Background
Exposure to environmental pollutants promotes Th2 cell responses. Aryl hydrocarbon receptor (AhR) activation aggravates allergic responses. Epithelium‐derived thymic stromal lymphopoietin ...(TSLP), interleukin (IL)‐25, and IL‐33 are implicated in the dysregulation of Th2 immune responses in severe allergic asthma.
Methods
Bronchial biopsies of 28 allergic severe asthma and 6 mild asthma subjects from highly polluted areas were analyzed for AhR nuclear translocation (NT), cytokine expression, and gene activation. Cultured primary epithelial cells were stimulated with diesel exhausted particles (DEP) to determine AhR‐mediated IL‐33, Il‐25, and TSLP synthesis and release.
Results
Primary bronchial epithelial cells exposed to DEP showed upregulation of IL‐33, IL‐25, and TSLP. These effects were abolished by knockdown of AhR by siRNA. Increased AhR/ARNT binding to promoters of IL‐33, IL‐25, and TSLP was found using chromatin immunoprecipitation (ChIP) assay. Allergic severe asthma with high AhR NT had higher bronchial gene and protein expression of IL‐33, IL‐25, and TSLP. These patients derived clinical benefit from anti‐IgE treatment.
Conclusion
Aryl hydrocarbon receptor activation by DEP mediates upregulation of IL‐33, IL‐25, and TSLP with Th2 activation, potentially linking environmental pollution and allergic severe asthma.
Environmental diesel exhaust particles (DEP) exposed to airway epithelium ligate cytoplasmic aryl hydrocarbon receptor (AhR), translocate to the nucleus with aryl hydrocarbon receptor nuclear translocator (ARNT), and then transactivate IL‐33, Il‐25, and TSLP gene expression. Patients with high AhR nucleus translocation overexpressed IL‐33, Il‐25, and TSLP cytokines compared to those with low. Patients with high AhR nucleus translocation are more response to anti‐IgE therapy compared to those with low.
ABSTRACT We present relativistic analyses of 9257 measurements of times-of-arrival from the first binary pulsar, PSR B1913+16, acquired over the last 35 years. The determination of the "Keplerian" ...orbital elements plus two relativistic terms completely characterizes the binary system, aside from an unknown rotation about the line of sight, leading to a determination of the masses of the pulsar and its companion: 1.438 0.001 M☉ and 1.390 0.001 M☉, respectively. In addition, the complete system characterization allows for the creation of relativistic gravitation test by comparing measured and predicted sizes of various relativistic phenomena. We find that the ratio of the observed orbital period decrease caused by gravitational wave damping (corrected by a kinematic term) to the general relativistic prediction is 0.9983 0.0016, thereby confirms the existence and strength of gravitational radiation as predicted by general relativity. For the first time in this system, we have also successfully measured the two parameters characterizing the Shapiro gravitational propagation delay, and found that their values are consistent with general relativistic predictions. For the first time in any system, we have also measured the relativistic shape correction to the elliptical orbit, δθ, although its intrinsic value is obscured by currently unquantified pulsar emission beam aberration. We have also marginally measured the time derivative of the projected semimajor axis, which, when improved in combination with beam aberration modeling from geodetic precession observations, should ultimately constrain the pulsar's moment of inertia.
We report the first results of a light weakly interacting massive particles (WIMPs) search from the CDEX-10 experiment with a 10 kg germanium detector array immersed in liquid nitrogen at the China ...Jinping Underground Laboratory with a physics data size of 102.8 kg day. At an analysis threshold of 160 eVee, improved limits of 8×10^{-42} and 3×10^{-36} cm^{2} at a 90% confidence level on spin-independent and spin-dependent WIMP-nucleon cross sections, respectively, at a WIMP mass (m_{χ}) of 5 GeV/c^{2} are achieved. The lower reach of m_{χ} is extended to 2 GeV/c^{2}.
The role of autotransplantation in end-stage hepatic alveolar echinococcosis (AE) is unclear. We aimed to present our 15-case experience and propose selection criteria for autotransplantation. All ...patients were considered to have unresectable hepatic AE by conventional resection due to critical invasion to retrohepatic vena cava, hepatocaval region along with three hepatic veins, and the tertiary portal and arterial branches. All patients successfully underwent ex vivo extended right hepatectomy and autotransplantation without intraoperative mortality. The median autograft weight was 706 g (380–1000 g); operative time was 15.5 hours (11.5–20.5 hours); and anhepatic time was 283.8 minutes (180–435 min). Postoperative hospital stay was 32.3 days (12–60 days). Postoperative complication Clavien–Dindo grade IIIa or higher occurred in three patients including one death that occurred 12 days after the surgery due to acute liver failure. One patient was lost to follow-up after the sixth month. Thirteen patients were followed for a median of 21.6 months with no relapse. This is the largest reported series of patients with end-stage hepatic AE treated with liver autotransplantation. The technique requires neither organ donor nor postoperative immunosuppressant. The early postoperative mortality was low with acceptable morbidity. Preoperative precise assessment and strict patient selection are of utmost importance.
The antiferroelectricity in HfZrO 2 (HZO) annealed at 600 °C with an abrupt turn ON of FET characteristics with SSmin = 23 mV/dec and SSavg = 50 mV/dec over 4 decades of IDS is demonstrated. The near ...non-hysteresis is achieved with an antiferroelectric-like HZO due to a small remanent polarization and a coercive field. A feasible concept of coupling the antiferroelectric and ferroelectric type HZO are used for low-power electronics and the memory applications, respectively.
Electrode potential–pH (Pourbaix) diagrams provide a phase map of the most stable compounds of a metal, its corrosion products, and associated ions in solution. The utility of these phase diagrams is ...that they enable the assessment of electrochemical stabilities, for example, of Ni metal and its derived oxides, hydroxides, and oxyhydroxides, against corrosion in aqueous environments. Remarkably, the Ni Pourbaix diagrams reported over the last 50 years are largely inconsistent with various electrochemical observations, which may be attributed to inaccurate experimental free energies of formation (Δf G) for the complex Ni-based compounds used in producing the available diagrams. Here we show that state-of-the-art density-functional theory (DFT) can be used to obtain accurate Δf G values, which lead to Ni Pourbaix diagrams that are more consistent with direct electrochemical experiments: Electrochemical impedance spectroscopy and surface-enhanced Raman spectroscopy are used to characterize the electrochemical stabilities of NiO and Ni(OH)2 formed on Ni, demonstrating the reliability in correction-free first-principles based Pourbaix diagrams. Our results show the importance in applying modern density functionals in combination with experimental advances in aqueous environment compound identification for assessing electrochemical phase stability of materials, which will be useful for the design, synthesis, and selection of corrosion-resistant metals, photoabsorbers, and photocatalytic materials.
The etiology and pathophysiology of schizophrenia remain unknown. A parallel transcriptomics, proteomics and metabolomics approach was employed on human brain tissue to explore the molecular disease ...signatures. Almost half the altered proteins identified by proteomics were associated with mitochondrial function and oxidative stress responses. This was mirrored by transcriptional and metabolite perturbations. Cluster analysis of transcriptional alterations showed that genes related to energy metabolism and oxidative stress differentiated almost 90% of schizophrenia patients from controls, while confounding drug effects could be ruled out. We propose that oxidative stress and the ensuing cellular adaptations are linked to the schizophrenia disease process and hope that this new disease concept may advance the approach to treatment, diagnosis and disease prevention of schizophrenia and related syndromes.
Signal extraction out of background noise is a common challenge in high-precision physics experiments, where the measurement output is often a continuous data stream. To improve the signal-to-noise ...ratio of the detection, witness sensors are often used to independently measure background noises and subtract them from the main signal. If the noise coupling is linear and stationary, optimal techniques already exist and are routinely implemented in many experiments. However, when the noise coupling is nonstationary, linear techniques often fail or are suboptimal. Inspired by the properties of the background noise in gravitational wave detectors, this work develops a novel algorithm to efficiently characterize and remove nonstationary noise couplings, provided there exist witnesses of the noise source and of the modulation. In this work, the algorithm is described in its most general formulation, and its efficiency is demonstrated with examples from the data of the Advanced LIGO gravitational-wave observatory, where we could obtain an improvement of the detector gravitational-wave reach without introducing any bias on the source parameter estimation.
Large peridotite massifs are scattered along the 1500km length of the Yarlung-Zangbo Suture Zone (southern Tibet, China), the major suture between Asia and Greater India. Diamonds occur in the ...peridotites and chromitites of several massifs, together with an extensive suite of trace phases that indicate extremely low fO sub(2) (SiC, nitrides, carbides, native elements) and/or ultrahigh pressures (UHP) (diamond, TiO sub(2) II, coesite, possible stishovite). New physical and isotopic (C, N) studies of the diamonds indicate that they are natural, crystallized in a disequilibrium, high-T environment, and spent only a short time at mantle temperatures before exhumation and cooling. These constraints are difficult to reconcile with previous models for the history of the diamond-bearing rocks. Possible evidence for metamorphism in or near the upper part of the Transition Zone includes the following: (1) chromite (in disseminated, nodular and massive chromitites) containing exsolved pyroxenes and coesite, suggesting inversion from a high-P polymorph of chromite; (2) microstructural studies suggesting that the chromitites recrystallized from fine-grained, highly deformed mixtures of wadsleyite and an octahedral polymorph of chromite; (3) a new cubic Mg-silicate, with the space group of ringwoodite but an inverse-spinel structure (all Si in octahedral coordination); (4) harzburgites with coarsely vermicular symplectites of opx + Cr-Al spinel plus or minus cpx; reconstructions suggest that these are the breakdown products of majoritic garnets, with estimated minimum pressures to>13GPa. Evidence for a shallow pre-metamorphic origin for the chromitites and peridotites includes the following: (1) trace-element data showing that the chromitites are typical of suprasubduction-zone (SSZ) chromitites formed by magma mixing or mingling, consistent with Hf-isotope data from magmatic (375Ma) zircons in the chromitites; (2) the composition of the new cubic Mg-silicate, which suggests a low-P origin as antigorite, subsequently dehydrated; (3) the peridotites themselves, which carry the trace element signature of metasomatism in an SSZ environment, a signature that must have been imposed before the incorporation of the UHP and low-fO sub(2) phases. A proposed P-T-t path involves the original formation of chromitites in mantle-wedge harzburgites, subduction of these harzburgites at c. 375Ma, residence in the upper Transition Zone for >200 Myr, and rapid exhumation at c. 170-150Ma or 130-120Ma. Os-isotope data suggest that the subducted mantle consisted of previously depleted subcontinental lithosphere, dragged down by a subducting oceanic slab. Thermomechanical modeling shows that roll-back of a (much later) subducting slab would produce a high-velocity channelized upwelling that could exhume the buoyant harzburgites (and their chromitites) from the Transition Zone in<10 Myr. This rapid upwelling, which may explain some characteristics of the diamonds, appears to have brought some massifs to the surface in forearc or back-arc basins, where they provided a basement for oceanic crust. This model can reconcile many apparently contradictory petrological and geological datasets. It also defines an important, previously unrecognized geodynamic process that may have operated along other large suture zones such as the Urals.
Physiologically based pharmacokinetic (PBPK) modeling and simulation is a tool that can help predict the pharmacokinetics of drugs in humans and evaluate the effects of intrinsic (e.g., organ ...dysfunction, age, genetics) and extrinsic (e.g., drug–drug interactions) factors, alone or in combinations, on drug exposure. The use of this tool is increasing at all stages of the drug development process. This report reviews recent instances of the use of PBPK in decision‐making during regulatory review. The examples are based on Center for Drug Evaluation and Research reviews of several submissions for investigational new drugs (INDs) and new drug applications (NDAs) received between July 2008 and June 2010. The use of PBPK modeling and simulation facilitated the following types of decisions: the need to conduct specific clinical pharmacology studies, specific study designs, and appropriate labeling language. The report also discusses the challenges encountered when PBPK modeling and simulation were used in these cases and recommends approaches to facilitating full utilization of this tool.
Clinical Pharmacology & Therapeutics (2011) 89 2, 259–267. doi:10.1038/clpt.2010.298
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