Transporter-mediated alterations in bile acid disposition may have significant toxicological implications. Current methods to predict interactions are limited by the interplay of multiple ...transporters, absence of protein in the experimental system, and inaccurate estimates of inhibitor concentrations. An integrated approach was developed to predict altered bile acid disposition due to inhibition of multiple transporters using the model bile acid taurocholate (TCA). TCA pharmacokinetic parameters were estimated by mechanistic modeling using sandwich-cultured human hepatocyte data with protein in the medium. Uptake, basolateral efflux, and biliary clearance estimates were 0.63, 0.034, and 0.074 mL/min/g liver, respectively. Cellular total TCA concentrations (Ct,Cells) were selected as the model output based on sensitivity analysis. Monte Carlo simulations of TCA Ct,Cells in the presence of model inhibitors (telmisartan and bosentan) were performed using inhibition constants for TCA transporters and inhibitor concentrations, including cellular total inhibitor concentrations (It,cell) or unbound concentrations, and cytosolic total or unbound concentrations. For telmisartan, the model prediction was accurate with an average fold error (AFE) of 0.99-1.0 when unbound inhibitor concentration (Iu) was used; accuracy dropped when total inhibitor concentration (It) was used. For bosentan, AFE was 1.2-1.3 using either Iu or It This difference was evaluated by sensitivity analysis of the cellular unbound fraction of inhibitor (fu,cell,inhibitor), which revealed higher sensitivity of fu,cell,inhibitor for predicting TCA Ct,Cells when inhibitors exhibited larger (It,cell/IC50) values. In conclusion, this study demonstrated the applicability of a framework to predict hepatocellular bile acid concentrations due to drug-mediated inhibition of transporters using mechanistic modeling and cytosolic or cellular unbound concentrations.
Kinetic‐scale magnetic dips (KSMDs), with a significant depression in magnetic field strength, and scale length close to and less than one proton gyroradius, were reported in the turbulent plasmas ...both in recent observation and numerical simulation studies. These KSMDs likely play important roles in energy conversion and dissipation. In this study, we present observations of the KSMDs that are labeled whistler mode waves, electrostatic solitary waves, and electron cyclotron waves in the magnetosheath. The observations suggest that electron temperature anisotropy or beams within KSMD structures provide free energy to generate these waves. In addition, the occurrence rates of the waves are higher in the center of the magnetic dips than at their edges, implying that the KSMDs might be the origin of various kinds of waves. We suggest that the KSMDs could provide favorable conditions for the generation of waves and transfer energy to the waves in turbulent magnetosheath plasmas.
Plain Language Summary
The Earth's magnetosheath is a turbulent plasma environment where energy conversion, particle acceleration, and mass and momentum transport take place. Many of these key processes involve kinetic‐scale physics. However, in‐depth studies from previous missions are limited by their lower spacecraft data resolution. The recent Magnetospheric Multiscale (MMS) mission provides us with a large amount of high‐temporal cadence data for studying kinetic‐scale physics in the magnetosheath. In this study, we report whistler mode waves, electrostatic solitary waves and electron cyclotron waves within kinetic‐scale magnetic dips (KSMDs) that can be generated in the turbulent magnetosheath. These waves could be excited by electron temperature anisotropy or beams. As is well known, plasma waves are important processes in converting energy, accelerating and scattering electrons and ions, and modifying the distributions of charged particles. If plasma instabilities develop within the KSMDs, the resulting waves could absorb free energy from plasma particles and may propagate out of the KSMDs. Thus, our discoveries could significantly advance the understanding of energy conversion and dissipation for kinetic‐scale turbulence. This study provides a new reference not only for observations in space physics but also for related basic plasma theories and numerical simulations.
Key Points
MMS observations reveal KSMDs coupled with whistler mode waves, electrostatic solitary waves, and electron cyclotron waves
These waves are excited by different plasma distributions, and the ESWs could affect the electron distributions in kinetic scale
Statistical results indicate that the KSMDs in the magnetosheath are a possible origin for various kinds of waves
Jupiter displays many distinct auroral structures, among which auroral dawn storms and auroral injections are often observed contemporaneously. However, it is unclear if the contemporaneous nature of ...the observations is a coincidence or part of an underlying physical connection. We show six clear examples from a recent Hubble Space Telescope campaign (GO‐14634) that each display both auroral dawn storms and auroral injection signatures. We found that these conjugate phenomena could exist during intervals of either relatively low or high auroral activity, as evidenced by the varied levels of total auroral power. In situ observations of the magnetosphere by Juno show a strong magnetic reconnection event inside of 45 Jupiter radii (RJ) on the predawn sector, followed by two dipolarization events within the following 2 hr, coincident with the auroral dawn storm and auroral injection event. We therefore suggest that the auroral dawn storm is the manifestation of magnetic reconnection in the dawnside magnetosphere. The dipolarization region is mapped to the auroral injection, strongly suggesting that this was associated with the auroral injection. Since magnetic reconnection and dipolarization are physically connected, we therefore suggest that the often‐conjugate auroral dawn storm and auroral injection events are also physically connected consequences.
Key Points
Jupiter's auroral dawn storm and auroral injection events are conjugate and physically connected phenomena
We report the recurrent nature of magnetic dipolarization at Jupiter
These observations suggest that reconnection manifests auroral dawn storms and subsequent dipolarization produces auroral injection events
We present simultaneous observations of aurorae at Jupiter from the Hubble Space Telescope and Hisaki, in combination with the in situ measurements of magnetic field, particles, and radio waves from ...the Juno Spacecraft in the outer magnetosphere, from ~ 80RJ to 60RJ during 17 to 22 March 2017. Two cycles of accumulation and release of magnetic flux, named magnetic loading/unloading, were identified during this period, which correlate well with electron energization and auroral intensifications. Magnetic reconnection events are identified during both the loading and unloading periods, indicating that reconnection and unloading are independent processes. These results show that the dynamics in the middle magnetosphere are coupled with auroral variability.
Key Points
Accumulation and release of magnetic flux in the middle Jovian magnetosphere modulate auroral intensifications
Magnetic reconnection process occurs independently of Jupiter's global loading and unloading of magnetic flux
We provide direct evidence that unloading of magnetic flux causes enhancements of auroral kilometric emissions
To present a clinical version of the 2000 Centers for Disease Control and Prevention (CDC) growth charts and to compare them with the previous version, the 1977 National Center for Health Statistics ...(NCHS) growth charts.
The 2000 CDC percentile curves were developed in 2 stages. In the first stage, the empirical percentiles were smoothed by a variety of parametric and nonparametric procedures. To obtain corresponding percentiles and z scores, we approximated the smoothed percentiles using a modified LMS estimation procedure in the second stage. The charts include of a set of curves for infants, birth to 36 months of age, and a set for children and adolescents, 2 to 20 years of age.
The charts represent a cross-section of children who live in the United States; breastfed infants are represented on the basis of their distribution in the US population. The 2000 CDC growth charts more closely match the national distribution of birth weights than did the 1977 NCHS growth charts, and the disjunction between weight-for-length and weight-for-stature or length-for-age and stature-for-age found in the 1977 charts has been corrected. Moreover, the 2000 CDC growth charts can be used to obtain both percentiles and z scores. Finally, body mass index-for-age charts are available for children and adolescents 2 to 20 years of age.
The 2000 CDC growth charts are recommended for use in the United States. Pediatric clinics should make the transition from the 1977 NCHS to the 2000 CDC charts for routine monitoring of growth in infants, children, and adolescents.
The generation of kinetic‐scale flux ropes (KSFRs) is closely related to magnetic reconnection. Both flux ropes and reconnection sites are detected in the magnetosheath and can impact the dynamics ...upstream of the magnetopause. In this study, using the Magnetospheric Multiscale satellite, 12,623 KSFRs with a scale <20 RCi are statistically studied in the Earth's dayside magnetosheath. It is found that they are mostly generated near the bow shock (BS), and propagate downstream in the magnetosheath. Their quantity significantly increases as the scale decreases, consistent with a flux rope coalescence model. Moreover, the solar wind parameters can control the occurrence rate of KSFRs. They are more easily generated at high Mach number, large proton density, and weak magnetic field strength of the solar wind, similar to the conditions that favor BS reconnection. Our study shows a close connection between KSFR generation and BS reconnection.
Plain Language Summary
Kinetic‐scale flux ropes (KSFRs) exist widely in near‐earth space and play an important role in mass transport, energy conversion, and dissipation during magnetic field reconnection. The KSFR in the magnetosheath can be generated by reconnection in three regions: the magnetopause, the magnetosheath, and the BS. The spatial distribution of KSFRs can indirectly reflect the reconnection situation in the magnetosheath. We use various methods to select the KSFRs and study their spatial distribution and generation in the magnetosheath. Our results show that BS reconnection plays an important role in generating the KSFR in the magnetosheath.
Key Points
Kinetic‐scale flux ropes observed in the magnetosheath are primarily generated near the bow shock (BS) and travel to downstream magnetosheath
The quantity of flux ropes significantly increases as their scale decreases, which is in accordance with the FR coalescence model
The occurrence of flux ropes is influenced by solar wind parameters, and could strongly correlate with BS reconnection
Background. Algorithms for the diagnosis of syphilis continue to be a source of great controversy, and numerous test interpretations have perplexed many clinicians. Methods. We conducted a ...cross-sectional study of 24 124 subjects to analyze 3 syphilis testing algorithms: traditional algorithm, reverse algorithm, and the European Centre for Disease Prevention and Control (ECDC) algorithm. Every serum sample was simultaneously evaluated using the rapid plasma reagin, Treponema pallidum particle agglutination, and chemiluminescence immunoassay tests. With the results of clinical diagnoses of syphilis as a gold standard, we evaluated the diagnostic accuracy of the 3 syphilis testing algorithms. The κ coefficient was used to compare the concordance between the reverse algorithm and the ECDC algorithm. Results. Overall, 2749 patients in our cohort were diagnosed with syphilis. The traditional algorithm had the highest negative likelihood ratio (0.24), a missed diagnosis rate of 24.2%, and only 75.81% sensitivity. However, both the reverse and ECDC algorithms had higher diagnostic efficacy than the traditional algorithm. Their sensitivity, specificity, and accuracy were 99.38%–99.85%, 99.98%–100.00%, and 99.93%–99.96%, respectively. Moreover, the overall percentage of agreement and κ value between the reverse and the ECDC algorithms were 99.9% and 0.996, respectively. Conclusions. Our research supported use of the ECDC algorithm, in which syphilis screening begins with a treponemal immunoassay that is followed by a second, different treponemal assay as a confirmatory test in high-prevalence populations. In addition, our results indicated that nontreponemal assay is unnecessary for syphilis diagnosis but can be recommended for determining serological activity and the effect of syphilis treatment.
Kauri (Agathis australis), which is one of the world's largest and longest‐living conifer species, is under threat from a root and collar dieback disease caused by the oomycete pathogen Phytophthora ...agathidicida. The noted incidence of kauri dieback has increased in the past decade, and even trees >1000 years old are not immune. This disease has profound effects on both forest ecosystems and human society, particularly indigenous Māori, for whom kauri is a taonga or treasure of immense significance. This review brings together existing scientific knowledge about the pathogen and the devastating disease it causes, as well as highlighting important knowledge gaps and potential approaches for disease management. The life cycle of P. agathidicida is similar to those of other soilborne Phytophthora pathogens, with roles for vegetative hyphae, zoospores and oospores in the disease. However, there is comparatively little known about many aspects of the biology of P. agathidicida, such as its host range and disease latency, or about the impact on the disease of abiotic and biotic factors such as soil health and co‐occurring Phytophthora species. This review discusses current and emerging tools and strategies for surveillance, diagnostics and management, including a consideration of genomic resources, and the role these play in understanding the pathogen and how it causes this deadly disease. Key aspects of indigenous Māori knowledge, which include rich ecological and historical knowledge of kauri forests and a holistic approach to forest health, are highlighted.
Abstract
Understanding the sources of lunar water is crucial for studying the history of lunar evolution, as well as the interaction of solar wind with the Moon and other airless bodies. Recent ...orbital spectral observations revealed that the solar wind is a significant exogenous driver of lunar surficial hydration. However, the solar wind is shielded over a period of 3–5 days per month as the Moon passes through the Earth’s magnetosphere, during which a significant loss of hydration is expected. Here we report the temporal and spatial distribution of polar surficial OH/H
2
O abundance, using Chandrayaan-1 Moon Mineralogy Mapper (
M
3
) data, which covers the regions inside/outside the Earth’s magnetosphere. The data shows that polar surficial OH/H
2
O abundance increases with latitude, and that the probability of polar surficial OH/H
2
O abundance remains at the same level when in the solar wind and in the magnetosphere by controlling latitude, composition, and lunar local time. This indicates that the OH/H
2
O abundance in the polar regions may be saturated, or supplemented from other possible sources, such as Earth wind (particles from the magnetosphere, distinct from the solar wind), which may compensate for thermal diffusion losses while the Moon lies within the Earth’s magnetosphere. This work provides some clues for studies of planet–moon systems, whereby the planetary wind serves as a bridge connecting the planet with its moons.
OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and ...cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.
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