurotoxicity.
The efficacy of the 8-aminoquinoline (8AQ) drug primaquine (PQ) has been historically linked to CYP-mediated metabolism. Although to date no clear evidence exists in the literature that unambiguously ...assigns the metabolic pathway or specific metabolites necessary for activity, recent literature suggests a role for CYP 2D6 in the generation of redox active metabolites.
In the present study, the specific CYP 2D6 inhibitor paroxetine was used to assess its effects on the production of specific phenolic metabolites thought to be involved in PQ efficacy. Further, PQ causal prophylactic (developing liver stage) efficacy against Plasmodium berghei in CYP 2D knockout mice was assessed in comparison with a normal C57 background and with humanized CYP 2D6 mice to determine the direct effects of CYP 2D6 metabolism on PQ activity.
PQ exhibited no activity at 20 or 40 mg/kg in CYP 2D knockout mice, compared to 5/5 cures in normal mice at 20 mg/kg. The activity against developing liver stages was partially restored in humanized CYP 2D6 mice.
These results unambiguously demonstrate that metabolism of PQ by CYP 2D6 is essential for anti-malarial causal prophylaxis efficacy.
The cellulose of the plant cell wall indirectly affects the cell shape and straw stiffness of the plant. Here, the novel brittleness mutant
(
) of the maize inbred line RP125 was characterized. We ...found that the mutant displayed brittleness of the stalk and even the whole plant, and that the brittleness phenotype existed during the whole growth period from germination to senescence. The compressive strength was reduced, the cell wall was thinner, and the cellulose content was decreased compared to that of the wild type. Genetic analysis and map-based cloning indicated that
was controlled by a single recessive nuclear gene and that it was located in a 90.2-Kb region on chromosome 3 that covers three open reading frames (ORFs). Sequence analysis revealed a single non-synonymous missense mutation, T-to-A, in the last exon of
(B73: version 4, named
) that caused the 951th amino acid to go from leucine to histidine.
encodes a cellulose synthase catalytic subunit (CesA), which is involved with cellulose synthesis. We found that
was constitutively expressed in all tissues of the germinating stage and silking stage, and highly expressed in the leaf, auricula, and root of the silking stage and the 2-cm root and bud of the germinating stage. We found that
mainly localized to the Golgi apparatus, suggesting that the protein might move to the plasma membrane with the aid of Golgi in maize. According to RNA-seq data,
had more downregulated genes than upregulated genes, and many of the downregulated genes were enzymes and transcription factors related to cellulose, hemicellulose, and lignin biosynthesis of the secondary cell wall. The other differentially expressed genes were related to metabolic and cellular processes, and were significantly enriched in hormone signal transduction, starch and sucrose metabolism, and the plant-pathogen interaction pathway. Taken together, we propose that the mutation of gene
causes the brittle stalk phenotype and provides important insights into the regulatory mechanism of cellulose biosynthesis and cell wall development in maize.
The existence of back pressure at outlet has a direct impact on the separation performance of the separation separator. However, the influence of back pressure is not understood well due to the ...complicated interaction of the supersonic flow, condensation and shock waves. In this study, the condensation flow models of water vapor were established, the influence of back pressure on supersonic condensation properties of water vapor was investigated. The results show that when the back pressure exists, the position of the shock wave is more forward than that without condensation, and the strength of shock wave is weaker. The nucleation rate is generated around the position of x = 115 mm and increases sharply from 0 to 1025 m−3 s−1. The shock wave is generated at x = 145 mm and x = 122 mm when the outlet back pressure is 20 kPa and 30 kPa, respectively. The condensed droplets evaporate again with the effect of shock wave, and then the secondary condensation of droplets occurs owing to the cooling effect of nozzle. When the back pressure is higher than a certain value, the refrigeration environment in the nozzle is completely destroyed with the effect of shock wave, and the condensed droplets evaporate again.
This review summarizes progress in treating severe and complicated malaria, which are global problems, claiming at least one million lives annually, and have been accompanied by advances in our ...understanding of the pathogenesis of severe malaria complications. New drugs such as intravenous artesunate (AS) and intramuscular artemether (AM) are improving outcomes and decreasing malaria deaths. Trials comparing AM to the traditional parenteral drug, quinine, have not demonstrated however convincing evidence of a mortality advantage for AM. The South East Asian Quinine Artesunate Malaria Trials (SEAQUAMAT), a multicenter, randomized, open-label study comparing AS with quinine showed that parenteral AS was shown to be associated with a 35% reduction in the risk of mortality compare to quinine, and is now the recommended treatment by the WHO for severe and complicated malaria in low-transmission areas and in the second and third trimesters of pregnancy, with almost all the benefit reported in those with high parasite counts. Artesunate is a semisynthetic derivative of artemisinin whose water solubility facilitates absorption and provides an advantage over other artemisinins because it can be formulated as oral, rectal, intramuscular, and intravenous preparations. Artesunate is rapidly hydrolyzed to dihydroartemisinin, which is the most active schizonticidal metabolite. Injectable AS results in a more rapid systemic availability of AS compared with intramuscular AM. This pharmacokinetic advantage may provide a clinical advantage in the treatments of severe and complicated malaria.
Primaquine (PQ) metabolism by the cytochrome P450 (CYP) 2D family of enzymes is required for antimalarial activity in both humans (2D6) and mice (2D). Human CYP 2D6 is highly polymorphic, and ...decreased CYP 2D6 enzyme activity has been linked to decreased PQ antimalarial activity. Despite the importance of CYP 2D metabolism in PQ efficacy, the exact role that these enzymes play in PQ metabolism and pharmacokinetics has not been extensively studied in vivo. In this study, a series of PQ pharmacokinetic experiments were conducted in mice with differential CYP 2D metabolism characteristics, including wild-type (WT), CYP 2D knockout (KO), and humanized CYP 2D6 (KO/knock-in KO/KI) mice. Plasma and liver pharmacokinetic profiles from a single PQ dose (20 mg/kg of body weight) differed significantly among the strains for PQ and carboxy-PQ. Additionally, due to the suspected role of phenolic metabolites in PQ efficacy, these were probed using reference standards. Levels of phenolic metabolites were highest in mice capable of metabolizing CYP 2D6 substrates (WT and KO/KI 2D6 mice). PQ phenolic metabolites were present in different quantities in the two strains, illustrating species-specific differences in PQ metabolism between the human and mouse enzymes. Taking the data together, this report furthers understanding of PQ pharmacokinetics in the context of differential CYP 2D metabolism and has important implications for PQ administration in humans with different levels of CYP 2D6 enzyme activity.
Rodent malaria models are extensively used to predict treatment outcomes in human infections. There is a constant need to improve and refine these models by innovating ways to apply new scientific ...findings and cutting edge technologies. In addition, and in accordance with the three R's of animal use in research, in vivo studies should be constantly refined to avoid unnecessary pain and distress to the experimental animals by using preemptive euthanasia as soon as the main scientific study objective has been accomplished.
The new methodology described in this manuscript uses the whole-body bioluminescence signal emitted by transgenic, luciferase-expressing Plasmodium berghei parasites to assess the parasite load predicted parasitaemia (PLPP) in drug and control treated female ICR-CD1 mice infected with 1 × 10
luciferase-expressing P. berghei (ANKA strain) infected erythrocytes. This methodology can replace other time-consuming and expensive methods that are routinely used to measure parasitaemia in infected animals, such as Giemsa-stained thin blood smears and flow cytometry.
There is a good correlation between whole-body bioluminescence signal and parasitaemia measured using Giemsa-stained thin blood smears and flow cytometry respectively in donor and study mice in the modified Thompson test. The algebraic formulas which represent these correlations can be successfully used to assess PLPP in donor and study mice. In addition, the new methodology can pinpoint sick animals 2-8 days before they would have been otherwise diagnosed based on behavioural or any other signs of malaria disease.
The new method for predicting parasitaemia in the modified Thompson test is simple, precise, objective, and minimizes false positive results that can lead to the premature removal of animals from study. Furthermore, from the animal welfare perspective of replace, reduce, and refine, this new method facilitates early removal of sick animals from study as soon as the study objective has been achieved, in many cases well before the clinical signs of disease are present.
Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a ...tetrahydroquinolone, with increased sp3-character to improve parasite selectivity. Relative to other cytochrome
inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces
tachyzoites and encysted bradyzoites
, and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant
. Causal prophylaxis and radical cure are achieved after
sporozoite infection with oral administration of a single dose (2.5 mg/kg) or 3 days treatment at reduced dose (0.625 mg/kg/day), eliminating parasitemia, and leading to 100% survival. Enzymatic, binding, and co-crystallography/pharmacophore studies demonstrate selectivity for apicomplexan relative to mammalian enzymes. JAG21 has significant promise as a pre-clinical candidate for prevention, treatment, and cure of toxoplasmosis and malaria.
Preclinical studies in rodents have demonstrated that artemisinins, especially injectable artesunate, can induce fetal death and congenital malformations at a low dose range. The embryotoxicity can ...be induced in those animals only within a narrow window in early embryogenesis. Evidence was presented that the mechanism by which embryotoxicity of artemisinins occurs seems to be limited to fetal erythropoiesis and vasculogenesis/ angiogenesis on the very earliest developing red blood cells, causing severe anemia in the embryos with higher drug peak concentrations. However, this embryotoxicity has not been convincingly observed in clinical trials from 1,837 pregnant women, including 176 patients in the first trimester exposed to an artemisinin agent or artemisinin-based combination therapy (ACT) from 1989 to 2009. In the rodent, the sensitive early red cells are produced synchronously over one day with single or multiple exposures to the drug can result in a high proportion of cell deaths. In contrast, primates required a longer period of treatment of 12 days to induce such embryonic loss. In humans only limited information is available about this stage of red cell development; however, it is known to take place over a longer time period, and it may well be that a limited period of treatment of 2 to 3 days for malaria would not produce serious toxic effects. In addition, current oral intake, the most commonly used route of administration in pregnant women with an ACT, results in lower peak concentration and shorter exposure time of artemisinins that demonstrated that such a concentration-course profile is unlikely to induce the embryotoxicity. When relating the animal and human toxicity of artemisinins, the different drug sensitive period and pharmacokinetic profiles as reviewed in the present report may provide a great margin of safety in the pregnant women.
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