Epidemiological Characterization of a Directed and Weighted Disease Network Using Data From a Cohort of One Million Patients: Network Analysis.

BACKGROUND: In the past 20 years, various methods have been introduced to construct disease networks. However, established disease networks have not been clinically useful to date because of differences among demographic factors, as well as the temporal order and intensity among disease-disease associations. OBJECTIVE: This study sought to investigate the overall patterns of the associations among diseases; network properties, such as clustering, degree, and strength; and the relationship between the structure of disease networks and demographic factors. METHODS: We used National Health Insurance Service-National Sample Cohort (NHIS-NSC) data from the Republic of Korea, which included the time series insurance information of 1 million out of 50 million Korean (approximately 2%) patients obtained between 2002 and 2013. After setting the observation and outcome periods, we selected only 520 common Korean Classification of Disease, sixth revision codes that were the most prevalent diagnoses, making up approximately 80% of the cases, for statistical validity. Using these data, we constructed a directional and weighted temporal network that considered both demographic factors and network properties. RESULTS: Our disease network contained 294 nodes and 3085 edges, a relative risk value of more than 4, and a false discovery rate-adjusted P value of <.001. Interestingly, our network presented four large clusters. Analysis of the network topology revealed a stronger correlation between in-strength and out-strength than between in-degree and out-degree. Further, the mean age of each disease population was related to the position along the regression line of the out/in-strength plot. Conversely, clustering analysis suggested that our network boasted four large clusters with different sex, age, and disease categories. CONCLUSIONS: We constructed a directional and weighted disease network visualizing demographic factors. Our proposed disease network model is expected to be a valuable tool for use by early clinical researchers seeking to explore the relationships among diseases in the future.

Phase-Centric MOCVD Enabled Synthetic Approaches for Wafer-Scale 2D Tin Selenides.

Following an initial nucleation stage at the flake level, atomically thin film growth of a van der Waals material is promoted by ultrafast lateral growth and prohibited vertical growth. To produce these highly anisotropic films, synthetic or post-synthetic modifications are required, or even a combination of both, to ensure large-area, pure-phase, and low-temperature deposition. A set of synthetic strategies is hereby presented to selectively produce wafer-scale tin selenides, SnSex (both x = 1 and 2), in the 2D forms. The 2D-SnSe2 films with tuneable thicknesses are directly grown via metal-organic chemical vapor deposition (MOCVD) at 200 °C, and they exhibit outstanding crystallinities and phase homogeneities and consistent film thickness across the entire wafer. This is enabled by excellent control of the volatile metal-organic precursors and decoupled dual-temperature regimes for high-temperature ligand cracking and low-temperature growth. In contrast, SnSe, which intrinsically inhibited from 2D growth, is indirectly prepared by a thermally driven phase transition of an as-grown 2D-SnSe2 film with all the benefits of the MOCVD technique. It is accompanied by the electronic n-type to p-type crossover at the wafer scale. These tailor-made synthetic routes will accelerate the low-thermal-budget production of multiphase 2D materials in a reliable and scalable fashion.

Double-Floating-Gate van der Waals Transistor for High-Precision Synaptic Operations.

Two-dimensional materials and their heterostructures have thus far been identified as leading candidates for nanoelectronics owing to the near-atom thickness, superior electrostatic control, and adjustable device architecture. These characteristics are indeed advantageous for neuro-inspired computing hardware where precise programming is strongly required. However, its successful demonstration fully utilizing all of the given benefits remains to be further developed. Herein, we present van der Waals (vdW) integrated synaptic transistors with multistacked floating gates, which are reconfigured upon surface oxidation. When compared with a conventional device structure with a single floating gate, our double-floating-gate (DFG) device exhibits better nonvolatile memory performance, including a large memory window (>100 V), high on-off current ratio (∼107), relatively long retention time (>5000 s), and satisfactory cyclic endurance (>500 cycles), all of which can be attributed to its increased charge-storage capacity and spatial redistribution. This facilitates highly effective modulation of trapped charge density with a large dynamic range. Consequently, the DFG transistor exhibits an improved weight update profile in long-term potentiation/depression synaptic behavior for nearly ideal classification accuracies of up to 96.12% (MNIST) and 81.68% (Fashion-MNIST). Our work adds a powerful option to vdW-bonded device structures for highly efficient neuromorphic computing.

Channel Scaling Dependent Photoresponse of Copper-Based Flexible Photodetectors Fabricated Using Laser-Induced Oxidation.

Copper (Cu) oxide compounds (CuxO), which include cupric (CuO) and cuprous (Cu2O) oxide, have been recognized as a promising p-channel material with useful photovoltaic properties and superior thermal conductivity. Typically, deposition methods or thermal oxidation can be used to obtain CuxO. However, these processes are difficult to apply to flexible substrates because plastics have a comparatively low glass transition temperature. Also, additional patterning steps are needed to fabricate applications. In this work, we fabricated a metal-semiconductor-metal photodetector using laser-induced oxidation of thin Cu films under ambient conditions. Raman spectroscopy, scanning electron microscopy-energy-dispersive X-ray spectroscopy, and atomic force microscopy were used to study the composition and morphology of our devices. Moreover, the photoresponse of this device is reported herein. We performed an in-depth analysis of the relationship between the channel size and number of carriers using scanning photocurrent microscopy. The carrier transport behaviors were identified; the photocurrent decreased as the length and width of the channel increased. Furthermore, we verified the suitability of the device as a flexible photodetector using a variety of bending tests. Our in-depth analysis of this Cu-based flexible photodetector could play an important role in understanding the mechanisms of other flexible photovoltaic applications.

Free Silicone Injections to the Breast: Delayed Complications and Surgical Management of Sequelae.

This case describes a healthy 37-year-old woman who presented with bilateral breast pain and nodules years after receiving free silicone injections to her breasts. Mammogram revealed extremely dense breasts with innumerable bilateral masses of various sizes. Ultrasound was non-diagnostic due to poor penetration and artifact from silicone. Histologic examination revealed vacuolated histiocytes and innumerable cystic spaces containing material consistent with silicone. Patient underwent bilateral nipple-sparing mastectomy with immediate reconstruction using tissue expanders. This case highlights the potential for serious complications developing years after free silicone injections as well as our team's surgical management of these complications.

Prognostic Implications of Arginase and Cytokeratin 19 Expression in Hepatocellular Carcinoma After Curative Hepatectomy: Correlation With Recurrence-Free Survival.

BACKGROUND: The prognostic value of arginase expression in hepatocellular carcinoma (HCC) has been evaluated previously. However, no clear distinction exists yet on the role of arginase-1 as a predictor of recurrence in HCC. Cytokeratin 19 (CK19), a cholangiocytic marker, is occasionally expressed in HCC, but the combination of arginase-1 and CK19 expression has never been evaluated. The aim of the study was to investigate the usefulness of arginase-1 and CK19 expression alone and in combination for prognosticating HCC tumor recurrence after surgical resection. METHODS: Tissue sections from 112 HCCs were immunostained using an automated method and the mouse monoclonal arginase-1 and mouse monoclonal CK19 antibodies. The clinicopathologic variables, including alpha-fetoprotein levels, viral hepatitis, cirrhosis, tumor size, grade and number, vascular invasion, tumor-node-metastasis (TNM) stage, and tumor recurrence and survival, were obtained from each patient's medical records. The variables were assessed for correlation with the immunochemical results. Comparisons of recurrence-free and overall survival were performed using univariate and multivariate regression analyses. A P-value of ≤ 0.05 was considered statistically significant. RESULTS: High arginase-1 expression was detected in the HCCs of 93 patients (83%), whereas CK19 was positive in the HCCs of only 19 patients (17%). In the univariate analyses, CK19 positivity in HCC was associated with decreased recurrence-free survival compared with CK19-negative HCC (P = 0.0002). Arginase-1 expression was associated with decreased recurrence-free survival when patients were stratified over advanced TNM stage and presence of vascular invasion. The combination of arginase-1 and CK19 expression was a better predictor of decreased recurrence-free survival (P = 0.00008). Arginase-1/CK19 expressions when combined with multiple tumors, TNM stage and vascular invasion were also associated with decreased recurrence-free survival. In the multivariate analysis, tumor grade, CK19 and arginase-1/CK19 expressions were identified as independent prognostic indicators for decreased recurrence-free survival. CONCLUSION: Arginase-1 and CK19 combination immunoreactivity is a potential biomarker of adverse prognosis in HCC, correlating with the presence of multiple tumors, vascular invasion and advanced stage.

Well differentiated arginase-1 negative hepatocellular carcinoma.

BACKGROUND: The diagnosis of hepatocellular carcinoma (HCC) is dependent on the histologic and immunohistochemical analysis of biopsy and resection specimens. The distinction of HCC from metastatic neoplasms is pertinent for treatment and prognostic purposes. Arginase-1 (Arg-1), a marker of hepatocellular differentiation, has shown superior sensitivity and specificity when compared to other immunohistochemical markers of detection of HCC such as hepatocyte paraffin antigen (HepPar-1). Studies have shown that poorly differentiated HCC can lose arginase expression, however well differentiated HCC are rarely ever arginase negative. METHODS: In this study Arg-1 expression was detected using immunohistochemical staining on tissue specimens from 40 confirmed cases of well differentiated HCC specimens using a highly specific monoclonal antibody for Arg-1. Specificity of the Arg-1 antibody was evaluated by immunostaining of 24 non-HCC tumors in the liver and 200 non-liver neoplasms using paraffin block and tissue micro-array (TMA) based immunohistochemistry. RESULTS: Four well differentiated HCC cases were found to be completely negative for Arg-1 and similarly all 224 non-HCC tumors did not express Arg-1. The arginase negative well differentiated tumors were positive for other hepatocellular markers such as HepPar-1 and polyclonal carcinoembryonic antigen (pCEA). Of the four tumors, only one recurred at 28 months. All patients are currently stable with a mean survival of 43 months. CONCLUSIONS: Arg-1 negative well differentiated HCC can be a clinical dilemma which can lead to misdiagnosis. Confirmation with other hepatocellular markers such as HepPar1 and pCEA is essential in making the correct diagnosis. The clinicopathologic outcomes of arginase negative well differentiated HCC has been poorly characterized, thus our findings are of utmost importance in understanding the clinical behavior of these tumors. This may have a potential role in understanding the mechanism of the use of targeted therapy in HCC tumors.

A MEMS ultrasound stimulation system for modulation of neural circuits with high spatial resolution in vitro.

Neuromodulation by ultrasound has recently received attention due to its noninvasive stimulation capability for treating brain diseases. Although there have been several studies related to ultrasonic neuromodulation, these studies have suffered from poor spatial resolution of the ultrasound and low repeatability with a fixed condition caused by conventional and commercialized ultrasound transducers. In addition, the underlying physics and mechanisms of ultrasonic neuromodulation are still unknown. To determine these mechanisms and accurately modulate neural circuits, researchers must have a precisely controllable ultrasound transducer to conduct experiments at the cellular level. Herein, we introduce a new MEMS ultrasound stimulation system for modulating neurons or brain slices with high spatial resolution. The piezoelectric micromachined ultrasonic transducers (pMUTs) with small membranes (sub-mm membranes) generate enough power to stimulate neurons and enable precise modulation of neural circuits. We designed the ultrasound transducer as an array structure to enable localized modulation in the target region. In addition, we integrated a cell culture chamber with the system to make it compatible with conventional cell-based experiments, such as in vitro cell cultures and brain slices. In this work, we successfully demonstrated the functionality of the system by showing that the number of responding cells is proportional to the acoustic intensity of the applied ultrasound. We also demonstrated localized stimulation capability with high spatial resolution by conducting experiments in which cocultured cells responded only around a working transducer.

Network-based analysis of diagnosis progression patterns using claims data.

In recent years, several network models have been introduced to elucidate the relationships between diseases. However, important risk factors that contribute to many human diseases, such as age, gender and prior diagnoses, have not been considered in most networks. Here, we construct a diagnosis progression network of human diseases using large-scale claims data and analyze the associations between diagnoses. Our network is a scale-free network, which means that a small number of diagnoses share a large number of links, while most diagnoses show limited associations. Moreover, we provide strong evidence that gender, age and disease class are major factors in determining the structure of the disease network. Practically, our network represents a methodology not only for identifying new connectivity that is not found in genome-based disease networks but also for estimating directionality, strength, and progression time to transition between diseases considering gender, age and incidence. Thus, our network provides a guide for investigators for future research and contributes to achieving precision medicine.

DHS-21, a dicarbonyl/L-xylulose reductase (DCXR) ortholog, regulates longevity and reproduction in Caenorhabditis elegans.

Dicarbonyl/L-xylulose reductase (DCXR) converts l-xylulose into xylitol, and reduces various α-dicarbonyl compounds, thus performing a dual role in carbohydrate metabolism and detoxification. In this study, we identified DHS-21 as the only DCXR ortholog in Caenorhabditis elegans. The dhs-21 gene is expressed in various tissues including the intestine, gonadal sheath cells, uterine seam (utse) cells, the spermathecal-uterus (sp-ut) valve and on the plasma membrane of spermatids. Recombinant DHS-21 was shown to convert L-xylulose to xylitol using NADPH as a cofactor. Dhs-21 null mutants of C. elegans show defects in longevity, reproduction and egg-laying. Knock-down of daf-16 and elt-2 transcription factors affected dhs-21 expression. These results suggest that DHS-21 is a bona fide DCXR of C. elegans, essential for normal life span and reproduction.

Genome-wide differential gene expression profiling of human bone marrow stromal cells.

Bone marrow stromal cells (BMSCs) reside in bone marrow and provide a lifelong source of new cells for various connective tissues. Although human BMSCs are regarded as highly suitable for the development of cell therapeutics and regenerative medicine, the molecular factors and the networks of signaling pathways responsible for their biological properties are as yet unclear. To gain a comprehensive understanding of human BMSCs at the transcriptional level, we have performed DNA microarray-based, genome-wide differential gene expression analysis with the use of peripheral blood-derived mononuclear cells (MNCs) as a baseline. The resulting molecular profile of BMSCs was revealed to share no meaningful overlap with those of other human stem cell types, suggesting that the cells might express a unique set of genes for their stemness. By contrast, the distinct molecular signature, consisting of 92 different genes whose expression strengths are at least 50-fold higher in BMSCs compared with MNCs, was shown to encompass largely a gene subset of umbilical cord blood-derived adherent cells, suggesting that adherent cells derived from bone marrow and umbilical cord blood may be defined by a common set of genes, regardless of their origin. Intriguingly, a large number of these genes, particularly ones for extracellular matrix products, coincide with normal or tumor endothelium-specific markers. Taken together, our results here provide a BMSC-specific genetic catalog that may facilitate future studies on molecular mechanisms governing core properties of these cells.

Membrane proteomic analysis of human mesenchymal stromal cells during adipogenesis.

Mesenchymal stromal cells (MSCs) have proven useful for cell and immune therapy, but the molecular constituents responsible for their functionalities, in particular, those on the plasma membrane, remain largely unknown. Here we employed both gel and nongel based MS to analyze human MSCs' membrane proteome before and after adipogenesis. 2-DE of cells that were pretreated with membrane impermeable fluorescent dyes revealed that both the whole cell proteome and the cell surface subproteome were independent of donors. LC coupled with tandem MS analysis of the plasma membrane-containing fraction allowed us to identify 707 proteins, approximately half of which could be annotated as membrane-related proteins. Of particular interest was a subset of ectodomain-containing membrane-bound proteins that encompass most known surface markers for MSCs, but also contain a multitude of solute carriers and ATPases. Upon adipogenic differentiation, this proteomic profile was amended to include several proteins involved in lipid metabolism and trafficking, at the expense of, most noticeably, ectoenzymes. Our results here provide not only a basis for future studies of MSC-specific molecular mechanisms, but also a molecular inventory for the development of antibody-based cell isolation and identification procedures.