Electron trapping in magnetic mirror structures at the edge of magnetopause flux ropes

Flux ropes are a proposed site for particle energization during magnetic reconnection, with several mechanisms proposed. Here, Magnetospheric Multiscale mission observations of magnetic mirror structures on the edge of two ion‐scale magnetopause flux ropes are presented. Donut‐shaped features in the electron pitch angle distributions provide evidence for electron trapping in the structures. Furthermore, both events show trapping with extended 3D structure along the body of the flux rope. Potential formation mechanisms, such as the magnetic mirror instability, are examined and the evolutionary states of the structures are compared. Pressure and force analysis suggest that such structures could provide an important electron acceleration mechanism for magnetopause flux ropes, and for magnetic reconnection more generally

Climate change and freshwater zooplankton: what does it boil down to?

Recently, major advances in the climate–zooplankton interface have been made some of which appeared to receive much attention in a broader audience of ecologists as well. In contrast to the marine realm, however, we still lack a more holistic summary of recent knowledge in freshwater. We discuss climate change-related variation in physical and biological attributes of lakes and running waters, high-order ecological functions, and subsequent alteration in zooplankton abundance, phenology, distribution, body size, community structure, life history parameters, and behavior by focusing on community level responses. The adequacy of large-scale climatic indices in ecology has received considerable support and provided a framework for the interpretation of community and species level responses in freshwater zooplankton. Modeling perspectives deserve particular consideration, since this promising stream of ecology is of particular applicability in climate change research owing to the inherently predictive nature of this field. In the future, ecologists should expand their research on species beyond daphnids, should address questions as to how different intrinsic and extrinsic drivers interact, should move beyond correlative approaches toward more mechanistic explanations, and last but not least, should facilitate transfer of biological data both across space and time

A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

This paper is a personal account on the discovery and characterization of the 5-HT2C receptor (first known as the 5- HT1C receptor) over 30 years ago and how it translated into a number of unsuspected features for a G protein-coupled receptor (GPCR) and a diversity of clinical applications. The 5-HT2C receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HT1CR, the 5-HT2CR was discovered while studying the pharmacological features and the distribution of [3H]mesulergine-labelled sites, primarily in the brain using radioligand binding and slice autoradiography. Mesulergine (SDZ CU-085), was, at the time, best defined as a ligand with serotonergic and dopaminergic properties. Autoradiographic studies showed remarkably strong [3H]mesulergine-labelling to the rat choroid plexus. [3H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT2 binding, the new binding site was called 5-HT1C because of its very high affinity for 5-HT itself. Within the following 10 years, the 5-HT1CR (later named 5- HT2C) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HT2CR is a GPCR, with a very complex gene structure. It constitutes a rarity in theGPCR family: many 5-HT2CR variants exist, especially in humans, due to RNA editing, in addition to a few 5-HT2CR splice variants. Intense research led to therapeutically active 5-HT2C receptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of antidepressants and antipsychotics are 5- HT2CR antagonists/inverse agonists. Agomelatine, a 5-HT2CR antagonist is registered for the treatment of major depression. The agonist Lorcaserin is registered for the treatment of aspects of obesity and has further potential in addiction, especially nicotine/ smoking. There is good evidence that the 5-HT2CR is involved in spinal cord injury-induced spasms of the lower limbs, which can be treated with 5-HT2CR antagonists/inverse agonists such as cyproheptadine or SB206553. The 5-HT2CR may play a role in schizophrenia and epilepsy. Vabicaserin, a 5-HT2CR agonist has been in development for the treatment of schizophrenia and obesity, but was stopped. As is common, there is potential for further indications for 5-HT2CR ligands, as suggested by a number of preclinical and/or genome-wide association studies (GWAS) on depression, suicide, sexual dysfunction, addictions and obesity. The 5-HT2CR is clearly affected by a number of established antidepressants/antipsychotics and may be one of the culprits in antipsychotic-induced weight gain

Thermal modification of wood and a complex study of its properties by magnetic resonance and other methods

© 2016, Springer-Verlag Berlin Heidelberg.Thermal modification of wood is an effective method to improve some of the properties of wood. It is reported on studies of vacuum thermal-treated wood species by magnetic resonance methods. Wood species such as Scots pine (Pinus sylvestris), birch (Betula pendula), Russian larch (Larix sibirica), Norway spruce (Picea abies), small-leaved lime (Tilia cordata) were vacuum treated by heat at 220 °C with various durations up to 8 h. This selection of wood species was investigated by electron paramagnetic resonance, nuclear magnetic resonance and microscopy methods before and after the thermal treatment. Electron paramagnetic resonance experiments revealed changes in the amount of free radicals in samples with the thermal treatment duration. Additional information on magnetic relaxation of 1H nuclei in samples at room temperature was obtained. Optical microscope analysis helped to detect structural changes in the thermally modified wood. Important properties of wood such as wood hardness and humidity absorption were also studied. The original results that were obtained correlate and complement each other, and clarify changes in the wood structure that appear with the heat treatment

Annual Variations in the Near-Earth Solar Wind

Earth’s orbit and rotation introduces systematic annual variations in geomagnetic activity, most notably via the changing orientation of the dayside magnetospheric magnetic field with respect to the heliospheric magnetic field (HMF). However, aside from these geometric effects, it is generally assumed that the solar wind is randomly sampled throughout the year. But systematic changes in the intrinsic solar wind conditions in near-Earth space could arise due to the variation in Earth heliocentric distance and heliographic latitude over the year. In this study we use 24 years of Advanced Composition Explorer (ACE) data to investigate the annual variations in the scalar properties of the solar wind, namely the solar wind proton density, the radial solar wind speed and the HMF intensity. All parameters do show some degree of systematic annual variation, with amplitudes of around 10 to 20%. For HMF intensity, the variation is in phase with the Earth’s heliocentric distance variation, and scaling observations for distance largely removes the variation. For proton density and solar wind speed, however, scaling for distance does not affect the variation and the annual phase is inconsistent with Earth’s heliocentric distance variation. Instead we attribute the annual variations to Earth’s heliographic latitude variation and systematic sampling of higher speed solar wind at higher latitude. These variations are most strongly ordered at solar minimum. Conversely, combining scalar solar wind parameters to produce dynamic pressure and potential power input to the magnetosphere estimates results in solar maximum exhibiting a greater annual variation, with an amplitude of around 40%. This suggests Earth’s position in the heliosphere makes a significant contribution to space weather, in addition to the well studied geometric effects

Optimal designs for population pharmacokinetic studies of the partner drugs co-administered with artemisinin derivatives in patients with uncomplicated falciparum malaria

<p>Abstract</p> <p>Background</p> <p>Artemisinin-based combination therapy (ACT) is currently recommended as first-line treatment for uncomplicated malaria, but of concern, it has been observed that the effectiveness of the main artemisinin derivative, artesunate, has been diminished due to parasite resistance. This reduction in effect highlights the importance of the partner drugs in ACT and provides motivation to gain more knowledge of their pharmacokinetic (PK) properties via population PK studies. Optimal design methodology has been developed for population PK studies, which analytically determines a sampling schedule that is clinically feasible and yields precise estimation of model parameters. In this work, optimal design methodology was used to determine sampling designs for typical future population PK studies of the partner drugs (mefloquine, lumefantrine, piperaquine and amodiaquine) co-administered with artemisinin derivatives.</p> <p>Methods</p> <p>The optimal designs were determined using freely available software and were based on structural PK models from the literature and the key specifications of 100 patients with five samples per patient, with one sample taken on the seventh day of treatment. The derived optimal designs were then evaluated via a simulation-estimation procedure.</p> <p>Results</p> <p>For all partner drugs, designs consisting of two sampling schedules (50 patients per schedule) with five samples per patient resulted in acceptable precision of the model parameter estimates.</p> <p>Conclusions</p> <p>The sampling schedules proposed in this paper should be considered in future population pharmacokinetic studies where intensive sampling over many days or weeks of follow-up is not possible due to either ethical, logistic or economical reasons.</p

IGF1 htSNPs in relation to IGF-1 levels in young women from high-risk breast cancer families: implications for early-onset breast cancer

High levels of insulin-like growth factor-1 (IGF-1) have been associated with increased risk of developing several types of cancer including breast cancer. A set of nine haplotype tagging SNPs (htSNPs) in the IGF1 gene were associated with IGF-1 levels and prostate cancer in a Swedish population. We aimed to study the nine htSNPs in three haplotype blocks (block1: rs855211, rs35765, rs2162679; block2: rs1019731, rs7956547, rs5742632; and block3 rs2033178, rs7136446, rs6220) combined into diplotypes, and three additional SNPs (rs5742612, rs35765817, rs35455143) in relation to IGF-1 levels, BRCA status, the IGF1 CA-repeat microsatellite, and breast cancer in a population of 325 Swedish women from breast cancer high-risk families. Questionnaire data and blood samples for IGF-1 and genetic analyses were obtained twice during the menstrual cycle from 269 women aged 40 years or younger. SNP analyses were also performed in 56 BRCA1/2 mutation carriers. Women (n = 14) with any rare variant block1 diplotype had higher odds to be BRCA1 mutation carriers OR 4.1 (95% CI 1.4-12.2), to lack the common IGF1 19 CA-repeat allele OR 33.3 (95% CI 6.6-166.7), and were more likely to develop early-onset breast cancer (Log Rank P < 0.001) than women with common block1 diplotypes. In the subgroup of BRCA1 mutation carriers, block1 rare diplotypes were associated with earlier diagnosis (Log Rank P = 0.031). No association was found between IGF-1 levels and individual SNPs or diplotypes. If confirmed, these rare diplotypes may identify women with particularly high risk for early-onset breast cancer and this group should be included in forthcoming studies

Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated <it>Plasmodium falciparum</it> malaria in Uganda

<p>Abstract</p> <p>Background</p> <p>Malaria in pregnancy increases the risk of maternal anemia, abortion and low birth weight. Approximately 85.3 million pregnancies occur annually in areas with <it>Plasmodium falciparum</it> transmission. Pregnancy has been reported to alter the pharmacokinetic properties of many anti-malarial drugs. Reduced drug exposure increases the risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of artemether and its active metabolite dihydroartemisinin in pregnant women with uncomplicated <it>P. falciparum</it> malaria in Uganda.</p> <p>Methods</p> <p>Twenty-one women with uncomplicated <it>P. falciparum</it> malaria in the second and third trimesters of pregnancy received the fixed oral combination of 80 mg artemether and 480 mg lumefantrine twice daily for three days. Artemether and dihydroartemisinin plasma concentrations after the last dose administration were quantified using liquid chromatography coupled to tandem mass-spectroscopy. A simultaneous drug-metabolite population pharmacokinetic model for artemether and dihydroartemisinin was developed taking into account different disposition, absorption, error and covariate models. A separate modeling approach and a non-compartmental analysis (NCA) were also performed to enable a comparison with literature values and different modeling strategies.</p> <p>Results</p> <p>The treatment was well tolerated and there were no cases of recurrent malaria. A flexible absorption model with sequential zero-order and transit-compartment absorption followed by a simultaneous one-compartment disposition model for both artemether and dihydroartemisinin provided the best fit to the data. Artemether and dihydroartemisinin exposure was lower than that reported in non-pregnant populations. An approximately four-fold higher apparent volume of distribution for dihydroartemisinin was obtained by non-compartmental analysis and separate modeling compared to that from simultaneous modeling of the drug and metabolite. This highlights a potential pitfall when analyzing drug/metabolite data with traditional approaches.</p> <p>Conclusion</p> <p>The population pharmacokinetic properties of artemether and dihydroartemisinin, in pregnant women with uncomplicated <it>P. falciparum</it> malaria in Uganda, were described satisfactorily by a simultaneous drug-metabolite model without covariates. Concentrations of artemether and its metabolite dihydroartemisinin were relatively low in pregnancy compared to literature data. However, this should be interpreted with caution considered the limited literature available. Further studies in larger series are urgently needed for this vulnerable group.</p