Following the early prediction of the skyrmion lattice (SkL)--a periodic array of spin vortices--it has been observed recently in various magnetic crystals mostly with chiral structure. Although ...non-chiral but polar crystals with Cnv symmetry were identified as ideal SkL hosts in pioneering theoretical studies, this archetype of SkL has remained experimentally unexplored. Here, we report the discovery of a SkL in the polar magnetic semiconductor GaV4S8 with rhombohedral (C3v) symmetry and easy axis anisotropy. The SkL exists over an unusually broad temperature range compared with other bulk crystals and the orientation of the vortices is not controlled by the external magnetic field, but instead confined to the magnetic easy axis. Supporting theory attributes these unique features to a new Néel-type of SkL describable as a superposition of spin cycloids in contrast to the Bloch-type SkL in chiral magnets described in terms of spin helices.
In recent years, high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS/MS) detection has been demonstrated to be a powerful technique for the quantitative determination of ...drugs and metabolites in biological fluids. However, the common and early perception that utilization of HPLC−MS/MS practically guarantees selectivity is being challenged by a number of reported examples of lack of selectivity due to ion suppression or enhancement caused by the sample matrix and interferences from metabolites. In light of these serious method liabilities, questions about how to develop and validate reliable HPLC−MS/MS methods, especially for supporting long-term human pharmacokinetic studies, are being raised. The central issue is what experiments, in addition to the validation data usually provided for the conventional bioanalytical methods, need to be conducted to confirm HPLC−MS/MS assay selectivity and reliability. The current regulatory requirements include the need for the assessment and elimination of the matrix effect in the bioanalytical methods, but the experimental procedures necessary to assess the matrix effect are not detailed. Practical, experimental approaches for studying, identifying, and eliminating the effect of matrix on the results of quantitative analyses by HPLC−MS/MS are described in this paper. Using as an example a set of validation experiments performed for one of our investigational new drug candidates, the concepts of the quantitative assessment of the “absolute” versus “relative” matrix effect are introduced. In addition, experiments for the determination of, the “true” recovery of analytes using HPLC−MS/MS are described eliminating the uncertainty about the effect of matrix on the determination of this commonly measured method parameter. Determination of the matrix effect allows the assessment of the reliability and selectivity of an existing HPLC−MS/MS method. If the results of these studies are not satisfactory, the parameters determined may provide a guide to what changes in the method need to be made to improve assay selectivity. In addition, a direct comparison of the extent of the matrix effect using two different interfaces (a heated nebulizer, HN, and ion spray, ISP) under otherwise the same sample preparation and chromatographic conditions was made. It was demonstrated that, for the investigational drug under study, the matrix effect was clearly observed when ISP interface was utilized but it was absent when the HN interface was employed.
Skyrmion crystals are regular arrangements of magnetic whirls that exist in a wide range of chiral magnets. Because of their topology, they cannot be created or destroyed by smooth rearrangements of ...the direction of the local magnetization. Using magnetic force microscopy, we tracked the destruction of the skyrmion lattice on the surface of a bulk crystal of Fe₁₋ x Co x Si (x=0.5). Our study revealed that skyrmions vanish by a coalescence, forming elongated structures. Numerical simulations showed that changes of topology are controlled by singular magnetic point defects. They can be viewed as quantized magnetic monopoles and antimonopoles, which provide sources and sinks of one flux quantum of emergent magnetic flux, respectively.
Magnetic skyrmions in chiral magnets are nanoscale, topologically protected magnetization swirls that are promising candidates for spintronics memory carriers. Therefore, observing and manipulating ...the skyrmion state on the surface level of the materials are of great importance for future applications. Here, we report a controlled way of creating a multidomain skyrmion state near the surface of a Cu2OSeO3 single crystal, observed by soft resonant elastic X-ray scattering. This technique is an ideal tool to probe the magnetic order at the L 3 edge of 3d metal compounds giving an average depth sensitivity of ∼50 nm. The single-domain 6-fold-symmetric skyrmion lattice can be broken up into domains, overcoming the propagation directions imposed by the cubic anisotropy by applying the magnetic field in directions deviating from the major cubic axes. Our findings open the door to a new way to manipulate and engineer the skyrmion state locally on the surface or on the level of individual skyrmions, which will enable applications in the future.
EGFR-mutant lung adenocarcinomas (LUAD) display diverse clinical trajectories and are characterized by rapid but short-lived responses to EGFR tyrosine kinase inhibitors (TKIs). Through sequencing of ...79 spatially distinct regions from 16 early stage tumors, we show that despite low mutation burdens, EGFR-mutant Asian LUADs unexpectedly exhibit a complex genomic landscape with frequent and early whole-genome doubling, aneuploidy, and high clonal diversity. Multiple truncal alterations, including TP53 mutations and loss of CDKN2A and RB1, converge on cell cycle dysregulation, with late sector-specific high-amplitude amplifications and deletions that potentially beget drug resistant clones. We highlight the association between genomic architecture and clinical phenotypes, such as co-occurring truncal drivers and primary TKI resistance. Through comparative analysis with published smoking-related LUAD, we postulate that the high intra-tumor heterogeneity observed in Asian EGFR-mutant LUAD may be contributed by an early dominant driver, genomic instability, and low background mutation rates.
Hunter syndrome is a rare, X-linked disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase. In the absence of sufficient enzyme activity, glycosaminoglycans accumulate in the ...lysosomes of many tissues and organs and contribute to the multisystem, progressive pathologies seen in Hunter syndrome. The nervous, cardiovascular, respiratory, and musculoskeletal systems can be involved in individuals with Hunter syndrome. Although the management of some clinical problems associated with the disease may seem routine, the management is typically complex and requires the physician to be aware of the special issues surrounding the patient with Hunter syndrome, and a multidisciplinary approach should be taken. Subspecialties such as otorhinolaryngology, neurosurgery, orthopedics, cardiology, anesthesiology, pulmonology, and neurodevelopment will all have a role in management, as will specialty areas such as physiotherapy, audiology, and others. The important management topics are discussed in this review, and the use of enzyme-replacement therapy with recombinant human iduronate-2-sulfatase as a specific treatment for Hunter syndrome is presented.
Montelukast, a leukotriene receptor antagonist commonly prescribed for treatment of asthma, is primarily metabolized by cytochrome P450 (CYP)2C8, and has been suggested as a probe substrate for ...investigating CYP2C8 activity in vivo. We evaluated the quantitative role of hepatic uptake transport in its pharmacokinetics and drug–drug interactions (DDIs). Montelukast was characterized with significant active uptake in human hepatocytes, and showed affinity towards organic anion transporting polypeptides (OATPs) in transfected cell systems. Single‐dose rifampicin, an OATP inhibitor, decreased montelukast clearance in rats and monkeys. Clinical DDIs of montelukast were evaluated using physiologically based pharmacokinetic modeling; and simulation of the interactions with gemfibrozil–CYP2C8 and OATP1B1/1B3 inhibitor, clarithromycin–CYP3A and OATP1B1/1B3 inhibitor, and itraconazole–CYP3A inhibitor, implicated OATPs‐CYP2C8‐CYP2C8 interplay as the primary determinant of montelukast pharmacokinetics. In conclusion, hepatic uptake plays a key role in the pharmacokinetics of montelukast, which should be taken into account when interpreting clinical interactions.
A planar slab of negative-index material works as a superlens with sub-diffraction-limited resolution, as propagating waves are focused and, moreover, evanescent waves are reconstructed in the image ...plane. Here we demonstrate a superlens for electric evanescent fields with low losses using perovskites in the mid-infrared regime. The combination of near-field microscopy with a tunable free-electron laser allows us to address precisely the polariton modes, which are critical for super-resolution imaging. We spectrally study the lateral and vertical distributions of evanescent waves around the image plane of such a lens, and achieve imaging resolution of λ/14 at the superlensing wavelength. Interestingly, at certain distances between the probe and sample surface, we observe a maximum of these evanescent fields. Comparisons with numerical simulations indicate that this maximum originates from an enhanced coupling between probe and object, which might be applicable for multifunctional circuits, infrared spectroscopy and thermal sensors.
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