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Hyperfine interactions between electron and nuclear spins have been widely used in material science, organic chemistry, and structural biology as a sensitive probe to the local chemical environment through spatial identification of nuclear spins. With the nuclear spins identified, the isotropic and anisotropic components of the hyperfine interactions in turn offer unique insight into the electronic ground-state properties of the paramagnetic centers. However, traditional ensemble measurements of hyperfine interactions average over a macroscopic number of spins with different geometrical locations and nuclear isotopes. Here, we use a scanning tunneling microscope (STM) combined with electron spin resonance (ESR) to measure hyperfine spectra of hydrogenated-titanium (Ti) atoms on MgO/Ag(100) and thereby determine the isotropic and anisotropic hyperfine interactions at the single-atom level. By combining vector-field ESR spectroscopy with STM-based atom manipulation, we characterize the full hyperfine tensor of individual Ti-47 and Ti-49 atoms and identify significant spatial anisotropy of hyperfine interaction for both isotopes when they are adsorbed at low-symmetry binding sites. Density functional theory calculations reveal that the large hyperfine anisotropy arises from a highly anisotropic distribution of the ground-state electron spin density. Our work highlights the power of ESR-STM-enabled single-atom hyperfine spectroscopy as a powerful tool in revealing ground-state electronic structures and atomic-scale chemical environments with nano-electronvolt resolution., 17 pages, 4 figures

Kimchi is a traditional Korean food, of which its constituent lactic acid bacteria have been reported to possess various physiological activities. However, few studies have investigated the immunological activity of these bacteria or their effect on atopic dermatitis (AD). We investigated whether a mixture of 6 types of lactic acid bacteria strains (LBS) isolated from kimchi has an immunomodulating effect on atopy. Mice with atopic dermatitis were orally administered LSB from kimchi for 8 weeks, and skin moisture content, scratching behavior, T-and B-cell proliferation, Th1/2 cytokines, and serum IgE and histamine levels were measured. In addition, hematoxylin and eosin and toluidine blue staining were con-ducted. Mice receiving LBS from kimchi had increased skin moisture content (164.3%) and T-cell proliferation (more than 4-fold), and decreased number of scratching behaviors (78.2%) and B-cell proliferation (63.7%) compared with the 2,4-dinitrochlorobenzene control group. In addition, LBS increased Th1 type cytokines, decreased Th2 type and pro-inflam-matory cytokines, and decreased blood IgE (70.4%), histamine (67.6%) and mast cell levels. Therefore, it suggests that LBS of kimchi may be helpful in improving AD caused by immunological imbalance.

Two-photon microscopy can resolve fluorescence dynamics deep in scattering tissue, but applying this techniquein vivois limited by short working distance water-immersion objectives. Here we present an ultra long working distance (20 mm) air objective called the Cousa objective. It is optimized for performance across multiphoton imaging wavelengths, offers a >4 mm2FOV with submicron lateral resolution, and is compatible with commonly used multiphoton imaging systems. We share the full optical prescription, along with data on real world performance includingin vivocalcium imaging in a range of species and approaches.

In vivo and real-time multicellular imaging enables the decoding of sensory circuits and the tracking of systemic drug uptake. However, in vivo imaging of the auditory periphery remains technically challenging owing to the deep location, mechanosensitivity and fluid-filled, bone-encased nature of the cochlear structure. Existing methods that expose the cochlea invariably cause irreversible damage to auditory function, severely limiting the experimental measurements possible in living animals. Here we present an in vivo surgical protocol that permits the imaging of cochlear cells in hearing mice. Our protocol describes a ventro-lateral approach for preserving external and middle ear structures while performing surgery, the correct mouse positioning for imaging cochlear cells with effective sound transmission into the ear, the chemo-mechanical cochleostomy for creating the imaging window in the otic capsule bone that prevents intracochlear fluid leakage by maintaining an intact endosteum, and the release of intracochlear pressure that separates the endosteum from the otic capsule bone while creating an imaging window. The procedure thus preserves hearing thresholds. Individual inner and outer hair cells, supporting cells and nerve fibers can be visualized in vivo while hearing function is preserved. This approach may enable future original investigations, such as the real-time tracking of ototoxic drug transport into the cochleae. The technique may be applied to the monitoring of sound-evoked functional activity in multiple cochlear cells, in combination with optogenetic tools, and may help to improve cochlear implantation in humans. The cochleostomy takes ~1 h and requires experience in surgery.

Aminoglycosides (AGs) are commonly used antibiotics that cause deafness through the irreversible loss of cochlear sensory hair cells (HCs). How AGs enter the cochlea and then target HCs remains unresolved. Here, we performed time-lapse multicellular imaging of cochlea in live adult hearing mice via a chemo-mechanical cochleostomy. The in vivo tracking revealed that systemically administered Texas Red–labeled gentamicin (GTTR) enters the cochlea via the stria vascularis and then HCs selectively. GTTR uptake into HCs was completely abolished in transmembrane channel-like protein 1 (TMC1) knockout mice, indicating mechanotransducer channel-dependent AG uptake. Blockage of megalin, the candidate AG transporter in the stria vascularis, by binding competitor cilastatin prevented GTTR accumulation in HCs. Furthermore, cilastatin treatment markedly reduced AG-induced HC degeneration and hearing loss in vivo. Together, our in vivo real-time tracking of megalin-dependent AG transport across the blood–labyrinth barrier identifies new therapeutic targets for preventing AG-induced ototoxicity.

Immunosuppression occurs in response to a variety of external antigens. However, various immune cells and cytokines can activate the immune system. In this study, it was found that fermented deer velvet (FD) and fermented

The stereocilia rootlet is a key structure in vertebrate hair cells, anchoring stereocilia firmly into the cell’s cuticular plate and protecting them from overstimulation. Using superresolution microscopy, we show that the ankyrin-repeat protein ANKRD24 concentrates at the stereocilia insertion point, forming a ring at the junction between the lower and upper rootlets. Annular ANKRD24 continues into the lower rootlet, where it surrounds and binds TRIOBP-5, which itself bundles rootlet F-actin. TRIOBP-5 is mislocalized in Ankrd24KO/KO hair cells, and ANKRD24 no longer localizes with rootlets in mice lacking TRIOBP-5; exogenous DsRed–TRIOBP-5 restores endogenous ANKRD24 to rootlets in these mice. Ankrd24KO/KO mice show progressive hearing loss and diminished recovery of auditory function after noise damage, as well as increased susceptibility to overstimulation of the hair bundle. We propose that ANKRD24 bridges the apical plasma membrane with the lower rootlet, maintaining a normal distribution of TRIOBP-5. Together with TRIOBP-5, ANKRD24 organizes rootlets to enable hearing with long-term resilience.

Atomic-scale control of multiple spins with individual addressability enables the bottom-up design of functional quantum devices. Tailored nanostructures can be built with atomic precision using scanning tunneling microscopes, but quantum-coherent driving has thus far been limited to a spin in the tunnel junction. Here we show the ability to drive and detect the spin resonance of a remote spin using the electric field from the tip and a single-atom magnet placed nearby. Read-out was achieved via a weakly coupled second spin in the tunnel junction that acted as a quantum sensor. We simultaneously and independently drove the sensor and remote spins by two radio frequency voltages in double resonance experiments, which provides a path to quantum-coherent multi-spin manipulation in customized spin structures on surfaces. One-Sentence Summary: Using a scanning tunneling microscope, we simultaneously control two spins using one tip, paving the way for multi-spin-qubit operations on surfaces.

Electronic states in the gap of a superconductor inherit intriguing many-body properties from the superconductor. Here, we create these in-gap states by manipulating Cr atomic chains on the $\ensuremath{\beta}\ensuremath{-}\mathrm{Bi}{}_{2}\mathrm{Pd}$ superconductor. We find that the topological properties of the in-gap states can greatly vary depending on the crafted spin chain. These systems make an ideal platform for nontrivial topological phases because of the large atom-superconductor interactions and the existence of a large Rashba coupling at the Bi-terminated surface. We study two spin chains, one with atoms two lattice parameters apart and one with $\sqrt{2}$ lattice parameters. Of these, only the second one is in a topologically nontrivial phase, in agreement with the spin interactions for this geometry.

Hospitalization rates for ambulatory care sensitive conditions (ACSCs) can indicate the accessibility of a community’s primary care. We examined regional variation in ACSC hospitalization rates and identified associated factors. ACSC hospitalization rates in the 232 districts in 2013 ranged from 4.08 to 101.53 per 1000 adults. Spatial analysis showed that none of the 24 highest rate districts were located near Seoul, whereas 80% of the 45 lowest rate districts were, suggesting health care inequality between people living near Seoul and in other areas. Regression analysis showed significantly higher ACSC hospitalization rates in districts with higher elderly (β = 0.94) and low-income populations (β = 2.25), more remote areas (β = 0.29), and more hospital beds (β = 0.03). The number of primary care clinics was negatively associated with ACSC hospitalization (β = −1.37). For these variables, geographically weighted regression analysis provided local regression coefficients, useful for developing region-specific strategies to reduce ACSC hospitalization.

Dissolving microneedles (DMNs) have been used as an alternative drug delivery system to deliver therapeutics across the skin barrier in a painless manner. In this study, we propose a novel heat-melting method for the fabrication of hydrophobic poly(lactic-co-glycolic acid) (PLGA) DMNs, without the use of potentially harmful organic solvents. The drug-loaded PLGA mixture, which consisted of a middle layer of the DMN, was optimized and successfully implanted into ex vivo porcine skin. Implanted HMP-DMNs separated from the patch within 10 min, enhancing user compliance, and the encapsulated molecules were released for nearly 4 weeks thereafter. In conclusion, the geometry of HMP-DMNs was successfully optimized for safe and effective transdermal sustained drug delivery without the use of organic solvents. This study provides a strategy for the innovative utilization of PLGA as a material for transdermal drug delivery systems.

Background: This study aimed to provide basic data for the development of COVID-19 infectionmanagement educational programs by confirming the factors that affect the performance of COVID-19infection management administration in general hospitals.Method: Data was collected from administrative staff at 192 general hospitals by means of a structuralizedquestionnaire, and SPSS Ver. 21.0 software was used for data analysis.Conclusion: The extent of knowledge and execution of COVID-19 infection management processes byadministrative staff in general hospitals was positively correlated with the extent of educational demandfor COVID-19 infection management, with explanatory power of 16.7%. It is necessary to include factorsincluding COVID-19 transmission route, transmission prevention, and staff safety in COVID-19 infectionmanagement educational program administration. In addition, it is essential also to performance COVID-19infection management education

The purpose of this study was to explore hospital management graduates’ experience in pathology courses. Data were gathered through four focus group interviews by 16 hospital management graduates who attended pathology courses. Data were collected from June to August, 2020. Conventional content analysis was used for data analysis. Six categories were extracted that described hospital management graduates’ experience in pathology courses, as follows: “Suggestions for the curriculum,” “Students’ preference for pathology professor,” “Demands for various teaching methods,” “Broad and difficult class content,” “Recognition of pathology courses during college years,” and “The importance of studying the pathology course realized after graduation.” The findings suggest that it is important to identify hospital management graduates’ perspectives to improve pathology curriculum in the educational process. Additionally, it is necessary to continuously connect educational and practical environments for the effective management of pathology courses.

We investigated spin-1/2 hydrogenated titanium (Ti) atoms on MgO using scanning tunneling microscopy (STM) combined with electron spin resonance (ESR) in vector magnetic fields. Rotating external magnetic fields, we observed rather drastic changes in both amplitude and frequency of resonance signals for single Ti atoms. While the variation of ESR amplitudes reflects the effects of the spin polarization of a magnetic tip and local magnetic fields created by the interaction between the tip and Ti, the change of resonance frequencies shows the anisotropy of g values for Ti atoms. Using the Ti atoms at the low-symmetry bridge adsorption site of the MgO lattice allowed for identifying the g values in all three spatial directions. Multiplet calculations confirmed the origin of this anisotropy as the spin-orbit coupling induced effects of crystal. Our results show the capability of single atomic spins as a sensor to probe magnetic surroundings and highlight the precision of ESR-STM to identify the single atom's spin states in a solid-state environment., This work was supported by the Institute for Basic Science (Grant No. IBS-R027-D1). D.-J.C. acknowledges financial support from the Spanish MICINN (Project No. RTI2018- 097895-B-C44 and Excelencia Project No. EUR2020-112116) and Eusko Jaurlaritza (Project No. PIBA_2020_-1_0017). F.D. acknowledges financial support from Spanish MICINN (Grant No. PID2019-109539GB-C41), Basque Government (Grant No. IT986-16), and Canary Islands program Viera y Clavijo (Grant No. 2017/0000231). C.P.L. acknowledges financial support from the ONR.

Aminoglycosides are potent antibiotics that are commonly prescribed worldwide. Their use carries significant risks of ototoxicity by directly causing inner ear hair cell degeneration. Despite their ototoxic side effects, there are currently no approved antidotes. Here we review recent advances in our understanding of aminoglycoside ototoxicity, mechanisms of drug transport, and promising sites for intervention to prevent ototoxicity.

Background/aim Few studies have examined the effect of 2'-hydroxycinnamaldehyde (HCA) on head and neck squamous cell carcinoma (HNSCC) cell invasion. This study examined the role of BMP7 on the anti-migration and anti-invasion activity of HCA using HNSCC cells. Materials and methods Matrigel invasion and wound healing assays were conducted to investigate cell migration or invasion. BMP7 overexpression vector or siRNA mixture was used for transient regulation of gene expression. Results HCA attenuated HNSCC cell migration and spheroids Matrigel invasion without cytotoxicity. mRNA and protein expression of BMP7 increased with HCA treatment. Exogenous BMP7 overexpression without HCA treatment attenuated Matrigel invasion of cells. Furthermore, suppression of BMP7 by siRNA alleviated the inhibitory effect of HCA on the invasion of Matrigel by the cell, indicating that BMP7 is responsible for the anti-migration effect of HCA in HNSCC cells. Conclusion HCA treatment led to a remarkable up-regulation of BMP7, which resulted in the attenuation of HNSCC cell invasion.

The effect of oxytocin (OXT) on cancer invasion is controversial. Few studies have examined the effect of early growth response-1 (EGR1) on the invasion of head and neck squamous cell carcinoma (HNSCC). Here, we evaluated how EGR1 affects HNSCC cell migration through the molecular mechanism of OXT in exerting anti-invasion activity. Matrigel invasion and wound-healing assays were used to measure the in-vitro cell migration. The molecular mechanism of OXT was assessed by knockdown or overexpression of EGR1 in HNSCC cells. Three-dimensional (3-D) spheroids formation, followed by the image analysis for quantification was performed. OXT at 500 nmol/l increased mRNA and protein expression of E-cadherin without cytotoxicity. OXT upregulated mRNA and protein expression of EGR1 in 6 h. p53, phosphatase and tensin, and p21 expression was increased in an EGR1-dependent manner with OXT treatment. In addition, OXT significantly downregulated 3-D spheroids' formation according to spheroids' number and size. Our data showed that OXT downregulated HNSCC cell migration by EGR1 upregulation. OXT inhibited spheroids' formation of HNSCC cells under 3-D culture conditions.

The exquisite sensitivity and frequency discrimination of mammalian hearing underlie the ability to understand complex speech in noise. This requires force generation by cochlear outer hair cells (OHCs) to amplify the basilar membrane traveling wave; however, it is unclear how amplification is achieved with sharp frequency tuning. Here we investigated the origin of tuning by measuring sound-induced 2-D vibrations within the mouse organ of Corti in vivo . Our goal was to determine the transfer function relating the radial shear between the structures that deflect the OHC bundle, the tectorial membrane and reticular lamina, to the transverse motion of the basilar membrane. We found that, after normalizing their responses to the vibration of the basilar membrane, the radial vibrations of the tectorial membrane and reticular lamina were tuned. The radial tuning peaked at a higher frequency than transverse basilar membrane tuning in the passive, postmortem condition. The radial tuning was similar in dead mice, indicating that this reflected passive, not active, mechanics. These findings were exaggerated in TectaC1509G/C1509G mice, where the tectorial membrane is detached from OHC stereocilia, arguing that the tuning of radial vibrations within the hair cell epithelium is distinct from tectorial membrane tuning. Together, these results reveal a passive, frequency-dependent contribution to cochlear filtering that is independent of basilar membrane filtering. These data argue that passive mechanics within the organ of Corti sharpen frequency selectivity by defining which OHCs enhance the vibration of the basilar membrane, thereby tuning the gain of cochlear amplification. SIGNIFICANCE STATEMENT Outer hair cells amplify the traveling wave within the mammalian cochlea. The resultant gain and frequency sharpening are necessary for speech discrimination, particularly in the presence of background noise. Here we measured the 2-D motion of the organ of Corti in mice and found that the structures that stimulate the outer hair cell stereocilia, the tectorial membrane and reticular lamina, were sharply tuned in the radial direction. Radial tuning was similar in dead mice and in mice lacking a tectorial membrane. This suggests that radial tuning comes from passive mechanics within the hair cell epithelium, and that these mechanics, at least in part, may tune the gain of cochlear amplification.

Traumatic noise causes hearing loss by damaging sensory hair cells and their auditory synapses. There are no treatments. Here, we investigated mice exposed to a blast wave approximating a roadside bomb. In vivo cochlear imaging revealed an increase in the volume of endolymph, the fluid within scala media, termed endolymphatic hydrops. Endolymphatic hydrops, hair cell loss, and cochlear synaptopathy were initiated by trauma to the mechanosensitive hair cell stereocilia and were K+-dependent. Increasing the osmolality of the adjacent perilymph treated endolymphatic hydrops and prevented synaptopathy, but did not prevent hair cell loss. Conversely, inducing endolymphatic hydrops in control mice by lowering perilymph osmolality caused cochlear synaptopathy that was glutamate-dependent, but did not cause hair cell loss. Thus, endolymphatic hydrops is a surrogate marker for synaptic bouton swelling after hair cells release excitotoxic levels of glutamate. Because osmotic stabilization prevents neural damage, it is a potential treatment to reduce hearing loss after noise exposure.

The dendritic planarity of Purkinje cells is critical for cerebellar circuit formation. In the absence of Crk and CrkL, the Reelin pathway does not function resulting in partial Purkinje cell migration and defective dendritogenesis. However, the relationships among Purkinje cell migration, dendritic development and Reelin signaling have not been clearly delineated. Here, we use synchrotron X-ray microscopy to obtain 3-D images of Golgi-stained Purkinje cell dendrites. Purkinje cells that failed to migrate completely exhibited conical dendrites with abnormal 3-D arborization and reduced dendritic complexity. Furthermore, their spines were fewer in number with a distorted morphology. In contrast, Purkinje cells that migrated successfully displayed planar dendritic and spine morphologies similar to normal cells, despite reduced dendritic complexity. These results indicate that, during cerebellar formation, Purkinje cells migrate into an environment that supports development of dendritic planarity and spine formation. While Reelin signaling is important for the migration process, it does not make a direct major contribution to dendrite formation. Electronic supplementary material The online version of this article (doi:10.1007/s00429-014-0780-2) contains supplementary material, which is available to authorized users.

In this paper, we provide a review of Professor Powers’s and his students’ work on connecting fault analysis, discrete process control, human operating procedures, and symbolic model checking. In recent years, this type of research is placed under the banner of “cyber-physical systems research”. Some of the techniques and procedures Powers and his students developed can be found in the open literature and conference proceedings. However, they have not been published broadly due to the untimely passing of Professor Powers. A complete overview of the methods are not available, and the cap-stone results obtained in the two last Ph.D. theses have not been published.