Transition metal oxides hold great potential for the development of new device paradigms because of the field-tunable functionalities driven by their strong electronic correlations, combined with ...their earth abundance and environmental friendliness. Recently, the interfaces between transition-metal oxides have revealed striking phenomena, such as insulator-metal transitions, magnetism, magnetoresistance and superconductivity. Such oxide interfaces are usually produced by sophisticated layer-by-layer growth techniques, which can yield high-quality, epitaxial interfaces with almost monolayer control of atomic positions. The resulting interfaces, however, are fixed in space by the arrangement of the atoms. Here we demonstrate a route to overcoming this geometric limitation. We show that the electrical conductance at the interfacial ferroelectric domain walls in hexagonal ErMnO(3) is a continuous function of the domain wall orientation, with a range of an order of magnitude. We explain the observed behaviour using first-principles density functional and phenomenological theories, and relate it to the unexpected stability of head-to-head and tail-to-tail domain walls in ErMnO(3) and related hexagonal manganites. As the domain wall orientation in ferroelectrics is tunable using modest external electric fields, our finding opens a degree of freedom that is not accessible to spatially fixed interfaces.
Elementary processes associated with ionization of liquid water provide a framework for understanding radiation-matter interactions in chemistry and biology. Although numerous studies have been ...conducted on the dynamics of the hydrated electron, its partner arising from ionization of liquid water, H
O
, remains elusive. We used tunable femtosecond soft x-ray pulses from an x-ray free electron laser to reveal the dynamics of the valence hole created by strong-field ionization and to track the primary proton transfer reaction giving rise to the formation of OH. The isolated resonance associated with the valence hole (H
O
/OH) enabled straightforward detection. Molecular dynamics simulations revealed that the x-ray spectra are sensitive to structural dynamics at the ionization site. We found signatures of hydrated-electron dynamics in the x-ray spectrum.
Ferroelectric domain walls hold great promise as functional two-dimensional materials because of their unusual electronic properties. Particularly intriguing are the so-called charged walls where a ...polarity mismatch causes local, diverging electrostatic potentials requiring charge compensation and hence a change in the electronic structure. These walls can exhibit significantly enhanced conductivity and serve as a circuit path. The development of all-domain-wall devices, however, also requires walls with controllable output to emulate electronic nano-components such as diodes and transistors. Here we demonstrate electric-field control of the electronic transport at ferroelectric domain walls. We reversibly switch from resistive to conductive behaviour at charged walls in semiconducting ErMnO
. We relate the transition to the formation-and eventual activation-of an inversion layer that acts as the channel for the charge transport. The findings provide new insight into the domain-wall physics in ferroelectrics and foreshadow the possibility to design elementary digital devices for all-domain-wall circuitry.
Clearance of atorvastatin occurs through hepatic uptake by organic anion transporting polypeptides (OATPs) and subsequent metabolism by cytochrome P450 (CYP) 3A4. To demonstrate the relative ...importance of OATPs and CYP3A4 in the hepatic elimination of atorvastatin in vivo, a clinical cassette microdose study was performed. A cocktail consisting of a microdose of atorvastatin along with probe substrates for OATPs (pravastatin) and CYP3A4 (midazolam) was orally administered to eight healthy volunteers. The pharmacokinetics of this cocktail was observed at baseline, after an oral dose of 600 mg rifampicin (an inhibitor of OATPs), and after an intravenous dose of 200 mg itraconazole (a CYP3A4 inhibitor). Rifampicin increased the pravastatin dose‐normalized area under the plasma concentration–time curve (AUC) (4.6‐fold), and itraconazole significantly increased the midazolam dose‐normalized AUC (1.7‐fold). The atorvastatin dose‐normalized AUC increased 12‐fold when coadministered with rifampicin but did not change when coadministered with itraconazole. These results indicate that hepatic uptake via OATPs makes the dominant contribution to the hepatic elimination of atorvastatin at a subtherapeutic microdose.
Clinical Pharmacology & Therapeutics (2011) 90 4, 575–581. doi:10.1038/clpt.2011.142
Unmethylated DNA with CpG-motifs is recognized by Toll-like receptor 9 (TLR9) and pleiotropic immune responses are elicited. Macrophages and conventional dendritic cells (cDCs) produce ...proinflammatory cytokines to B/K-type CpG-DNA, whereas plasmacytoid DCs induce type I interferons to A/D-type CpG-DNA and DNA viruses. The TLR9 mediated signaling pathway is not only responsible for activation of innate immune cells, but also for mounting acquired responses. Thus, it has been attempted to exploit TLR9 ligands as a vaccine adjuvant for anti-cancer immunotherapy. Further, TLR9 mediated signaling is implicated in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus. Nevertheless, recent studies revealed that double-stranded DNA can be recognized by intracellular receptor(s) in a TLR9-independent manner. This review will focus on the roles of TLR9 in immune responses, and its signaling pathways.
A microdose study of metformin was conducted to investigate the predictability of drug–drug interactions at the therapeutic dose (ThD). Healthy subjects received a microdose (100 µg) or ThD (250 mg) ...of metformin orally, with or without a potent and competitive multidrug and toxin extrusion (MATE) inhibitor, pyrimethamine (50 mg, p.o.), in a crossover fashion. Pyrimethamine significantly reduced the renal clearance of metformin by 23 and 35% at the microdose and ThD, respectively. At ThD, but not at microdose, it caused significant increases in the maximum concentration (Cmax) and area under the plasma concentration–time curve (AUC) of metformin (142 and 139% of control values, respectively). Human canalicular membrane vesicles showed pyrimethamine‐inhibitable metformin uptake. Pyrimethamine did not affect plasma lactate/pyruvate after ThD of metformin but significantly reduced the renal clearance of creatinine, thereby causing elevation of plasma creatinine level. This microdose study quantitatively predicted a drug–drug interaction involving the renal clearance of metformin at ThD by pyrimethamine. Pyrimethamine is a useful in vivo inhibitor of MATE proteins.
Clinical Pharmacology & Therapeutics (2011) 89 6, 837–844. doi:10.1038/clpt.2011.36
We show that the improper ferroelectric phase transition in the multiferroic hexagonal manganites displays appropriate symmetry-breaking characteristics for testing the Kibble-Zurek mechanism ...originally proposed to describe early-universe phase transitions. We present an analysis of the Kibble-Zurek theory of topological defect formation applied to the hexagonal manganites, discuss the conditions determining the range of cooling rates in which Kibble-Zurek behavior is expected, and show that recent literature data are consistent with our predictions. Finally, we explore experimentally the crossover out of the Kibble-Zurek regime and find a surprising reversal of the scaling behavior.
By examining the reconstructed gastric tube during esophagectomy using indocyanine green fluorescence (ICG) angiography, we have established a '90-second rule' to confirm good blood perfusion at the ...anastomosis site. We examined the surgical outcome (rate of anastomotic leakage) of 70 consecutive patients who underwent esophagectomy with gastric tube reconstruction using ICG fluorescence angiography. All of the anastomoses were made in the area where less than 90 seconds was needed for enhancement using ICG fluorescence angiography (i.e. within the 90-second rule). In 18 cases for which the time until enhancement of the gastric tube tip exceeded 60 seconds, the anastomosis site was decided by reference to the ICG fluorescence angiogram, and the hypoperfused area was excised, and this significantly shortened the median time until enhancement of the gastric tube tip from 95.5 (60.0-204.0) seconds to 41.0 (9.0-77.0) seconds (P < 0.001). In three cases, the anastomosis was made at the site where more than 60 seconds was needed for ICG enhancement. In one case where ICG enhancement had taken 77 seconds, minor anastomotic leakage occurred. The overall rate of anastomotic leakage in this series was 1.4%. Blood flow in the reconstructed gastric tube is sufficient if the anastomosis is made in the area where ICG fluorescence angiography demonstrates enhancement within 60 seconds. Gastric tube necrosis can be avoided if the area showing an enhancement time exceeding 90 seconds is excised. The 90-second rule is a safe and effective method for deciding the site of anastomosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Summary
Background
The cytokine interleukin‐31 (IL‐31) is considered to be responsible for the development of pruritus in humans. At present, no available evidence has been provided on the safety and ...efficacy of blocking the IL‐31 signal in humans for the amelioration of pruritus in atopic dermatitis (AD). CIM331 is a humanized antihuman IL‐31 receptor A (IL‐31RA) monoclonal antibody, which binds to IL‐31RA to inhibit subsequent IL‐31 signalling.
Objectives
To assess the tolerability, safety, pharmacokinetics and preliminary efficacy of CIM331 in healthy Japanese and white volunteers, and Japanese patients with AD.
Methods
In this randomized, double‐blind, placebo‐controlled phase I/Ib study, CIM331 was administered in a single subcutaneous dose. The primary outcomes were safety and tolerability; the exploratory analysis was efficacy.
Results
No deaths, serious adverse events (AEs) or discontinuations due to AEs were reported in any part of the study. No dose‐dependent increase in the incidence of AEs occurred in any part of the study. In healthy volunteers, all AEs occurred once in the placebo groups, and increased creatine phosphokinase was more common in the CIM331 groups. In patients with AD, CIM331 reduced pruritus visual analogue scale score to about −50% at week 4 with CIM331 compared with −20% with placebo. CIM331 increased sleep efficiency and decreased the use of hydrocortisone butyrate.
Conclusions
A single subcutaneous administration of CIM331 was well tolerated in healthy volunteers and patients with AD. It decreased pruritus, sleep disturbance and topical use of hydrocortisone. CIM331 may become a novel therapeutic option for AD by inhibiting IL‐31.
What's already known about this topic?
Interleukin‐31 (IL‐31) has been implicated in the induction of pruritus, the major symptom of atopic dermatitis (AD).
What does this study add?
This is the first human trial to investigate whether inhibition of IL‐31 signalling ameliorates pruritus in AD.
Single subcutaneous administration of CIM331, a humanized antihuman IL‐31 receptor A monoclonal antibody, was well tolerated in healthy volunteers and patients with AD.
CIM331 markedly improved pruritus in patients with AD.
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