BMP10 functions independently from BMP9 for the development of a proper arteriovenous network.

Hereditary hemorrhagic telangiectasia (HHT) is a genetic vascular disorder characterized by the presence of arteriovenous malformation (AVM) in multiple organs. HHT is caused by mutations in genes encoding major constituents for transforming growth factor-ß (TGF-ß) family signaling: endoglin (ENG), activin receptor-like kinase 1 (ALK1), and SMAD4. The identity of physiological ligands for this ENG-ALK1 signaling pertinent to AVM formation has yet to be clearly determined. To investigate whether bone morphogenetic protein 9 (BMP9), BMP10, or both are physiological ligands of ENG-ALK1 signaling involved in arteriovenous network formation, we generated a novel Bmp10 conditional knockout mouse strain. We examined whether global Bmp10-inducible knockout (iKO) mice develop AVMs at neonatal and adult stages in comparison with control, Bmp9-KO, and Bmp9/10-double KO (dKO) mice. Bmp10-iKO and Bmp9/10-dKO mice showed AVMs in developing retina, postnatal brain, and adult wounded skin, while Bmp9-KO did not display any noticeable vascular defects. Bmp10 deficiency resulted in increased proliferation and size of endothelial cells in AVM vessels. The impaired neurovascular integrity in the brain and retina of Bmp10-iKO and Bmp9/10-dKO mice was detected. Bmp9/10-dKO mice exhibited the lethality and vascular malformation similar to Bmp10-iKO mice, but their phenotypes were more pronounced. Administration of BMP10 protein, but not BMP9 protein, prevented retinal AVM in Bmp9/10-dKO and endothelial-specific Eng-iKO mice. These data indicate that BMP10 is indispensable for the development of a proper arteriovenous network, whereas BMP9 has limited compensatory functions for the loss of BMP10. We suggest that BMP10 is the most relevant physiological ligand of the ENG-ALK1 signaling pathway pertinent to HHT pathogenesis.

Genetic Variants and Clinical Phenotypes in Korean Patients With Hereditary Hemorrhagic Telangiectasia.

OBJECTIVES: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by recurrent epistaxis, telangiectasia, and visceral arteriovenous malformations (AVMs). Activin A receptor-like type 1 (ACVRL1/ALK1) and endoglin (ENG) are the principal genes whose mutations cause HHT. No multicenter study has yet investigated correlations between genetic variations and clinical outcomes in Korean HHT patients. METHODS: Seventy-two members from 40 families suspected to have HHT based on symptoms were genetically screened for pathogenic variants of ACVRL1 and ENG. Patients with genetically diagnosed HHT were also evaluated. RESULTS: In the HHT genetic screening, 42 patients from 24 of the 40 families had genetic variants that met the pathogenic criteria (pathogenic very strong, pathogenic strong, pathogenic moderate, or pathogenic supporting) based on the American College of Medical Genetics and Genomics Standards and Guidelines for either ENG or ACVRL1: 26 from 12 families (50%) for ENG, and 16 from 12 families (50%) for ACVRL1. Diagnostic screening of 42 genetically positive HHT patients based on the Curaçao criteria revealed that 24 patients (57%) were classified as having definite HHT, 17 (41%) as having probable HHT, and 1 (2%) as unlikely to have HHT. Epistaxis was the most common clinical presentation (38/42, 90%), followed by visceral AVMs (24/42, 57%) and telangiectasia (21/42, 50%). Five patients (12%) did not have a family history of HHT clinical symptoms. CONCLUSION: Only approximately half of patients with ACVRL1 or ENG genetic variants could be clinically diagnosed as having definite HHT, suggesting that genetic screening is important to confirm the diagnosis.

Thermal processing under oxygen-free condition of blueberry puree: Effect on anthocyanin, ascorbic acid, antioxidant activity, and enzyme activities.

The effect of thermal treatment of blueberry was investigated using a designed grinding and continuous packaging system under oxygen-free conditions. The grinding, packaging, and heating at 90 °C for 30 min under anaerobic condition were compared to heating under aerobic conditions, showing complete inactivation of oxidative enzymes. Heating without oxygen retained anthocyanins and ascorbic acid whereas heating in atmospheric air does not. Delphinidin glycoside was mostly influenced by oxygen deficiency during heating, followed by petunidin and malvidin glycosides. The differences in oxygen sensitivity may be closely associated with the number of hydroxylation in the B ring. The result of anthocyanin led to higher antioxidant activity and redness values of purees heated without oxygen than purees heated with oxygen. Consequently, thermal processing under oxygen-free condition can prevent oxidation of anthocyanin, resulting in higher retention of color and nutritional values of blueberry products.

Prevalence and clinical features of bone morphogenetic protein receptor type 2 mutation in Korean idiopathic pulmonary arterial hypertension patients: The PILGRIM explorative cohort.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive chronic disease with poor outcomes. One reason for poor prognosis is the lack of understanding regarding individual variability in response to treatment. Idiopathic PAH (IPAH) patients with bone morphogenetic protein receptor type 2 (BMPR2) mutations have distinct phenotypes that are crucial for individualized therapy but evidence regarding their prevalence and clinical features in the Korean population is lacking. Therefore, the present study aimed to screen Korean IPAH patients for BMPR2 mutations and analyze their clinical phenotypes. METHODS: We enrolled 73 unrelated IPAH patients for BMPR2 mutation screening between March 2010 to November 2015 from 11 hospitals in Korea. Thirty-three lineal family members from 6 families of BMPR2 mutation carriers were also screened. RESULTS: Among 73 patients, 16 (22%) had BMPR2 mutations. Mutation carriers were younger (27 vs. 47 years; p = 0.02) and had a higher mean pulmonary arterial pressure (mPAP) than non-carriers (64 vs. 51 mmHg; p<0.05). Of the 16 individuals with mutations, 5 deletion, 2 splice-site, 6 nonsense, and 3 missense mutations were found, among which, 9 were newly identified mutation types. Patients less than 30 years old had more BMPR2 mutations (44 vs. 14%; p = 0.04) and a higher mPAP (64 vs. 50 mmHg; p = 0.04) compared with those equaled to or over 30 years old. There were no differences in hemodynamic profiles or the proportion of BMPR2 mutation carriers between groups according to sex. CONCLUSION: The prevalence of BMPR2 mutations in Korean IPAH patients was 22%. Mutation carriers were younger and had a poorer hemodynamic profile compared with the non-carriers. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT01054105.

Analysis of Electrical Characteristics of InAlGaN/GaN-Based High Electron Mobility Transistors with AlGaN Back Barriers.

In this study, the effect of an AlGaN back-barrier on the electrical characteristics of InAlGaN/GaN high electron mobility transistors (HEMTs) was investigated. The dependence of the thickness and the Al composition of the AlGaN back-barrier on the off-state current (Ioff) of the devices was investigated. An InAlGaN/GaN HEMT with an Al0.1GaN back-barrier of thickness 20 nm exhibited lower Ioff because of the carrier confinement effect, which was caused by the back-barrier. The carrier confinement effect also improved the maximum output current density and the transconductance (gm). Thus, the obtained cut-off frequency (fT) and maximum oscillation frequency (fmax) values for the InAlGaN/GaN HEMT with the 20 nm thick AlGaN back-barrier were 2.6% and 13% higher than those without the AlGaN back-barrier. In addition, the impact of the buffer trap density and GaN channel thickness were evaluated. In the case of a thickness of 20 nm for the Al0.1GaN back-barrier, a low Ioff was maintained although the trap density in the buffer layer was changed. In addition, as the gate length (LGa) decreased to 50 nm, the InAlGaN/GaN HEMT with the 20 nm thick Al0.1GaN back-barrier achieved better Ioff characteristics, lower drain-induced barrier lowering (DIBL) of 85.8 mV/V, and subthreshold swing (S) of 269 mV/dec owing to a reduction in the short-channel effect.

Capacitorless One-Transistor Dynamic Random-Access Memory Based on Double-Gate Metal-Oxide-Semiconductor Field-Effect Transistor with Si/SiGe Heterojunction and Underlap Structure for Improvement of Sensing Margin and Retention Time.

We present a capacitorless one-transistor dynamic random-access memory (1T-DRAM) based on a Si/SiGe heterojunction double-gate MOSFET. In the proposed 1T-DRAM, the program process is based on band-to-band tunneling (BTBT) between gate 1 and gate 2 regions, and a sensing margin is defined by the amount of excess holes stored in the SiGe body region. Therefore, the sensing margin and retention time were affected by SiGe in the body region. The BTBT rate, enhanced by the small band-gap energy in SiGe, increased the sensing margin. The Si/SiGe heterojunction between the source/drain and body regions formed a potential barrier for hole carriers. The retention time was improved by suppressing the diffusion of hole carriers in the floating-body storage node. In addition, the retention characteristic was also enhanced by applying a gate underlap structure, which significantly reduced the electric field-induced recombination rate. The optimized device with a Si0.7Ge0.3 body and underlap length (Lunderlap) of 5 nm exhibited a high sensing margin of 6.16 µA/µm and long retention time of 131 ms at a high temperature of 358 K.

Effect of Interface Traps on the Device Performance of InGaAs-Based Gate-All-Around Tunneling Field-Effect Transistors.

The effect of interface traps on InGaAs-based vertical gate-all-around (GAA) tunneling field-effect transistors (TFETs) has been investigated using technology computer-aided design (TCAD) simulation. The interface traps distributed within different energy levels (Et) in the energy bandgap of a semiconductor material exhibit various influences on the device performances. In this work, InGaAs-based TFETs are simulated to analyze the effects on the on-state current (Ion), off-state current (Ioff), threshold voltage (Vth), subthreshold swing (SS), and the ambipolar characteristics according to Et and type of the interface traps. We have confirmed that Ioff and SS are degraded by the interface traps. Further, it can be shown that Ion is mainly affected by the acceptor-like traps and ambipolar behavior is affected by the donor-like traps. All the effects increase as Et becomes closer to the midgap. The effects of the interface traps with gate underlap and overlap at the source-channel region also have been investigated, considering the device fabrication. Additionally, the analysis of the effect of junction trap created at the source-channel junction has been performed.

Simulation for Electrical Performances of the Capacitorless Dynamic Random Access Memory Based on Junctionless FinFETs.

This paper report a junctionless fin-type field-effect-transistor based capacitorless dynamic random access memory using three-dimensional technology computer-aided design simulations. The proposed 1T-DRAM is made up of a silicon germanium storage region surrounding a silicon fin. When the two materials form a heterojunction, a potential well is formed by the band discontinuity which carriers can be stored. During the program operation, band-to-band tunneling and gate-induced drain leakage occur simultaneously due to the gate and drain bias. Because of these phenomena, the electron-hole pair occurs, and generated holes are stored in the storage region by potential well. The holes formed are positively charged within the storage region, which mitigates the depletion of the channel and improves the operating current. The proposed device realizes the memory operation by the difference of the operating current depending on the presence or absence of the stored holes. In this work, the device is analyzed and optimized in detail. The proposed 1T-DRAM shows excellent performance with a retention time of 161 ms based on 50% of the maximum data margin.

Design Optimization of InGaAs/GaAsSb-Based P-Type Gate-All-Around Arch-Shaped Tunneling Field-Effect Transistor.

In this work, an InGaAs/GaAsSb-based P-type gate-all-around (GAA) arch-shaped tunneling fieldeffect transistor (TFET) was designed and analyzed using technology computer-aided design (TCAD) simulations. The device performance was investigated in views of the on-state current (Ion), subthreshold swing (SS), and Ion/Ioff ratio. For high current drivability, InGaAs/GaAsSb heterojunction is used to form the broken bandgap. Owing to the GAA arch-shaped structure of the TFET, the tunneling region between source and channel extended, thus Ion and SS are improved. However, it has some performance variations that are related with the height of the source region (Hsource), the epitaxially grown thickness of the channel (tepi), and the height of the drain region (Hdrain). Therefore, we performed a design optimization of the proposed device with the variables of Hsource, tepi, and Hdrain. The designed and optimized InGaAs/GaAsSb-based P-type GAA arch-shaped TFET demonstrated an Ion of 215 µA/µm SS of 18 mV/dec and Ion/Ioff of 1.64 × 1012.

Pneumococcal pep27 mutant immunization suppresses allergic asthma in mice.

Asthma is an allergic airway disease (AAD) characterized by eosinophilic inflammation, mucus hypersecretion, and airway hyper responsiveness, and it is caused by dysregulated immune responses. Conversely, regulatory T cells (Tregs) control aberrant immune responses and maintain homeostasis. Recent evidence suggests that Streptococcus pneumoniae, including its components as well as a live attenuated mutant, and pneumococcal infection induce Tregs and can thus potentially be harnessed therapeutically for asthma treatment. Previously, a pep27 deletion mutant (Δpep27) demonstrated a significantly attenuated virulence in a sepsis model, and Δpep27 immunization induced serotype-nonspecific protection against S. pneumoniae infection, as well as influenza virus, possibly via an immune tolerance mechanism. Here, the potential of Δpep27 immunization for asthma protection was studied. Mice were immunized intranasally with Δpep27 before or after ovalbumin sensitization and subsequent challenge. Δpep27 immunization suppressed hallmark features of AAD, including antigen-specific type 2 helper T cell cytokine and antibody responses, peripheral and pulmonary eosinophil accumulation, and goblet cell hyperplasia. Thus, a Δpep27 vaccine may be highly feasible as a preventive or therapeutic agent for asthma.

Simulation of One-Transistor Dynamic Random-Access Memory Based on Symmetric Double-Gate Si Junctionless Transistor.

In this study, one-transistor dynamic random-access memory (1T-DRAM) based on a symmetric double-gate Si junctionless transistor is proposed using technology computer-aided design simulation. The proposed device uses double gates that play different roles in realizing 1T-DRAM operation. Gate 1 is used as a switching node, and Gate 2 is used as a storage node. By controlling the different two gate workfunctions, a potential barrier is adjusted to store hole effectively. The operation characteristics were investigated regarding four different memory operation states to write "1", write "0", read, and hold. Also, the effects of two different gate workfunctions on sensing margin and retention characteristics are closely investigated. Through a set of optimally set gate workfunctions, 33 µA/µm of sensing margin and 38 ms of retention time have been obtained.

CXCL12-CXCR4 signalling plays an essential role in proper patterning of aortic arch and pulmonary arteries.

AIMS: Chemokine CXCL12 (stromal derived factor 1: SDF1) has been shown to play important roles in various processes of cardiovascular development. In recent avian studies, CXCL12 signalling has been implicated in guidance of cardiac neural crest cells for their participation in the development of outflow tract and cardiac septum. The goal of this study is to investigate the extent to which CXCL12 signalling contribute to the development of aortic arch and pulmonary arteries in mammals. METHODS AND RESULTS: Novel Cxcl12-LacZ reporter and conditional alleles were generated. Using whole mount X-gal staining with the reporter allele and vascular casting techniques, we show that the domain branching pattern of pulmonary arteries in Cxcl12-null mice is completely disrupted and discordant with that of pulmonary veins and airways. Cxcl12-null mice also displayed abnormal and superfluous arterial branches from the aortic arch. The early steps of pharyngeal arch remodelling in Cxcl12-null mice appeared to be unaffected, but vertebral arteries were often missing and prominent aberrant arteries were present parallel to carotid arteries or trachea, similar to aberrant vertebral artery or thyroid ima artery, respectively. Analysis with computed tomography not only confirmed the results from vascular casting studies but also identified abnormal systemic arterial supply to lungs in the Cxcl12-null mice. Tie2-Cre mediated Cxcr4 deletion phenocopied the Cxcl12-null phenotypes, indicating that CXCR4 is the primary receptor for arterial patterning, whereas Cxcl12 or Cxcr4 deletion by Wnt1-Cre did not affect aortic arch patterning. CONCLUSION: CXCL12-CXCR4 signalling is essential for the correct patterning of aortic arches and pulmonary arteries during development. Superfluous arteries in Cxcl12-null lungs and the aortic arch infer a role of CXCL12 in protecting arteries from uncontrolled sprouting during development of the arterial system.

Enhanced electrical properties of reduced graphene oxide multilayer films by in-situ insertion of a TiO2 layer.

Wrinkle-free reduced graphene oxide (rGO)/TiO(2) hybrid multilayer films were directly fabricated using an rGO solution stabilized by a TiO(2) precursor sol applied over a large area by an air spraying method without the use of additional reduction processes. In-situ insertion of the TiO(2) layer between rGO sheets dramatically increased the conductivity and carrier mobility despite the insulating properties of amorphous TiO(2). The TiO(2) situated between rGO sheets also induced significant hole doping. Electrical hysteresis caused by adsorbed water molecules and residual oxidative moieties in the rGO nanosheets vanished due to TiO(2)-assisted screening of charged impurities. These effects decreased the thermal carrier activation energy and increased the density of states at the Fermi level. Ambipolar transport properties were converted into unipolar-like hole transport characteristics by extensive hole doping in the TiO(2) layer.

Titania-assisted dispersion of carboxylated single-walled carbon nanotubes in a ZnO sol for transparent conducting hybrid films.

We report a facile chemical route for stabilizing a dispersion of carboxylated single-walled carbon nanotubes (SWCNTs) in a ZnO sol. The dispersion is stabilized via capping of the carboxyl groups on the SWCNT surface by a titania layer, which was confirmed by Fourier transform infrared spectroscopy and transmission electron microscopy. We also demonstrate that the conductivity of the films prepared from the SWCNT/TiO(x)/ZnO sol is dramatically enhanced by thermal treatment and that the thermal stability of the hybridized films with the ZnO sol is notably improved relative to that of a pristine SWCNT film. The structural and chemical changes of the fabricated films were characterized by Raman spectroscopy. As one application, it was presented that thermally treated SWCNT/TiO(x)/ZnO hybrid thin film sensors showed hydrogen sensing characteristics even at room temperature.

The adsorption of mercury-species on relaxed and rumpled CaO (0 0 1) surfaces investigated by density functional theory.

This research examines the importance of several computational choices in modeling mercury species adsorption on calcium oxide surfaces and is the second in a series of papers. The importance of surface relaxation was tested and it was found that adsorption energies changed for HgCl(2), moving adsorption from being at the borderline of physisorption and chemisorption to being strongly chemisorbed. Results for Hg and HgCl were unaffected. A second computational choice, that of the cluster or periodic model size was tested in both the plane of the model (4 × 4 or 5 × 5 model sizes) and for the depth (two or three layers). It was found that the minimum cluster size for handling mercury adsorption was 5 × 5 and that only two layers of depth were needed. The energetic results show that rumpled CaO surfaces will only weakly physisorb elemental mercury, but could be used to capture HgCl(2) from coal combustion flue gases, which is in agreement with limited experimental data.

Adsorption energies of mercury-containing species on CaO and temperature effects on equilibrium constants predicted by density functional theory calculations.

The adsorption of Hg, HgCl, and HgCl2 on the CaO surface was investigated theoretically so the fundamental interactions between Hg species and this potential sorbent can be explored. Surface models of a 4 x 4 x 2 cluster, a 5 x 5 x 2 cluster, and a periodic structure using density functional theory calculations with LDA/PWC and GGA/BLYP functionals, as employed in the present work, offer a useful description for the thermodynamic properties of adsorption on metal oxides. The effect of temperature on the equilibrium constant for the adsorption of mercury-containing species on the CaO (0 0 1) surface was investigated with GGA/BLYP calculations in the temperature range of 250-600 K. Results show that, at low coverage of elemental mercury, adsorption on the surface is physisorption while the two forms of oxidized mercury adsorption undergo stronger adsorption. The adsorption energies decrease with increasing coverage for elemental mercury on the surfaces. The chlorine atom enhances the adsorption capacity and adsorbs mercury to the CaO surface more strongly. The adsorption energy is changed as the oxidation state varies, and the equilibrium constant decreases as the temperature increases, in good agreement with data for exothermic adsorption systems.