Summary
Background and objective: CYP2C19 is a drug‐metabolizing enzyme showing various genetic polymorphisms that may cause marked interindividual and interethnic variability in the disposition of ...its substrates. We assessed CYP2C19 genetic polymorphisms in a Korean population using a newly developed multiplex pyrosequencing method.
Method: A multiplex pyrosequencing method to simultaneously detect CYP2C19*2, *3, and *17 alleles was designed. We established the frequency of these CYP2C19 alleles in 271 Korean subjects using the multiplex pyrosequencing method.
Results: The results showed 100% concordance between single and multiplex pyrosequencing methods. We also validated the polymorphisms identified by pyrosequencing with direct sequencing method. The allele frequencies of CYP2C19*2, CYP2C19*3, and CYP2C19*17 were 0·284, 0·101 and 0·015 respectively. These frequencies are similar to that reported for other Asian populations including Japanese and Chinese but different from that of Caucasians and Africans.
Conclusions: The multiplex pyrosequencing method to detect CYP2C19*2, CYP2C19*3, and CYP2C19*17 concurrently, seems to be a rapid and reliable genotyping method for the detection of important CYP2C19 genetic polymorphisms. Similar to studies conducted on other Asian populations, this study reported that in the Korean population tested, the CYP2C19*2 and CYP2C19*3 alleles were relatively frequently found, whereas the frequency of CYP2C19*17 was very low.
Manipulating the atomic and electronic structure of matter with strong terahertz (THz) fields while probing the response with ultrafast pulses at x-ray free electron lasers (FELs) has offered unique ...insights into a multitude of physical phenomena in solid state and atomic physics. Recent upgrades of x-ray FEL facilities are pushing to much higher repetition rates, enabling unprecedented signal-to-noise ratio for pump probe experiments. This requires the development of suitable THz pump sources that are able to deliver intense pulses at compatible repetition rates. Here we present a high-power laser-driven THz source based on optical rectification in LiNbO
3
using tilted pulse front pumping. Our source is driven by a kilowatt-level Yb:YAG amplifier system operating at 100 kHz repetition rate and employing nonlinear spectral broadening and recompression to achieve sub-100 fs pulses with pulse energies up to 7 mJ that are necessary for high THz conversion efficiency and peak field strength. We demonstrate a maximum of 144 mW average THz power (1.44
μ
J pulse energy), consisting of single-cycle pulses centered at 0.6 THz with a peak electric field strength exceeding 150 kV/cm. These high field pulses open up a range of possibilities for nonlinear time-resolved THz experiments at unprecedented rates.
Objectives To investigate antimicrobial resistance in clinical isolates of Acinetobacter spp. from two Korean hospitals. Methods Two hundred and sixty-five isolates of Acinetobacter spp. from two ...Korean hospitals were collected and were identified to species level using partial rpoB gene sequences. Antimicrobial susceptibility testing was performed using a broth microdilution method. Results rpoB gene sequences indicated that 214 isolates (80.8%) were Acinetobacter baumannii, and allowed these to be classified into three subgroups (I, II and III); 142 isolates (53.6%) belonged to subgroup I, 54 (20.4%) to subgroup II and 18 (6.8%) to subgroup III. Forty-eight isolates (18.1%) and 74 isolates (27.9%) were resistant to polymyxin B and colistin, respectively. However, antimicrobial resistance rates varied markedly between subgroups. While A. baumannii subgroup I showed low resistance rates to polymyxin B and colistin (2.1% and 7.0%, respectively), subgroups II and III showed high resistance rates to these antibiotics (38.9% and 64.8% in subgroup II and 72.2% and 88.9%, in subgroup III, respectively). Multidrug resistance was also significantly more frequent in subgroup I (45.1%) than in subgroups II and III (13.0% and 16.7%, respectively). Conclusions Our data indicate that subgroup identification of A. baumannii may aid selection of appropriate antimicrobial agents for the treatment of Acinetobacter infections.
Carboxypeptidase E (CPE) or carboxypeptidase H was first discovered in 1982 as an enkephalin-convertase that cleaved a C-terminal basic residue from enkephalin precursors to generate enkephalin. ...Since then, CPE has been shown to be a multifunctional protein that subserves many essential nonenzymatic roles in the endocrine and nervous systems. Here, we review the phylogeny, structure, and function of CPE in hormone and neuropeptide sorting and vesicle transport for secretion, alternative splicing of the CPE transcript, and single nucleotide polymorphisms in humans. With this and the analysis of mutant and knockout mice, the data collectively support important roles for CPE in the modulation of metabolic and glucose homeostasis, bone remodeling, obesity, fertility, neuroprotection, stress, sexual behavior, mood and emotional responses, learning, and memory. Recently, a splice variant form of CPE has been found to be an inducer of tumor growth and metastasis and a prognostic biomarker for metastasis in endocrine and nonendocrine tumors.
SOX2 is a well-known core transcription factor in embryonic stem cells (ESCs) and has an important role in the maintenance of pluripotency. Recently, SOX2 expression has also been reported in adult ...stem cells (ASCs), but the role of SOX2 in ASCs remains unknown. In this study, we examined the molecular mechanisms of SOX2 in human mesenchymal stem cells (hMSCs), a type of ASCs, by performing inhibition studies. SOX2 inhibition resulted in altered cell growth and differentiation capabilities. These changes coincided with a decrease in Dickkopf-1 (DKK1), a soluble inhibitor of WNT signaling. Chromatin immunoprecipitation and luciferase assays showed that SOX2 binds to DKK1 and has a positive regulatory role in transcription. The enforced expression of DKK1 in SOX2-inhibited hMSCs reversed the differentiation deformities, but could not abrogate the cell proliferation defect. Proliferation was regulated by c-MYC, whose expression can also be controlled by SOX2. Our study shows that SOX2 directly regulates DKK1 expression and, as a consequence, determines the differentiation lineage of hMSCs. Moreover, SOX2 also regulates proliferation by affecting c-MYC. Therefore, these results suggest that SOX2 might have a specific function by regulating DKK1 and c-MYC in the differentiation and growth of ASCs, which is separate from its roles in ESCs.
Host behavior can affect host-pathogen dynamics, and sociality is predicted to increase risk of pathogen exposure. Many species minimize costs of parasitism by only aggregating seasonally, such as ...during reproductive periods, but colonial species may still be limited in their potential to evade pathogens. Bats are among the most gregarious mammals and females of many temperate species form maternity colonies in summer where they communally raise pups in both natural and anthropogenic roost structures. Social network structure may differ between natural and anthropogenic roosts in ways that affect pathogen dynamics. We used social network analysis to quantify interactions of big brown bats (Eptesicus fuscus) in a tree-roosting colony, where the colony is divided among multiple trees each day, and a building colony, where most of the colony roosts together each day. We simulated transmission of a pathogen throughout both sets of networks. We tested three hypotheses: (1) network metrics differ between pregnancy and lactation; (2) changing network structure between reproductive stages influences predicted pathogen dynamics; and (3) network metrics and predicted pathogen dynamics differ between colonies of bats in trees versus buildings. Network structure was weaker for bats roosting in trees during pregnancy and lactation compared to bats roosting in a building, and our models showed that a hypothetical pathogen would spread more rapidly for bats in the building colony. Our results are important for understanding variation in social tendencies and pathogen transmission among colonies of bats and have implications for conservation and public health. SIGNIFICANCE STATEMENT: Host behavior, particularly social behavior, can affect dynamics of wildlife pathogens. Bats are highly social mammals and females of temperate species form colonies in spring and early summer in tree or building roosts. Thermal characteristics of trees and buildings appear to differ in ways that affect roosting behavior and social interactions. We used social network analyses to quantify interactions of big brown bats in tree and building roosts and simulated consequences for pathogen dynamics. Network structure was weaker for bats roosting in trees with more frequent roost switching and relatively diffuse contacts across the network. Our models showed that a hypothetical pathogen could spread up to four times faster in a building colony compared to a colony of bats roosting in trees. Our results are important for understanding how sociality can influence pathogen dynamics in bats and have implications for conservation and public health.
MitoQ is a mitochondria-targeted derivative of the antioxidant ubiquinone, with antioxidant and anti-apoptotic functions. Reactive oxygen species are involved in many inflammatory diseases including ...inflammatory bowel disease. In this study, we assessed the therapeutic effects of MitoQ in a mouse model of experimental colitis and investigated the possible mechanisms underlying its effects on intestinal inflammation.
Reactive oxygen species levels and mitochondrial function were measured in blood mononuclear cells of patients with inflammatory bowel disease. The effects of MitoQ were evaluated in a dextran sulfate sodium-induced colitis mouse model. Clinical and pathological markers of disease severity and oxidative injury, and levels of inflammatory cytokines in mouse colonic tissue were measured. The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed.
Cellular and mitochondrial reactive oxygen species levels in mononuclear cells were significantly higher in patients with inflammatory bowel disease (P <0.003, cellular reactive oxygen species; P <0.001, mitochondrial reactive oxygen species). MitoQ significantly ameliorated colitis in the dextran sulfate sodium-induced mouse model in vivo, reduced the increased oxidative stress response (malondialdehyde and 3-nitrotyrosine formation), and suppressed mitochondrial and histopathological injury by decreasing levels of inflammatory cytokines IL-1 beta and IL-18 (P <0.001 and P <0.01 respectively). By decreasing mitochondrial reactive oxygen species, MitoQ also suppressed activation of the NLRP3 inflammasome that was responsible for maturation of IL-1 beta and IL-18. In vitro studies demonstrated that MitoQ decreases IL-1 beta and IL-18 production in human THP-1 cells.
Taken together, our results suggest that MitoQ may have potential as a novel therapeutic agent for the treatment of acute phases of inflammatory bowel disease.
The remarkable discovery by the Chandra X-ray observatory that the Crab nebula's jet periodically changes direction provides a challenge to our understanding of astrophysical jet dynamics. It has ...been suggested that this phenomenon may be the consequence of magnetic fields and magnetohydrodynamic instabilities, but experimental demonstration in a controlled laboratory environment has remained elusive. Here we report experiments that use high-power lasers to create a plasma jet that can be directly compared with the Crab jet through well-defined physical scaling laws. The jet generates its own embedded toroidal magnetic fields; as it moves, plasma instabilities result in multiple deflections of the propagation direction, mimicking the kink behaviour of the Crab jet. The experiment is modelled with three-dimensional numerical simulations that show exactly how the instability develops and results in changes of direction of the jet.
We combine all available information to constrain the nature of OGLE-2005-BLG-071Lb, the second planet discovered by microlensing and the first in a high-magnification event. These include ...photometric and astrometric measurements from the Hubble Space Telescope, as well as constraints from higher order effects extracted from the ground-based light curve, such as microlens parallax, planetary orbital motion, and finite-source effects. Our primary analysis leads to the conclusion that the host of Jovian planet OGLE-2005-BLG-071Lb is an M dwarf in the foreground disk with mass M = 0.46 ± 0.04 M, distance Dl = 3.2 ± 0.4 kpc, and thick-disk kinematics vLSR ~ 103 km s-1. From the best-fit model, the planet has mass Mp = 3.8 ± 0.4 MJupiter, lies at a projected separation r{up tack} = 3.6 ± 0.2AU from its host, and so has an equilibrium temperature of T ~ 55 K, that is, similar to Neptune. A degenerate model gives similar planetary mass Mp = 3.4 ± 0.4 MJupiter with a smaller projected separation, r{up tack} = 2.1 ± 0.1AU, and higher equilibrium temperature, T ~ 71 K. These results from the primary analysis suggest that OGLE-2005-BLG-071Lb is likely to be the most massive planet yet discovered that is hosted by an M dwarf. However, the formation of such high-mass planetary companions in the outer regions of M dwarf planetary systems is predicted to be unlikely within the core-accretion scenario. There are a number of caveats to this primary analysis, which assumes (based on real but limited evidence) that the unlensed light coincident with the source is actually due to the lens, that is, the planetary host. However, these caveats could mostly be resolved by a single astrometric measurement a few years after the event.
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