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Abstract It has been reported that the retinal vessel and macular region of the retina are displaced after macular hole (MH) surgery. However, there is no detailed information for correlations between retinal and choroidal displacements. We obtained optical coherence tomography angiography (OCTA) and en-face optical coherence tomography (OCT) images from 24 eyes to measure the retinal and choroidal vascular displacement before and after surgery. These images were merged into infrared images using blood vessel patterns. The same vascular bifurcation points were automatically selected for each follow-up image, and the displacements of the bifurcation points were analyzed as a vector unit for prespecified grid regions in a semi-automated fashion. The results showed displacements of the choroidal intermediate vessels and retinal vessels following MH surgery (p = 0.002, p

Abstract Patient-derived organoids (PDOs) are valuable in predicting response to cancer therapy. PDOs are ideal models for precision oncologists. However, their practical application in guiding timely clinical decisions remains challenging. This study focused on patients with advanced EGFR-mutated non-small cell lung cancer and employed a cancer organoid-based diagnosis reactivity prediction (CODRP)-based precision oncology platform to assess the efficacy of EGFR inhibitor treatments. CODRP was employed to evaluate EGFR-tyrosine kinase inhibitors (TKI) drug sensitivity. The results were compared to those obtained using area under the curve index. This study validated this index by testing lung cancer-derived organoids in 14 patients with lung cancer. The CODRP index-based drug sensitivity test reliably classified patient responses to EGFR-TKI treatment within a clinically suitable 10-day timeline, which aligned with clinical drug treatment responses. This approach is promising for predicting and analyzing the efficacy of anticancer, ultimately contributing to the development of a precision medicine platform.

SUMMARY: Poultry coccidiosis is a catastrophic parasitic disease and the industry is currently seeking alternative compounds to replace conventional antibiotics. Accordingly, the current study determined the effect of dietary violacein supplementation on growth performance and anticoccidial indices of Eimeria-infected broiler chickens. A total of 336-day-old “Ross 308” broiler chicks were allotted to 6 treatments: that is, positive control (PC), negative control (NC), 1 treatment with salinomycin (6 ppm), and 3 treatments with different violacein concentrations (10, 15, 20 ppm). Experimental coccidiosis was induced in all chickens (except NC) by inoculating 3.2 × 105 sporulated oocysts. The treatment with 15 ppm violacein (VIO 15) significantly improved chicken growth performance compared to PC. Furthermore, significant reductions in lesion score, oocyst per gram of feces (OPG), and oocysts index (OI) were observed in the VIO 15 and the salinomycin treatments compared to other treatments. Violacein was reported as ‘moderately effective’ on Eimeria spp. based on the “anticoccidial index (ACI),” whereas “reduction in lesion score (RLS)” and “percentage anticoccidial activity (POAA)” indices designated its 15 ppm treatment as “highly sensitive” on them. Additionally, VIO 15 downregulated “interleukin-8 (IL-8)” and “interleukin-6 (IL-6)” compared to PC, in both spleen and cecal tonsils. Besides, expression levels of “chemokine C–C motif ligand 2 (CCLi-2),” were reduced in cecal tonsils of VIO 15 broiler chickens compared to PC. Conclusively, dietary violacein supplementation suppressed the deleterious effects of coccidial infection in broiler chickens with improved growth, and its 15 ppm level is recommended for use.

Abstract The SARS‐CoV‐2 caused COVID‐19 pandemic has posed a global health hazard. While some vaccines have been developed, protection against viral infection is not perfect because of the urgent approval process and the emergence of mutant SARS‐CoV‐2 variants. Here, we employed UDCA as an FXR antagonist to regulate ACE2 expression, which is one of the key pathways activated by SARS‐CoV‐2 Delta variant infection. UDCA is a well‐known reagent of liver health supplements and the only clinically approved bile acid. In this paper, we investigated the protective efficacy of UDCA on Omicron variation, since it has previously been verified for protection against Delta variant. When co‐housing with an Omicron variant‐infected hamster group resulted in spontaneous airborne transmission, the UDCA pre‐supplied group was protected from weight loss relative to the non‐treated group at 4 days post‐infection by more than 5%–10%. Furthermore, UDCA‐treated groups had a 3‐fold decrease in ACE2 expression in nasal cavities, as well as reduced viral expressing genes in the respiratory tract. Here, the data show that the UDCA serves an alternative option for preventive drug, providing SARS‐CoV‐2 protection against not only Delta but also Omicron variant. Our results of this study will help to propose drug‐repositioning of UDCA from liver health supplement to preventive drug of SARS‐CoV‐2 infection.

Abstract Non-trivial linking invariant encodes robust information of topological matter. It has been recently shown that the linking and winding of complex eigenenergy strings can classify one-dimensional non-Hermitian topological matter. However, in higher dimensions, bundles of linked strings can emerge such that every string is mutually linked with all the other strings. To the best of our knowledge, a non-Hermitian Hopf bundle has not been experimentally clarified. Here, we attempt to explore the non-Hermitian Hopf bundle by visualizing the global linking structure of spinor strings in the momentum space of a two-dimensional electric circuit. By exploiting the flexibility of reconfigurable couplings between circuit nodes, we study the non-Hermitian topological phase transition by exploring the intricate structure of the Hopf bundle. Furthermore, we find that the higher-order skin effect in real space is accompanied by the linking of spinor strings in momentum space, revealing bulk-boundary correspondence between the two domains.

Abstract Graft-versus-host disease (GvHD) is a severe complication of hematopoietic stem cell transplantation driven by activated allogeneic T cells. Here, we identify a distinct subset of T cell factor-1 (TCF1)+ CD8+ T cells in mouse allogeneic and xenogeneic transplant models of acute GvHD. These TCF1+ cells exhibit distinct characteristics compared to TCF1- cells, including lower expression of inhibitory receptors and higher expression of costimulatory molecules. Notably, the TCF1+ subset displays exclusive proliferative potential and could differentiate into TCF1- effector cells upon antigenic stimulation. Pathway analyses support the role of TCF1+ and TCF1- subsets as resource cells and effector cells, respectively. Furthermore, the TCF1+ CD8+ T cell subset is primarily present in the spleen and exhibits a resident phenotype. These findings provide insight into the differentiation of allogeneic and xenogeneic CD8+ T cells and have implications for the development of immunotherapeutic strategies targeting acute GvHD.

Abstract Polypoidal choroidal vasculopathy (PCV) is characterized by choroidal vascular abnormalities including polypoidal lesion and branching vascular networks. Not only choroidal structural changes, but also choroidal hyperpermeability and congestion are also thought to be involved in pathogenesis of PCV. We investigated choroidal vascular brightness intensity (CVB) using ultra-widefield indocyanine green angiography (UWF-ICGA) images and analyzed its association with clinical features in patients with PCV. In this study, 33 eyes with PCV and 27 eyes of age-matched controls were included. CVB was measured by extracting the enhanced pixels of choroidal vessels after the reference brightness across the images was adjusted to be uniform. Associations between choroidal vascular features and the clinical features of PCV were also determined. The mean CVB was higher in PCV than control eyes, regardless of the segmented region (all p

Purpose To evaluate the circuit patency after nitinol bare-metal stent (BMS) placement according to the type of access and location of the stent in dysfunctional hemodialysis access. Materials and Methods Between January 2017 and December 2019, 159 patients (mean age, 64.1 ± 13.2 years) underwent nitinol BMS placement for dysfunctional access. The location of stents was as follows: 18 brachiocephalic vein, 51 cephalic arch, 40 upper arm vein, 10 juxta-anastomotic vein, 7 arteriovenous (AV) anastomosis, and 33 graft-vein (GV) anastomosis. Circuit patency was evaluated by the Kaplan-Meier method, and cox regression model. Results A total of 159 stents were successfully deployed in 103 AV fistula (AVF) and 56 AV graft (AVG). AVG showed lower primary and secondary patency at 12-months compared with AVF (primary patency; 25.0% vs. 44.7%; p = 0.005, secondary patency; 76.8% vs. 92.2%; p = 0.014). Cox regression model demonstrated poorer primary patency at 12 months after stenting in the cephalic arch and GV anastomosis compared with the other sites. Conclusion AVF showed better primary and secondary circuit patency at 12 months following the placement of BMS compared with AVG. Stents in the cephalic arch and GV anastomosis were associated with poorer primary patency at 12 months compared to those in other locations.

To improve plasma and chemical resistance on various vacuum components used for semiconductor manufacturing equipment, various ceramic coating techniques have been applied. Among these methods for ceramic coating, the well-known atmospheric plasma spray (APS) is advantageous for providing thick film (100 µm or more) deposition. However, there are problems associated with the phase transition of the coating film and poor film quality due to formation of voids. To solve these problems, the aerosol deposition (AD) method has been developed. This method provides nice ceramic film quality. However, the coating rate is quite slow and has difficulty producing thick films (>30 µm). To overcome these limitations, microwave plasma-assisted aerosol deposition (μ-PAD) is applied at low vacuum conditions without the AD nozzle. This method uses a microwave plasma source during the AD process. After enduring a long-term durability test, as a trial run, μ-PAD has been applied on the actual process site. With the Al2O3 powder, μ-PAD shows a coating rate that is 12 times higher than the AD method. In addition, the formation of a thicker film (96 µm) deposition has been demonstrated. On the other hand, the coating film hardness, porosity, adhesion, and withstand voltage characteristics were confirmed to be less than the AD method.

Multiple AV engines are used to ensure more effective system protection against malicious files. These AV engines are capable of distinguishing between benign and malicious files, but even if a file of interest is proven to be malicious, it is still necessary to refer to a list of AV labels provided by each AV engine to determine what family name the malicious file belongs to. However, oftentimes, such AV labels lack a consistent naming scheme, and even family names differ from one AV engine to another.The present study presents Sumav, a fully automated labeling tool that assigns each file a family name based on AV labels. According to previous studies, such a task required prior knowledge or malicious file datasets that had already been labeled. In contrast, Sumav can assign family names with only the AV labels. This system also requires no maintenance and can provide high-quality labeling performance even if sudden changes have been made to the AV label system.

In chronic infections and cancer, exhausted CD8 T cells exhibit heterogeneous subpopulations. TCF1+PD-1+ progenitor exhausted CD8 T cells (Tpex) can self-renew and give rise to Tim-3+PD-1+ terminally differentiated CD8 T cells that retain their effector functions. Tpex cells are thus essential to maintaining a pool of antigen-specific CD8 T cells during persistent antigenic stimulation, and only they respond to PD-1-targeted therapy. Despite their potential as a crucial therapeutic target for immune interventions, the mechanisms controlling the maintenance of virus-specific Tpex cells remain to be determined. We observed approximately 10-fold fewer Tpex cells in the spleens of mice chronically infected with lymphocytic choriomeningitis virus (LCMV) one-year post-infection (p.i.) than at three months p.i. Similar to memory CD8 T cells, Tpex cells have been found to undergo self-renewal in the lymphoid organs, prominently the bone marrow, during chronic LCMV infection. Furthermore, ex vivo treatment with IL-15 preferentially induced the proliferation of Tpex cells rather than the terminally differentiated subsets. Interestingly, single-cell RNA sequencing analysis of LCMV-specific exhausted CD8 T cells after ex vivo IL-15 treatment compared with those before treatment revealed increased expression of ribosome-related genes and decreased expression of genes associated with the TCR signaling pathway and apoptosis in both Tpex and Ttex subsets. The exogenous administration of IL-15 to chronically LCMV-infected mice also significantly increased self-renewal of Tpex cells in the spleen and bone marrow. In addition, we assessed the responsiveness of CD8 tumor-infiltrating lymphocytes (TILs) from renal cell carcinoma patients to IL-15. Similar to the data we obtained from chronic viral infection in mice, the expansion of the Tpex subset of PD-1+ CD8 TILs upon ex vivo IL-15 treatment was significantly higher than that of the terminally differentiated subset. These results show that IL-15 could promote self-renewal of Tpex cells, which has important therapeutic implications.

Variational quantum machine learning (VQML) models based on parameterized quantum circuits (PQC) have been expected to offer a potential quantum advantage for machine learning (ML) applications. However, comparison between VQML models and their classical counterparts is hard due to the lack of interpretability of VQML models. In this study, we introduce a graphical approach to analyze the PQC and the corresponding operation of VQML models to deal with this problem. In particular, we utilize the Stokes representation of quantum states to treat VQML models as network models based on the corresponding representations of basic gates. From this approach, we suggest the notion of active paths in the networks and relate the expressivity of VQML models with it. We investigate the growth of active paths in VQML models and observe that the expressivity of VQML models can be significantly limited for certain cases. Then we construct classical models inspired by our graphical interpretation of VQML models and show that they can emulate or outperform the outputs of VQML models for these cases. Our result provides a new way to interpret the operation of VQML models and facilitates the interconnection between quantum and classical ML areas.

Abstract As the prevalence of diabetes increases, millions of people need to be screened for diabetic retinopathy (DR). Remarkable advances in technology have made it possible to use artificial intelligence to screen DR from retinal images with high accuracy and reliability, resulting in reducing human labor by processing large amounts of data in a shorter time. We developed a fully automated classification algorithm to diagnose DR and identify referable status using optical coherence tomography angiography (OCTA) images with convolutional neural network (CNN) model and verified its feasibility by comparing its performance with that of conventional machine learning model. Ground truths for classifications were made based on ultra-widefield fluorescein angiography to increase the accuracy of data annotation. The proposed CNN classifier achieved an accuracy of 91–98%, a sensitivity of 86–97%, a specificity of 94–99%, and an area under the curve of 0.919–0.976. In the external validation, overall similar performances were also achieved. The results were similar regardless of the size and depth of the OCTA images, indicating that DR could be satisfactorily classified even with images comprising narrow area of the macular region and a single image slab of retina. The CNN-based classification using OCTA is expected to create a novel diagnostic workflow for DR detection and referral.

Abstract Autophagy is a lysosomal degradation pathway that regulates cellular homeostasis. It is constitutively active in neurons and controls the essential steps of neuronal development, leading to its dysfunction in neurodevelopmental disorders. Although mTOR-associated impaired autophagy has previously been reported in neurodevelopmental disorders, there is lack of information about the dysregulation of mTOR-independent autophagy in neurodevelopmental disorders. In this study, we investigated whether the loss of Epac2, involved in the mTOR-independent pathway, affects autophagy activity and whether the activity of autophagy is associated with social–behavioral phenotypes in mice with Epac2 deficiencies. We observed an accumulation of autophagosomes and a significant increase in autophagic flux in Epac2-deficient neurons, which had no effect on mTOR activity. Next, we examined whether an increase in autophagic activity contributed to the social behavior exhibited in Epac2 −/− mice. The social recognition deficit observed in Epac2 −/− mice recovered in double transgenic Epac2 −/− : Atg5 +/− mice. Our study suggests that excessive autophagy due to Epac2 deficiencies may contribute to social recognition defects through an mTOR-independent pathway.

This study proposes that the gestures of an agent tutor in a multimedia learning environment can generate positive and negative emotions in learners and influence their cognitive processes. To achieve this, we developed and integrated positive and negative agent tutor gestures in a multimedia learning environment directed by cognitive gestures. The effects of emotion type on cognition were examined in terms of cognitive load, learning motivation, and achievement. The subjects were 46 university students in Gyeonggi Province, South Korea. The students were divided into three learner groups: cognition, cognition + negative emotion, and cognition + positive emotion. The learners watched a tutorial lecture on the Notion note-taking app by an agent tutor. Data analysis was conducted using one-way ANOVA to determine the cognitive load, learning motivation, and achievement. The results showed that the positive emotion design was more effective in terms of intrinsic cognitive load, learning motivation, and achievement but had a higher extrinsic cognitive load. However, even the negative + passive group showed more positive learning than the cognition group. Although this study focused on gestures by an agent tutor, it implies that such gestures in multimedia learning contexts must be informed by emotional as well as cognitive design to provide a more meaningful learning experience.

Abstract CCCTC-binding factor (CTCF) is a transcription factor that is involved in organizing chromatin structure. A reduction of CTCF expression is known to develop distinct clinical features. Furthermore, conditional knock out (cKO) study revealed reactive gliosis of astrocytes and microglia followed by age-dependent cell death in the excitatory neurons of CTCF cKO mice. To assess the cognitive ability in CTCF cKO mice of over 20 weeks of age, we examined pairwise discrimination (PD), PD reversal learning (PDr), and different paired-associate learning (dPAL) tasks using a touch screen apparatus. We found cognitive impairment in dPAL touch screen tests, suggesting that prolonged Ctcf gene deficiency results in cognitive deficits.

Abstract Metal-to-insulator transitions (MIT) can be driven by a number of different mechanisms, each resulting in a different type of insulator—Change in chemical potential can induce a transition from a metal to a band insulator; strong correlations can drive a metal into a Mott insulator with an energy gap; an Anderson transition, on the other hand, due to disorder leads to a localized insulator without a gap in the spectrum. Here, we report the discovery of an alternative route for MIT driven by the creation of a network of narrow channels. Transport data on Pt substituted for Ti in 1T-TiSe2 shows a dramatic increase of resistivity by five orders of magnitude for few % of Pt substitution, with a power-law dependence of the temperature-dependent resistivity ρ(T). Our scanning tunneling microscopy data show that Pt induces an irregular network of nanometer-thick domain walls (DWs) of charge density wave (CDW) order, which pull charge carriers out of the bulk and into the DWs. While the CDW domains are gapped, the charges confined to the narrow DWs interact strongly, with pseudogap-like suppression in the local density of states, even when they were weakly interacting in the bulk, and scatter at the DW network interconnects thereby generating the highly resistive state. Angle-resolved photoemission spectroscopy spectra exhibit pseudogap behavior corroborating the spatial coexistence of gapped domains and narrow domain walls with excess charge carriers.

Abstract Background Radiographs are integral in evaluating implant space and inter-root distance. The purpose of this report is to introduce a method for evaluating the 3D root position with minimal radiation using a 3D tooth model composed of an intraoral-scanned crown and a cone-beam computed tomography (CBCT)-scanned root. Materials and methods Intraoral scan and CBCT scan of the patient were obtained before treatment. In the CBCT image, tooth segmentation was performed by isolating individual teeth from the maxillary and mandibular alveolar bone using software program. The 3D tooth model was fabricated by combining segmented individual teeth with the intraoral scan. Results A post-treatment intraoral scan was integrated into the tooth model, and the resulting position of the root could be predicted without additional radiographs. It is possible to monitor the root position after a pretreatment CBCT scan using a 3D tooth model without additional radiographs. Conclusion The application of the 3D tooth model benefits the patient by reducing repeated radiation exposure while providing the clinician with a precise treatment evaluation to monitor tooth movement.

Abstract Significant clinical symptoms of Cohen syndrome (CS), a rare autosomal recessive disorder, include intellectual disability, facial dysmorphism, postnatal microcephaly, retinal dystrophy, and intermittent neutropenia. CS has been associated with mutations in the VPS13B (vacuolar protein sorting 13 homolog B) gene, which regulates vesicle-mediated protein sorting and transport; however, the cellular mechanism underlying CS pathogenesis in patient-derived neurons remains uncertain. This report states that autophagic vacuoles accumulate in CS fibroblasts and the axonal terminals of CS patient-specific induced pluripotent stem cells (CS iPSC)-derived neurons; additionally, autophagic flux was significantly increased in CS-derived neurons compared to control neurons. VPS13B knockout HeLa cell lines generated using the CRISPR/Cas9 genome editing system showed significant upregulation of autophagic flux, indicating that VSP13B may be associated with autophagy in CS. Transcriptomic analysis focusing on the autophagy pathway revealed that genes associated with autophagosome organization were dysregulated in CS-derived neurons. ATG4C is a mammalian ATG4 paralog and a crucial regulatory component of the autophagosome biogenesis/recycling pathway. ATG4C was significantly upregulated in CS-derived neurons, indicating that autophagy is upregulated in CS neurons. The autophagy pathway in CS neurons may be associated with the pathophysiology exhibited in the neural network of CS patients.

Abstract Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders that are highly heterogeneous in clinical symptoms as well as etiologies. Mutations in SHANK2 are associated with ASD and accordingly, Shank2 knockout mouse shows ASD-like behavioral phenotypes, including social deficits. Intriguingly, two lines of Shank2 knockout (KO) mouse generated by deleting different exons (exon 6–7 or exon 7) showed distinct cellular phenotypes. Previously, we compared gene expressions between Shank2 KOs lacking exon 6–7 (e6–7 KO) and KOs lacking exon 7 (e7 KO) by performing RNA-seq. In this study, we expanded transcriptomic analyses to identify novel transcriptional variants in the KO mice. We found prominent expression of a novel exon (exon 4′ or e4’) between the existing exons 4 and 5 in the Shank2 e6–7 KO model. Expression of the transcriptional variant harboring this novel exon was confirmed by RT-PCR and western blotting. These findings suggest that the novel variant may function as a modifier gene, which contributes to the differences between the two Shank2 mutant lines. Furthermore, our result further represents an example of genetic compensation that may lead to phenotypic heterogeneity among ASD patients with mutations in the same gene.

Abstract Aim cAMP signal transduction cascade activation is important in regulating neurogenesis in adult rodents by increasing the proliferation of newborn cells. Although the ventricular-subventricular zone (V-SVZ) and subgranular zone (SGZ) both contain large populations of neural stem/precursor cells; it remains unclear whether an alternative target of cAMP, the exchange protein directly activated by cAMP (Epac2), is involved in adult neurogenesis in the V-SVZ and SGZ. Here, we investigated the cell-specific expression of Epac2 protein in the V-SVZ and SGZ of the adult mouse brain. Methods Immunohistochemical analyses were performed using antibodies against Epac2, glial fibrillary acidic protein (GFAP), doublecortin (DCX), and beta-catenin, to examine the co-localization of Epac2 protein and neural stem/precursor cells in the V-SVZ and SGZ in three 8-week-old male mice. Results In the V-SVZ of the lateral ventricle, most GFAP-positive adult neural stem cells (NSC, defined as type B cells) and 75% of DCX-positive migrating neuroblasts (type A cells) expressed Epac2 proteins. Ninety-three percent of beta-catenin-positive ependymal cells (type E cells), which are in direct contact with NSCs and the ventricles, also expressed Epac2 protein. Similarly, in the SGZ of the hippocampus, Epac2-immunopositive signals were shown by 83% of GFAP-positive radial-glia-like NSCs (type 1 cells), 86% of DCX-positive transiently amplifying cells (type 2 and type 3 cells), and 71% of DCX-positive immature neurons. The present data suggest that a PKA-independent cAMP signaling pathway via Epac2 may be party to adult neurogenesis in the V-SVZ and the SGZ.

Abstract Background Silica nanoparticles (SiNPs) are widely used for biosensing and diagnostics, and for the targeted delivery of therapeutic agents. Safety concerns about the biomedical and clinical applications of SiNPs have been raised, necessitating analysis of the effects of their intrinsic properties, such as sizes, shapes, and surface physicochemical characteristics, on human health to minimize risk in biomedical applications. In particular, SiNP size-associated toxicological effects, and the underlying molecular mechanisms in the vascular endothelium remain unclear. This study aimed to elucidate the detailed mechanisms underlying the cellular response to exposure to trace amounts of SiNPs and to determine applicable size criteria for biomedical application. Methods To clarify whether these SiNP-mediated cytotoxicity due to induction of apoptosis or necrosis, human ECs were treated with SiNPs of four different non-overlapping sizes under low serum-containing condition, stained with annexin V and propidium iodide (PI), and subjected to flow cytometric analysis (FACS). Two types of cell death mechanisms were assessed in terms of production of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress induction, and autophagy activity. Results Spherical SiNPs had a diameter of 21.8 nm; this was further increased to 31.4, 42.9, and 56.7 nm. Hence, we investigated these effects in human endothelial cells (ECs) treated with these nanoparticles under overlap- or agglomerate-free conditions. The 20-nm SiNPs, but not SiNPs of other sizes, significantly induced apoptosis and necrosis. Surprisingly, the two types of cell death occurred independently and through different mechanisms. Apoptotic cell death resulted from ROS-mediated ER stress. Furthermore, autophagy-mediated necrotic cell death was induced through the PI3K/AKT/eNOS signaling axis. Together, the present results indicate that SiNPs within a diameter of

PURPOSE:To evaluate the image quality of low-dose chest digital radiographic images obtained with a new spatial noise reduction algorithm, compared to a conventional de-noising technique. MATERIALS AND METHODS:In 69 patients, the dose reduction protocol was divided into A, B, and C test groups- 60% (n = 22), 50% (n = 23), and 40% (n = 24) of the baseline dose. In each patient, baseline dose radiographs were obtained with conventional image processing while low-dose images were acquired with new image processing. A set of baseline and low-dose radiographic images per patient was evaluated and scored on a 5-point scale over seven anatomical landmarks (radiolucency of unobscured lung, pulmonary vascularity, trachea, edge of rib, heart border, intervertebral disc space, and pulmonary vessels in the retrocardiac area) and three representative abnormal findings (nodule, consolidation, and interstitial marking) by two thoracic radiologists. A comparison of paired baseline and low-dose images was statistically analyzed using a non-inferiority test based on the paired t-test or the Wilcoxon signed-rank test. RESULTS:In A, B, and C test groups, the mean dose reduction rate of the baseline radiation dose was 63.4%, 53.9%, and 47.8%, respectively. In all test groups, the upper limit of the 95% confidence interval was less than the non-inferiority margin of 0.5 every seven anatomical landmarks and three representative abnormal findings, which suggested that the image quality of the low-dose image was not inferior to that of the baseline dose image even if the maximum average dose reduction rate was reduced to 47.8% of the baseline dose. CONCLUSION:In our study, an image processing technique integrating a new noise reduction algorithm achieved dose reductions of approximately half without compromising image quality for abnormal lung findings and anatomical landmarks seen on chest radiographs. This feature-preserving, noise reduction algorithm adopted in the proposed engine enables a lower radiation dose boundary for the sake of patient's and radiography technologist's radiation safety in routine clinical practice, in compliance with regulatory guidelines.

Abstract Spatial mapping of genomic data to tissue context in a high-throughput and high-resolution manner has been challenging due to technical limitations. Here, we describe PHLI-seq, a novel approach that enables high-throughput isolation and genome-wide sequence analysis of single cells or small numbers of cells to construct genomic maps within cancer tissue in relation to the images or phenotypes of the cells. By applying PHLI-seq, we reveal the heterogeneity of breast cancer tissues at a high resolution and map the genomic landscape of the cells to their corresponding spatial locations and phenotypes in the 3D tumor mass.

Summary: Pluripotent stem cells (PSCs) represent the most promising clinical source for regenerative medicine. However, given the cellular heterogeneity within cultivation and safety concerns, the development of specific and efficient tools to isolate a pure population and eliminate all residual undifferentiated PSCs from differentiated derivatives is a prerequisite for clinical applications. In this study, we raised a monoclonal antibody and identified its target antigen as desmoglein-2 (DSG2). DSG2 co-localized with human PSC (hPSC)-specific cell surface markers, and its expression was rapidly downregulated upon differentiation. The depletion of DSG2 markedly decreased hPSC proliferation and pluripotency marker expression. In addition, DSG2-negative population in hPSCs exhibited a notable suppression in embryonic body and teratoma formation. The actions of DSG2 in regulating the self-renewal and pluripotency of hPSCs were predominantly exerted through the regulation of β-catenin/Slug-mediated epithelial-to-mesenchymal transition. Our results demonstrate that DSG2 is a valuable PSC surface marker that is essential for the maintenance of PSC self-renewal. : DSG2 is a desmosomal cadherin molecule. In this article, Min and colleagues show that DSG2 is a valuable PSC surface marker that is essential for the maintenance of PSC self-renewal and pluripotency and the acquisition of pluripotency during somatic cell reprogramming through the regulation of β-catenin-mediated EMT signaling. keywords: desmoglein-2, cell surface marker, pluripotent stem cells, monoclonal antibody, EMT

The present study tested whether visuo-spatial vs. verbal executive working memory capacity (hereafter EWM) modulates the degree to which non-numerical visual magnitudes influence numerosity comparison using pairs of dot arrays. We hypothesized that visuo-spatial (rather than verbal) EWM capacity would influence one's ability to selectively focus on numerical as opposed to non-numerical visual properties (such as dot size, cumulative area, density) of the dot arrays during numerosity comparison. Participants' performance was better on trials in which non-numerical visual magnitudes were negatively (vs. positively) correlated with numerosity (i.e., reverse congruency effect). The Low visuo-spatial EWM group manifested greater reverse congruency effect compared to the High visuo-spatial EWM group. A trial-based hierarchical regression on the accuracy of each trial using the ratio of (numerical and non-numerical) visual magnitudes as predictors revealed that the ratio of numerical vs. non-numerical visual magnitudes explained the greatest variance in the performance of the High vs. Low visuo-spatial EWM groups, respectively. In contrast, there was no difference between the High vs. Low verbal EWM groups from the same analysis. These results reveal differential susceptibility to numerical vs. non-numerical visual information depending on the capacity of visuo-spatial (but not verbal) EWM. Taken together, numerosity comparison performance measured with the dot comparison paradigm seems to reflect not only one's acuity for numerosity discrimination but also visuo-spatial EWM capacity likely required during integration of visual magnitudes during numerosity comparison.

Cohen syndrome (CS), a rare autosomal recessive disorder, has been associated with genetic mutations in the VPS13B gene, which regulates vesicle-mediated protein sorting and transport. However, the cellular mechanism underlying CS pathogenesis in patient-derived human neurons remains unknown. We identified a novel compound heterozygous mutation, due to homozygous variation of biparental origin and heterozygous variation inherited from the father, in the VPS13B gene in a 20-month-old female patient. To understand the cellular pathogenic mechanisms, we generated induced pluripotent stem cells (iPSCs) from the fibroblasts of the CS patient. The iPSCs were differentiated into forebrain-like functional glutamatergic neurons or neurospheres. Functional annotation from transcriptomic analysis using CS iPSC-derived neurons revealed that synapse-related functions were enriched among the upregulated and downregulated genes in the CS neurons, whereas processes associated with neurodevelopment were enriched in the downregulated genes. The developing CS neurospheres were small in size compared to control neurospheres, likely due to the reduced proliferation of SOX2-positive neural stem cells. Moreover, the number of SV2B-positive puncta and spine-like structures was significantly reduced in the CS neurons, suggesting synaptic dysfunction. Taking these findings together, for the first time, we report a potential cellular pathogenic mechanism which reveals the alteration of neurodevelopment-related genes and the dysregulation of synaptic function in the human induced neurons differentiated from iPSCs and neurospheres of a CS patient.

Recently, significant research efforts have been devoted toward the development of magnetically controllable drug delivery systems, however, drug fixation after targeting remains a challenge hindering long-term therapeutic efficacy. To overcome this issue, we present a wearable therapeutic fixation device for fixing magnetically controllable therapeutic agent carriers (MCTACs) at defect sites and its application to cartilage repair using stem cell therapeutics. The developed device comprises an array of permanent magnets based on the Halbach array principle and a wearable band capable of wrapping the target body. The design of the permanent magnet array, in terms of the number of magnets and array configuration, was determined through univariate search optimization and 3D simulation. The device was fabricated for a given rat model and yielded a strong magnetic flux density (exceeding 40 mT) in the region of interest that was capable of fixing the MCTAC at the desired defect site. Through in-vitro and in-vivo experiments, we successfully demonstrated that MCTACs, both a stem cell spheroid and a micro-scaffold for cartilage repair, could be immobilized at defect sites. This research is expected to advance precise drug delivery technology based on MCTACs, enabling subject-specific routine life therapeutics. Further studies involving the proposed wearable fixation device will be conducted considering prognostics under actual clinical settings.

Fibroblast growth factor 21 (FGF21) plays important roles in regulating glucose, lipid, and energy metabolism; however, its effects in tumors remain poorly understood. To understand the role of FGF21 in regulating tumor aggressiveness in thyroid cancer, serum levels of FGF21 were measured in healthy subjects and patients with papillary thyroid cancer (PTC), and expression levels of FGF21, FGF receptors (FGFRs), and β-klotho (KLB) were investigated in human thyroid tissues. The cell viability, migrating cells, and invading cells were measured in PTC cells after treatment with recombinant FGF21. Higher serum levels of FGF21 were found in patients with thyroid cancer than in control participants, and were significantly associated with body mass index (BMI), fasting glucose levels, triglyceride levels, tumor stage, lymphovascular invasion, and recurrence. Serum FGF21 levels were positively correlated with the BMI in patients with PTC, and significantly associated with recurrence. Recombinant FGF21 led to tumor aggressiveness via activation of the FGFR signaling axis and epithelial-to-mesenchymal transition (EMT) signaling in PTC cells, and AZD4547, an FGFR tyrosine kinase inhibitor, attenuated the effects of FGF21. Hence, FGF21 may be a new biomarker for predicting tumor progression, and targeting FGFR may be a novel therapy for the treatment of obese patients with PTC.

Phosphoinositide 3-kinases (PI3Ks) play key roles in synapticplasticity and cognitive functions in the brain. We recentlyfound that genetic deletion of PI3Kγ, the only known memberof class IB PI3Ks, results in impaired N-methyl-D-aspartatereceptor-dependent long-term depression (NMDAR-LTD) inthe hippocampus. The activity of RalA, a small GTP-bindingprotein, increases following NMDAR-LTD inducing stimuli,and this increase in RalA activity is essential for inducingNMDAR-LTD. We found that RalA activity increased significantlyin PI3Kγ knockout mice. Furthermore, NMDAR-LTDinducingstimuli did not increase RalA activity in PI3Kγknockout mice. These results suggest that constitutivelyincreased RalA activity occludes further increases in RalAactivity during induction of LTD, causing impaired NMDARLTD.We propose that PI3Kγ regulates the activity of RalA,which is one of the molecular mechanisms inducing NMDARdependentLTD. [BMB Reports 2013; 46(2): 103-106]

A major question in Fe-based superconductors remains the structure of the pairing, in particular whether it is of unconventional nature. The electronic structure near a vortex can serve as a platform for phase-sensitive measurements to answer this question. By solving the Bogoliubov–de Gennes equations for LiFeAs, we calculate the energy-dependent local electronic structure near a vortex for different nodeless gap-structure possibilities. At low energies, the local density of states (LDOS) around a vortex is determined by the normal-state electronic structure. At energies closer to the gap value, however, the LDOS can distinguish an anisotropic s-wave gap from a conventional isotropic s-wave gap. We show within our self-consistent calculation that in addition, the local gap profile differs between a conventional and an unconventional pairing. We explain this through admixing of a secondary order parameter within Ginzburg–Landau theory. In-field scanning tunneling spectroscopy near a vortex can therefore be used as a real-space probe of the gap structure.