Mesoscopic Structures and Coexisting Phases in Silica Films.

Silica films represent a unique two-dimensional film system, exhibiting both crystalline and vitreous forms. While much scientific work has focused on the atomic-scale features of this film system, mesoscale structures can play an important role for understanding confined space reactions and other applications of silica films. Here, we report on mesoscale structures in silica films grown under ultrahigh vacuum and examined with scanning tunneling microscopy (STM). Silica films can exhibit coexisting phases of monolayer, zigzag, and bilayer structures. Both holes in the film structure and atomic-scale substrate steps are observed to influence these coexisting phases. In particular, film regions bordering holes in silica bilayer films exhibit vitreous character, even in regions where the majority film structure is crystalline. At high coverages mixed zigzag and bilayer phases are observed at step edges, while at lower coverages silica phases with lower silicon densities are observed more prevalently near step edges. The STM images reveal that silica films exhibit rich structural diversity at the mesoscale.

Deep learning model enables the discovery of a novel immunotherapeutic agent regulating the kynurenine pathway.

Kynurenine (Kyn) is a key inducer of an immunosuppressive tumor microenvironment (TME). Although indoleamine 2,3-dioxygenase (IDO)-selective inhibitors have been developed to suppress the Kyn pathway, the results were not satisfactory due to the presence of various opposing mechanisms. Here, we employed an orally administered novel Kyn pathway regulator to overcome the limitation of anti-tumor immune response. We identified a novel core structure that inhibited both IDO and TDO. An orally available lead compound, STB-C017 (designated hereafter as STB), effectively inhibited the enzymatic and cellular activity of IDO and TDO in vitro. Moreover, it potently suppressed Kyn levels in both the plasma and tumor in vivo. STB monotherapy increased the infiltration of CD8+ T cells into TME. In addition, STB reprogrammed the TME with widespread changes in immune-mediated gene signatures. Notably, STB-based combination immunotherapy elicited the most potent anti-tumor efficacy through concurrent treatment with immune checkpoint inhibitors, leading to complete tumor regression and long-term overall survival. Our study demonstrated that a novel Kyn pathway regulator derived using deep learning technology can activate T cell immunity and potentiate immune checkpoint blockade by overcoming an immunosuppressive TME.

The "Intermediate" CD14 + CD16 + monocyte subpopulation plays a role in IVIG responsiveness of children with Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is an acute, self-limited febrile illness of unknown cause. Intravenous immunoglobulin (IVIG)-resistance are related to greater risk for permanent cardiac complications. We aimed to determine the correlation between monocytes and the phenotype of KD in relation to IVIG responsiveness in children. MATERIALS AND METHODS: The study cohort included 62 patients who were diagnosed with KD, 20 non febrile healthy controls (NFC), and 15 other febrile controls (OFC). In all enrolled patients, blood was taken at least 4 times and laboratory tests were performed. In addition, subtypes of monocytes were characterized via flow cytometry. RESULTS: The numbers of intermediate monocytes were significantly lower in IVIG-resistant group compared to IVIG-responsive group before IVIG infusion (p < 0.0001). After infusion, intermediate monocytes decreased in the responsive group, while a trend of increase was observed in the resistant group. Only intermediate monocytes were significant in logistic regression with adjusted OR of 0.001 and p value of 0.03. CONCLUSIONS: CD14 + CD16 + intermediate monocyte may play an important role in IVIG responsiveness among KD children. Low starting levels of intermediate monocytes, followed by a dramatic increase post-IVIG infusion during acute phase of KD are associated with IVIG-resistance. Functional studies on intermediate monocyte may help to reveal the pathophysiology.

Ce=O Terminated CeO2.

Multiply bonded lanthanide oxo groups are rare in coordination compounds and have not previously been reported for a surface termination of a lanthanide oxide. Here we report the observation of a Ce=O terminated ceria surface in a CeO2 (111)-( 3 × 3 )R30° reconstruction of ≈3 nm thick ceria islands prepared on Pt(111). This is evidenced by scanning tunnelling microscopy (STM), low energy electron diffraction (LEED) and high-resolution electron energy loss spectroscopy (HREELS) measurements in conjunction with density functional theory (DFT) calculations. A Ce=O stretching frequency of 775 cm-1 is observed in HREELS, compared with 766 cm-1 calculated by DFT. The calculations also predict that the Ce=O bond is weak, with an oxygen vacancy formation energy of 0.85 eV. This could play an important role in the facile removal of lattice oxygen from CeO2 , accompanied by the reduction of CeIV to CeIII , which is a key attribute of ceria-based systems in connection with their unique catalytic properties.

Photonic scheme of quantum phase estimation for quantum algorithms via cross-Kerr nonlinearities under decoherence effect.

Quantum phase estimation (QPE) is the key procedure in various quantum algorithms. The main aim of the QPE scheme is to estimate the phase of an unknown eigenvalue, corresponding to an eigenstate of an arbitrary unitary operation. The QPE scheme can be applied as a subroutine to design many quantum algorithms. In this paper, we propose the basic structure of a QPE scheme that could be applied in quantum algorithms, with feasibility by utilizing cross-Kerr nonlinearities (controlled-unitary gates) and linearly optical devices. Subsequently, we analyze the efficiency and the performance of the controlled-unitary gate. This gate consists of a controlled-path gate and a merging-path gate via cross-Kerr nonlinearities under the decoherence effect. Also shown in this paper is a method by which to enhance robustness against the decoherence effect to provide a reliable QPE scheme based on controlled-unitary gates.

Characteristics of sulfur atoms adsorbed on Ag(100), Ag(110), and Ag(111) as probed with scanning tunneling microscopy: experiment and theory.

In this paper, we report that S atoms on Ag(100) and Ag(110) exhibit a distinctive range of appearances in scanning tunneling microscopy (STM) images, depending on the sample bias voltage, VS. Progressing from negative to positive VS, the atomic shape can be described as a round protrusion surrounded by a dark halo (sombrero) in which the central protrusion shrinks, leaving only a round depression. This progression resembles that reported previously for S atoms on Cu(100). We test whether DFT can reproduce these shapes and the transition between them, using a modified version of the Lang-Tersoff-Hamann method to simulate STM images. The sombrero shape is easily reproduced, but the sombrero-depression transition appears only for relatively low tunneling current and correspondingly realistic tip-sample separation, dT, of 0.5-0.8 nm. Achieving these conditions in the calculations requires sufficiently large separation (vacuum) between slabs, together with high energy cutoff, to ensure appropriate exponential decay of electron density into vacuum. From DFT, we also predict that an analogous transition is not expected for S atoms on Ag(111) surfaces. The results are explained in terms of the through-surface conductance, which defines the background level in STM, and through-adsorbate conductance, which defines the apparent height at the point directly above the adsorbate. With increasing VS, for Ag(100) and Ag(110), we show that through-surface conductance increases much more rapidly than through-adsorbate conductance, so the apparent adsorbate height drops below background. In contrast, for Ag(111) the two contributions increase at more comparable rates, so the adsorbate level always remains above background and no transition is seen.

Cancer Drug Response Profile scan (CDRscan): A Deep Learning Model That Predicts Drug Effectiveness from Cancer Genomic Signature.

In the era of precision medicine, cancer therapy can be tailored to an individual patient based on the genomic profile of a tumour. Despite the ever-increasing abundance of cancer genomic data, linking mutation profiles to drug efficacy remains a challenge. Herein, we report Cancer Drug Response profile scan (CDRscan) a novel deep learning model that predicts anticancer drug responsiveness based on a large-scale drug screening assay data encompassing genomic profiles of 787 human cancer cell lines and structural profiles of 244 drugs. CDRscan employs a two-step convolution architecture, where the genomic mutational fingerprints of cell lines and the molecular fingerprints of drugs are processed individually, then merged by 'virtual docking', an in silico modelling of drug treatment. Analysis of the goodness-of-fit between observed and predicted drug response revealed a high prediction accuracy of CDRscan (R2 > 0.84; AUROC > 0.98). We applied CDRscan to 1,487 approved drugs and identified 14 oncology and 23 non-oncology drugs having new potential cancer indications. This, to our knowledge, is the first-time application of a deep learning model in predicting the feasibility of drug repurposing. By further clinical validation, CDRscan is expected to allow selection of the most effective anticancer drugs for the genomic profile of the individual patient.

A Two-Dimensional 'Zigzag' Silica Polymorph on a Metal Support.

We present a new polymorph of the two-dimensional (2D) silica film with a characteristic 'zigzag' line structure and a rectangular unit cell which forms on a Ru(0001) metal substrate. This new silica polymorph may allow for important insights into growth modes and transformations of 2D silica films as a model system for the study of glass transitions. Based on scanning tunneling microscopy, low energy electron diffraction, infrared reflection absorption spectroscopy, and X-ray photoelectron spectroscopy measurements on the one hand, and density functional theory calculations on the other, a structural model for the 'zigzag' polymorph is proposed. In comparison to established monolayer and bilayer silica, this 'zigzag' structure system has intermediate characteristics in terms of coupling to the substrate and stoichiometry. The silica 'zigzag' phase is transformed upon reoxidation at higher annealing temperature into a SiO2 silica bilayer film which is chemically decoupled from the substrate.

Sulfur Atoms Adsorbed on Cu(100) at Low Coverage: Characterization and Stability against Complexation.

Using scanning tunneling microscopy, we characterize the size and bias-dependent shape of sulfur atoms on Cu(100) at low coverage (below 0.1 monolayers) and low temperature (quenched from 300 to 5 K). Sulfur atoms populate the Cu(100) terraces more heavily than steps at low coverage, but as coverage approaches 0.1 monolayers, close-packed step edges become fully populated, with sulfur atoms occupying sites on top of the step. Density functional theory (DFT) corroborates the preferential population of terraces at low coverage as well as the step adsorption site. In experiment, small regions with p(2 × 2)-like atomic arrangements emerge on the terraces as sulfur coverage approaches 0.1 monolayer. Using DFT, a lattice gas model has been developed, and Monte Carlo simulations based on this model have been compared with the observed terrace configurations. A model containing eight pairwise interaction energies, all repulsive, gives qualitative agreement. Experiment shows that atomic adsorbed sulfur is the only species on Cu(100) up to a coverage of 0.09 monolayers. There are no Cu-S complexes. In contrast, prior work has shown that a Cu2S3 complex forms on Cu(111) under comparable conditions. On the basis of DFT, this difference can be attributed mainly to stronger adsorption of sulfur on Cu(100) as compared with Cu(111).

Rhinoplasty with Barbed Threads.

BACKGROUND: Strong strut structures are necessary for nasal tip projection in Asian rhinoplasty. Traditionally, strut structures have been constructed by open skin incisions. METHODS: Barbed threads were implanted for rhinoplasties. The threads have multiple sharp barbs and umbrella-like longitudinal splits at both ends. Autologous micronized fat tissue graft was also simultaneously used when volume replacement was necessary. RESULTS: Since 2003, barbed threads have been used in approximately 1,200 rhinoplasties for nasal tip projection, dorsal length elongation, and nostril correction. The results of relative length ratios comparing true lateral photographs showed significant increase in tip projection. CONCLUSION: The results of long-term observation (> 6 months) indicate that the surgical procedure of lifting the nasal tips with barbed threads is significantly effective for the anterior projection of nasal tip in Asians.

Regulation of Noncoding Transcriptome in Developing Photoreceptors by Rod Differentiation Factor NRL.

Purpose: Transcriptome analysis by next generation sequencing allows qualitative and quantitative profiling of expression patterns associated with development and disease. However, most transcribed sequences do not encode proteins, and little is known about the functional relevance of noncoding (nc) transcriptome in neuronal subtypes. The goal of this study was to perform a comprehensive analysis of long noncoding (lncRNAs) and antisense (asRNAs) RNAs expressed in mouse retinal photoreceptors. Methods: Transcriptomic profiles were generated at six developmental time points from flow-sorted Nrlp-GFP (rods) and Nrlp-GFP;Nrl-/- (S-cone like) mouse photoreceptors. Bioinformatic analysis was performed to identify novel noncoding transcripts and assess their regulation by rod differentiation factor neural retina leucine zipper (NRL). In situ hybridization (ISH) was used for validation and cellular localization. Results: NcRNA profiles demonstrated dynamic yet specific expression signature and coexpression clusters during rod development. In addition to currently annotated 586 lncRNAs and 454 asRNAs, we identified 1037 lncRNAs and 243 asRNAs by de novo assembly. Of these, 119 lncRNAs showed altered expression in the absence of NRL and included NRL binding sites in their promoter/enhancer regions. ISH studies validated the expression of 24 lncRNAs (including 12 previously unannotated) and 4 asRNAs in photoreceptors. Coexpression analysis demonstrated 63 functional modules and 209 significant antisense-gene correlations, allowing us to predict possible role of these lncRNAs in rods. Conclusions: Our studies reveal coregulation of coding and noncoding transcripts in rod photoreceptors by NRL and establish the framework for deciphering the function of ncRNAs during retinal development.

NRL-Regulated Transcriptome Dynamics of Developing Rod Photoreceptors.

Gene regulatory networks (GRNs) guiding differentiation of cell types and cell assemblies in the nervous system are poorly understood because of inherent complexities and interdependence of signaling pathways. Here, we report transcriptome dynamics of differentiating rod photoreceptors in the mammalian retina. Given that the transcription factor NRL determines rod cell fate, we performed expression profiling of developing NRL-positive (rods) and NRL-negative (S-cone-like) mouse photoreceptors. We identified a large-scale, sharp transition in the transcriptome landscape between postnatal days 6 and 10 concordant with rod morphogenesis. Rod-specific temporal DNA methylation corroborated gene expression patterns. De novo assembly and alternative splicing analyses revealed previously unannotated rod-enriched transcripts and the role of NRL in transcript maturation. Furthermore, we defined the relationship of NRL with other transcriptional regulators and downstream cognate effectors. Our studies provide the framework for comprehensive system-level analysis of the GRN underlying the development of a single sensory neuron, the rod photoreceptor.

Single-Molecule Dynamics in the Presence of Strong Intermolecular Interactions.

In contrast to conventional spectroscopic studies of adsorbates at high coverage that provide only spatially averaged information, we have characterized the laterally confined shuttling dynamics of a single molecule under the influence of intermolecular interactions by vibrational spectroscopy using a scanning tunneling microscope. The bridge sites on Pt(111) are only occupied by a CO molecule that is surrounded by four other CO molecules at on-top sites. The bridge-site CO undergoes laterally confined shuttling toward an adjacent on-top site to transiently occupy a metastable site, which is slightly displaced from the center of an on-top site through repulsive interaction with adjacent on-top CO molecules. Analysis of action spectra for the shuttling events reveals the C-O stretch frequency of the metastable CO. We also constructed a modified potential energy surface incorporating the intermolecular interaction, which reveals the underlying mechanism and provides a new way to experimentally determine detailed information on the energetics of the metastable state.

Recruitment of Rod Photoreceptors from Short-Wavelength-Sensitive Cones during the Evolution of Nocturnal Vision in Mammals.

Vertebrate ancestors had only cone-like photoreceptors. The duplex retina evolved in jawless vertebrates with the advent of highly photosensitive rod-like photoreceptors. Despite cones being the arbiters of high-resolution color vision, rods emerged as the dominant photoreceptor in mammals during a nocturnal phase early in their evolution. We investigated the evolutionary and developmental origins of rods in two divergent vertebrate retinas. In mice, we discovered genetic and epigenetic vestiges of short-wavelength cones in developing rods, and cell-lineage tracing validated the genesis of rods from S cones. Curiously, rods did not derive from S cones in zebrafish. Our study illuminates several questions regarding the evolution of duplex retina and supports the hypothesis that, in mammals, the S-cone lineage was recruited via the Maf-family transcription factor NRL to augment rod photoreceptors. We propose that this developmental mechanism allowed the adaptive exploitation of scotopic niches during the nocturnal bottleneck early in mammalian evolution.

Formation of Two-Dimensional Copper Selenide on Cu(111) at Very Low Selenium Coverage.

Using scanning tunneling microscopy (STM), we observed that adsorption of Se on Cu(111) produced islands with a (√3×√3)R30° structure at Se coverages far below the structure's ideal coverage of 1/3 monolayer. On the basis of density functional theory (DFT), these islands cannot form due to attractive interactions between chemisorbed Se atoms. DFT showed that incorporating Cu atoms into the √3-Se lattice stabilizes the structure, which provided a plausible explanation for the experimental observations. STM revealed three types of √3 textures. We assigned two of these as two-dimensional layers of strained CuSe, analogous to dense planes of bulk klockmannite (CuSe). Klockmannite has a bulk lattice constant that is 11 % shorter than √3 times the surface lattice constant of Cu(111). This offers a rationale for the differences observed between these textures, for which strain limits the island size or distorts the √3 lattice. STM showed that existing step edges adsorb Se and facet toward ⟨12‾ 1⟩, which is consistent with DFT.

Early Intervention with Highly Condensed Adipose-Derived Stem Cells for Complicated Wounds Following Filler Injections.

BACKGROUND: A rise in cosmetic procedures has seen the use of fillers become more prevalent. Complications resulting from use of fillers have prompted introduction of various medical and surgical interventions. Recently, stem cell therapies have become more widely used as a new treatment option for tissue repair and regeneration. METHODS: We utilized adipose-derived stem cells (ASCs) for tissue regeneration in patients with filler-related complications such as necrosis. All 12 patients were treated with ASCs and some patients had additional treatment. After relief of symptoms, wound surface area was compared in terms of pixel numbers and scar condition was evaluated using the Vancouver Scar Scale (VSS). RESULTS: In general, we achieved satisfactory resolution of filler-related complications in a short period of time without serious side effects. The average number of days from stem cell treatment to symptom relief was 7.3 days. The proportion of wound surface area from photographic record was 4.39 % before treatment, decreasing considerably to 1.01 % following treatment. Last, the VSS showed almost all patients scored below 3, with two patients receiving scores of 7 and 8; the average score was 2.78 (range from 0 to 8). CONCLUSIONS: ASCs are a new treatment option for post-filler injection wounds such as necrosis. Using stem cells, we were able to obtain satisfactory results in a short period of time without complications requiring surgical procedures. We suggest stem cell injections could be used as the first option for treatment of complications from filler injections. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Identification of Au-S complexes on Au(100).

Using a combination of scanning tunneling microscopy and density functional theory (DFT) calculations, we have identified a set of related Au-S complexes that form on Au(100), when sulfur adsorbs and lifts the hexagonal surface reconstruction. The predominant complex is diamond-shaped with stoichiometry Au4S5. All of the complexes can be regarded as combinations of S-Au-S subunits. The complexes exist within, or at the edges of, p(2 × 2) sulfur islands that cover the unreconstructed Au regions, and are observed throughout the range of S coverage examined in this study, 0.009 to 0.12 monolayers. A qualitative model is developed which incorporates competitive formation of complexes, Au rafts, and p(2 × 2) sulfur islands, as Au atoms are released by the surface structure transformation.

Atomic-Scale Dynamics of Surface-Catalyzed Hydrogenation/Dehydrogenation: NH on Pt(111).

Low-temperature scanning tunneling microscopy (LT-STM) was used to move hydrogen atoms and dissociate NH molecules on a Pt(111) surface covered with an ordered array of nitrogen atoms in a (2 × 2) structure. The N-covered Pt(111) surface was prepared by ammonia oxydehydrogenation, which was achieved by annealing an ammonia-oxygen overlayer to 400 K. Exposing the N-covered surface to H2(g) forms H atoms and NH molecules. The NH molecules occupy face-centered cubic hollow sites, while the H atoms occupy atop sites. The STM tip was used to dissociate NH and to induce hopping of H atoms. Action spectra consisting of the reaction yield versus applied bias voltage were recorded for both processes, which revealed that they are vibrationally mediated. The threshold voltages for NH dissociation and H hopping were found to be 430 and 272 meV, corresponding to the excitation energy of the N-H stretching and the Pt-H stretching modes, respectively. Substituting H with D results in an isotopic shift of -110 and -84 meV for the threshold voltages for ND dissociation and D hopping, respectively. This further supports the conclusion that these processes are vibrationally mediated.

Vision from next generation sequencing: multi-dimensional genome-wide analysis for producing gene regulatory networks underlying retinal development, aging and disease.

Genomics and genetics have invaded all aspects of biology and medicine, opening uncharted territory for scientific exploration. The definition of "gene" itself has become ambiguous, and the central dogma is continuously being revised and expanded. Computational biology and computational medicine are no longer intellectual domains of the chosen few. Next generation sequencing (NGS) technology, together with novel methods of pattern recognition and network analyses, has revolutionized the way we think about fundamental biological mechanisms and cellular pathways. In this review, we discuss NGS-based genome-wide approaches that can provide deeper insights into retinal development, aging and disease pathogenesis. We first focus on gene regulatory networks (GRNs) that govern the differentiation of retinal photoreceptors and modulate adaptive response during aging. Then, we discuss NGS technology in the context of retinal disease and develop a vision for therapies based on network biology. We should emphasize that basic strategies for network construction and analyses can be transported to any tissue or cell type. We believe that specific and uniform guidelines are required for generation of genome, transcriptome and epigenome data to facilitate comparative analysis and integration of multi-dimensional data sets, and for constructing networks underlying complex biological processes. As cellular homeostasis and organismal survival are dependent on gene-gene and gene-environment interactions, we believe that network-based biology will provide the foundation for deciphering disease mechanisms and discovering novel drug targets for retinal neurodegenerative diseases.

Adipose tissue regeneration in vivo using micronized acellular allogenic dermis as an injectable scaffold.

Over the past few years, the clinical use of injectable artificial materials in plastic surgery has increased. In addition, autologous lipoimplantation is being performed for volume replacement of soft tissue for aesthetic purposes. In this study, acellular allogenic dermis was utilized as a scaffold for the culturing of preadipocytes, confirming the possibility of three-dimensional proliferation of progenitor cells, the eventual differentiation of stromal cells in adipose tissue into the adipocytes, and the in vivo implantation of such adipocytes to form fat tissue. Preadipocytes, recently called ASCs (adipose tissue-derived stromal/stem cells), were cultured in acellular allogenic dermis, successfully attached to the dermal particles in a three-dimensional structure, and proliferated, differentiated, and eventually formed a cluster. For the in vivo implantation, four groups were formed: the first group was cultured within the dermal scaffold for 24 h before implantation (24-h preconditioned group), the second group was induced for differentiation for 10 days before implantation (10-day preconditioned group), the third group was implanted immediately after cell propagation (nonpreconditioned group), and the control group was implanted with only dermal scaffold. In vivo implanted preadipocytes showed great differentiation into adipocytes within the dermal scaffolds. Also, the 10-day preconditioned group showed a greater volume of fat tissue compared to the 24-h preconditioned group. From these results, we confirmed that after a three-dimensional culture in acellular allogenic dermis, implanted preadipocytes formed a greater amount of fat tissue and that this could be a possible effective method for future soft tissue restoration.