Remarkable Reduction in IG with an Explicit Investigation of the Leakage Conduction Mechanisms in a Dual Surface-Modified Al2O3/SiO2 Stack Layer AlGaN/GaN MOS-HEMT.

We demonstrated the performance of an Al2O3/SiO2 stack layer AlGaN/GaN metal−oxide semiconductor (MOS) high-electron-mobility transistor (HEMT) combined with a dual surface treatment that used tetramethylammonium hydroxide (TMAH) and hydrochloric acid (HCl) with post-gate annealing (PGA) modulation at 400 °C for 10 min. A remarkable reduction in the reverse gate leakage current (IG) up to 1.5×10−12 A/mm (@ VG = −12 V) was observed in the stack layer MOS-HEMT due to the combined treatment. The performance of the dual surface-treated MOS−HEMT was significantly improved, particularly in terms of hysteresis, gate leakage, and subthreshold characteristics, with optimized gate annealing treatment. In addition, an organized gate leakage conduction mechanism in the AlGaN/GaN MOS−HEMT with the Al2O3/SiO2 stack gate dielectric layer was investigated before and after gate annealing treatment and compared with the conventional Schottky gate. The conduction mechanism in the reverse gate bias was Poole−Frankel emission for the Schottky-gate HEMT and the MOS−HEMT before annealing. The dominant conduction mechanism was ohmic/Poole-Frankel at low/medium forward bias. Meanwhile, gate leakage was governed by the hopping conduction mechanism in the MOS−HEMT without gate annealing modulation at a higher forward bias. After post-gate annealing (PGA) treatment, however, the leakage conduction mechanism was dominated by trap-assisted tunneling at the low to medium forward bias region and by Fowler−Nordheim tunneling at the higher forward bias region. Moreover, a decent product of maximum oscillation frequency and gate length (fmax × LG) was found to reach 27.16 GHz∙µm for the stack layer MOS−HEMT with PGA modulation. The dual surface-treated Al2O3/SiO2 stack layer MOS−HEMT with PGA modulation exhibited decent performance with an IDMAX of 720 mA/mm, a peak extrinsic transconductance (GMMAX) of 120 mS/mm, a threshold voltage (VTH) of −4.8 V, a higher ION/IOFF ratio of approximately 1.2×109, a subthreshold swing of 82 mV/dec, and a cutoff frequency(ft)/maximum frequency of (fmax) of 7.5/13.58 GHz.

Improved Electrical Characteristics of AlGaN/GaN High-Electron-Mobility Transistor with Al2O3/ZrO2 Stacked Gate Dielectrics.

A metal-oxide-semiconductor high-electron-mobility transistor (MOS-HEMT) is proposed based on using a Al2O3/ZrO2 stacked layer on conventional AlGaN/GaN HEMT to suppress the gate leakage current, decrease flicker noise, increase high-frequency performance, improve power performance, and enhance the stability after thermal stress or time stress. The MOS-HEMT has a maximum drain current density of 847 mA/mm and peak transconductance of 181 mS/mm. The corresponding subthreshold swing and on/off ratio are 95 mV/dec and 3.3 × 107. The gate leakage current can be reduced by three orders of magnitude due to the Al2O3/ZrO2 stacked layer, which also contributes to the lower flicker noise. The temperature-dependent degradation of drain current density is 26%, which is smaller than the 47% of reference HEMT. The variation of subthreshold characteristics caused by thermal or time stress is smaller than that of the reference case, showing the proposed Al2O3/ZrO2 stacked gate dielectrics are reliable for device applications.

Investigation of the Stability of Methylammonium Lead Iodide (MAPbI3) Film Doped with Lead Cesium Triiodide (CsPbI3) Quantum Dots under an Oxygen Plasma Atmosphere.

In this study, we describe composited perovskite films based on the doping of lead cesium triiodide (CsPbI3) quantum dots (QDs) into methylammonium lead iodide (MAPbI3). CsPbI3 QDs and MAPbI3 were prepared by ligand-assisted re-precipitation and solution mixing, respectively. These films were optimized by oxygen plasma treatment, and the effect of powers from 0 to 80 W on the structural properties of the composited perovskite films is discussed. The experimental results showed that the light-harvesting ability of the films was enhanced at 20 W. The formation of the metastable state (lead(II) oxide and lead tetroxide) was demonstrated by peak differentiation-imitating. A low power enhanced the quality of the films due to the removal of organic impurities, whereas a high power caused surface damage in the films owing to the severe degradation of MAPbI3.

Inverted-Type InAlAs/InAs High-Electron-Mobility Transistor with Liquid Phase Oxidized InAlAs as Gate Insulator.

An inverted-type InAlAs/InAs metal-oxide-semiconductor high-electron-mobility transistor (MOS-HEMT) with liquid phase oxidized (LPO) InAlAs as the gate insulator is demonstrated. A thin InAs layer is inserted in the sub-channel layers of InGaAs to enhance the device performance. The proposed inverted-type InAlAs/InAs MOS-HEMT exhibits an improved maximum drain current density, higher transconductance, lower leakage current density, suppressed noise figures, and enhanced associated gain compared to the conventional Schottky-gate HEMT. Employing LPO to generate MOS structure improves the surface states and enhances the energy barrier. These results reveal that the proposed inverted-type InAlAs/InAs MOS-HEMT can provide an alternative option for device applications.

Perovskite Quantum Dot Lasing in a Gap-Plasmon Nanocavity with Ultralow Threshold.

Lead halide perovskite materials have recently received considerable attention for achieving an economic and tunable laser owing to their solution-processable feature and promising optical properties. However, most reported perovskite-based lasers operate with a large lasing-mode volume, resulting in a high lasing threshold due to the inefficient coupling between the optical gain medium and cavity. Here, we demonstrate a continuous-wave nanolasing from a single lead halide perovskite (CsPbBr3) quantum dot (PQD) in a plasmonic gap-mode nanocavity with an ultralow threshold of 1.9 Wcm-2 under 120 K. The calculated ultrasmall mode volume (∼0.002 λ3) with a z-polarized dipole and the significantly large Purcell enhancement at the corner of the nanocavity inside the gap dramatically enhance the light-matter interaction in the nanocavity, thus facilitating lasing. The demonstration of PQD nanolasing with an ultralow-threshold provides an approach for realizing on-chip electrically driven lasing and integration into on-chip plasmonic circuitry for ultrafast optical communication and quantum information processing.

Low-Dissipation Thermosets Derived from Oligo(2,6-Dimethyl Phenylene Oxide)-Containing Benzoxazines.

Poly(2,6-dimethyl phenyl oxide) (PPO) is known for its low dissipation factor. To achieve insulating materials with low dissipation factors for high-frequency communication applications, a telechelic oligomer-type benzoxazine (P-APPO) and a main-chain type benzoxazine polymer (BPA-APPO) were prepared from an amine end-capped oligo (2,6-dimethyl phenylene oxide) (APPO). The APPO was prepared from a nucleophilic substitution of a phenol-end capped oligo (2,6-dimethyl phenylene oxide) (a commercial product, SA 90) with fluoronitrobenzene, and followed by catalytic hydrogenation. After self-curing or curing with a dicyclopentadiene-phenol epoxy (HP 7200), thermosets with high-Tg and low-dissipation factor can be achieved. Furthermore, the resulting epoxy thermosets show better thermal and dielectric properties than those of epoxy thermoset cured from its precursor SA90, demonstrating it is a successful modification in simultaneously enhancing the thermal and dielectric properties.

Potential natural mTOR inhibitors screened by in silico approach and suppress hepatic stellate cells activation.

The mammalian target of rapamycin (mTOR), an atypical serine/threonine kinase, plays a central role in the regulation of cell proliferation, growth, differentiation, migration, and survival. In this study, the 3-D structure of the mTOR (PDB ID: 2FAP) was used for the docking of 47 natural compounds and compared with pharmacophore model of 14 known mTOR inhibitors to identify the novel and specific natural inhibitor. The top four compounds, rutin, curcumin, antroquinonol, and benzyl cinnamate, have been selected based on their PLP score and further validated with hepatic stellate cells NHSC and THSC. Curcumin and antroquinonol significantly inhibited NHSC and THSC cells proliferation in a dose-dependent manner, whereas rutin and benzyl cinnamate showed less alteration of cell viability. Rutin inhibited the phosphorylation of mTOR (p-mTOR) and p-p70 S6 K in NHSC and THSC cells by Western blotting. Additionally, p-p70 S6 K protein was significantly decreased by incubation with benzyl cinnamate and curcumin in THSC cells. Taken together, this result suggests that rutin is a potential mTOR inhibitor in screen hits of molecular docking to hamper the activation of HSC and further applications in the treatment of liver fibrosis.

Difference in bilateral digital volume pulse as a novel non-invasive approach to assessing arteriosclerosis in aged and diabetic subjects: A preliminary study.

OBJECTIVE: This study aimed at validating photoplethysmography for assessing bilateral blood pressure differences through investigating the correlations of digital volume pulse with arteriosclerosis risk. METHODS: Totally, 111 subjects (70 healthy and 41 diabetic) were recruited. Demographic, blood pressure and anthropometric data were recorded. Blood was collected for determining serum cholesterol, total triglyceride, total cholesterol, high-/low-density lipoprotein cholesterol, fasting blood sugar and glycated haemoglobin concentrations. Arterial stiffness was assessed with electrocardiogram-based pulse wave velocity, crest time and inter-digital volume pulse differences. RESULTS: Receiver operating characteristic curve demonstrated high inter-digital volume pulse difference sensitivity to glycated haemoglobin level over 6.5%. Linear regression analysis demonstrated significant correlation between inter-digital volume pulse difference and electrocardiogram-based pulse wave velocity ( r = 0.692, p < 0.001). Compared with electrocardiogram-based pulse wave velocity, inter-digital volume pulse difference exhibited highly significant correlations with age, glycated haemoglobin level, pulse pressure, total cholesterol/high-density lipoprotein ratio, crest time, high-density lipoprotein and systolic blood pressure (all ps < 0.001). CONCLUSION: In conclusion, the results not only demonstrated successful application of a novel non-invasive waveform contour index, inter-digital volume pulse difference, in differentiating young from aged subjects and patients with good diabetic control from those with poor diabetic control but also validated its use in identifying arteriosclerosis risks. The results, therefore, endorse its domestic application as non-invasive tool for arteriosclerosis risk screening.

A Preclinical Assessment of Early Continuous Passive Motion and Treadmill Therapeutic Exercises for Generating Chondroprotective Effects After Anterior Cruciate Ligament Rupture.

BACKGROUND: Anterior cruciate ligament (ACL) injury is a well-known risk factor for the development of posttraumatic osteoarthritis (PTOA). However, whether using continuous passive motion (CPM) with or without additional treadmill exercise (TRE) in early ACL injury might provide chondroprotective effects and further decrease the risk of PTOA has yet to be determined. HYPOTHESIS: CPM may offer an enhanced chondroprotective effect, but TRE may attenuate that effect due to the mechanical stress on the joint and inflammatory cytokines in the joint. STUDY DESIGN: Controlled laboratory study. METHODS: Thirty adult New Zealand White male rabbits were randomly allocated to sedentary (SED), CPM, TRE, or CPM+TRE groups. Each rabbit underwent an ACL transection (ACLT) on the right knee, with the contralateral knee used as an internal control (sham). The 4 joint surfaces (ie, medial and lateral femoral condyles and tibial plateaus) were evaluated 4 weeks after surgery for gross appearance, histological characteristics, and quantitative osteoarthritis (OA) scores. RESULTS: Overall, at the end of testing, the CPM group experienced the best protective therapeutic effects in all compartments. In gross appearance, CPM resulted in normal articular surfaces, while the TRE and SED groups exhibited surface abrasion. Histological analysis showed significant differences in articular cartilage status. The CPM group had significantly better histological OA scores ( P < .01), corresponding to the smoothest cartilage surface and sound chondrocyte and collagen arrangement. This group also showed abundant glycosaminoglycan (GAG) content and a sound growth microenvironment, with significantly lower expression levels of the inflammatory cytokine tumor necrosis factor α and the apoptotic marker caspase 3. In contrast, the TRE and SED groups showed several features of damage: distinct graded cartilage abrasion; damaged collagen fibers, corresponding to noticeable collagen type X (osteoarthritic cartilage); reduced cartilage thickness; fewer cartilaginous cells; and the appearance of chondrocyte clusters. These groups also showed loss of GAG, corresponding to higher levels of inflammatory cytokines and apoptosis of articular chondrocytes. Furthermore, the CPM+TRE group displayed visible pathological changes in the superficial cartilage, indicating that early loading exercise may contribute to osteoarthritis. The sham treatment showed no difference in the changes in all compartments between groups. CONCLUSION: Immediate CPM therapy produces a superior in situ microenvironment for reducing the occurrence of PTOA after ACL injury without reconstruction in rabbits. CLINICAL RELEVANCE: These data suggest that immediate application of CPM therapy may be necessary to create a sound microenvironment in joints and possibly to decrease the risk of PTOA without or while awaiting ACL reconstruction. In contrast, both early active loading exercise and inactivity lead to the development of PTOA.

Can Early Rehabilitation Prevent Posttraumatic Osteoarthritis in the Patellofemoral Joint after Anterior Cruciate Ligament Rupture? Understanding the Pathological Features.

Knee instability resulting from anterior cruciate ligament (ACL) rupture is a high-risk factor for posttraumatic osteoarthritis (PTOA) in the patellofemoral joint (PFJ). However, whether non-weight-bearing and weight-bearing treatments have chondroprotective effects remains unclear. Twenty-four adult New Zealand White male rabbits were employed in this study. All animals received ACL transection in the right knee and sham surgery in the left knee. The rabbits were randomly assigned to the following groups: (I) In the sedentary (SED) group, the rabbits (n = 6) were simply kept in their cage; (II) In the continuous passive motion (CPM) group, the rabbits (n = 6) performed CPM exercise for 7 days, starting from the first postoperative day; (III) In the active treadmill exercise (TRE) group, the rabbits (n = 6) performed TRE for 2 weeks; (IV) In the CPM + TRE group, the rabbits (n = 6) executed CPM exercise, followed by TRE. Two joint surfaces (the retropatella and femoral trochlear groove) were assessed at 4 weeks after operation. Although the gross appearance in each group was comparable, histological examination revealed significant differences in the articular cartilage status. The CPM group exhibited a greater thickness of articular cartilage, maintenance of tidemark continuity, abundant glycosaminoglycan (GAG), and significantly lower inflammatory cytokine 9, e.g., tumor necrosis factor-alpha (TNF-α) 0 levels, with modest cell apoptosis (i.e., caspase-3). By contrast, the TRE group displayed the worst pathological features: an irregular cartilage surface and chondrocyte disorganization, reduced cartilage thickness, breakdown of the tidemark, depletion of collagen fibers, loss of GAG, and the highest levels of TNF-α and caspase-3 expression. Furthermore, the CPM + TRE group had more favorable outcomes than the SED group, indicating that suitable exercise is needed. The sham treatment displayed no variance in the changes in the two joint surfaces among groups. These data indicate that the application of early CPM rehabilitation is suggested for subjects in order to decrease the risk of PTOA without ACL reconstruction in the PFJ compartment in rabbits. The early TRE program, however, had harmful outcomes. Additionally, inactivity was discovered to initiate the development of PTOA.

High-Tg, Low-Dielectric Epoxy Thermosets Derived from Methacrylate-Containing Polyimides.

Three methacrylate-containing polyimides (Px⁻MMA; x = 1⁻3) were prepared from the esterification of hydroxyl-containing polyimides (Px⁻OH; x = 1⁻3) with methacrylic anhydride. Px⁻MMA exhibits active ester linkages (Ph⁻O⁻C(=O)⁻) that can react with epoxy in the presence of 4-dimethylaminopyridine (DMAP), so Px⁻MMA acted as a curing agent for a dicyclopentadiene-phenol epoxy (HP7200) to prepare epoxy thermosets (Px⁻MMA/HP7200; x = 1⁻3) thermosets. For property comparisons, P1⁻OH/HP7200 thermosets were also prepared. The reaction between active ester and epoxy results in an ester linkage, which is less polar than secondary alcohol resulting from the reaction between phenolic OH and epoxy, so P1⁻MMA/HP7200 are more hydrophobic and exhibit better dielectric properties than P1⁻OH/HP7200. The double bond of methacrylate can cure at higher temperatures, leading to epoxy thermosets with a high-Tg and moderate-to-low dielectric properties.

Comparative analysis of novel autoantibody isotypes against citrullinated-inter-alpha-trypsin inhibitor heavy chain 3 (ITIH3)(542-556) peptide in serum from Taiwanese females with rheumatoid arthritis, primary Sjögren's syndrome and secondary Sjögren's syndrome in rheumatoid arthritis.

UNLABELLED: The purpose of this study was to discover and validate inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) as novel biomarkers, and evaluate autoantibody isotypes against an unmodified and citrullinated ITIH3(542-556) peptide among Taiwanese female patients with rheumatoid arthritis (RA), primary Sjögren's syndrome (pSS), secondary Sjögren's syndrome in rheumatoid arthritis (RA-sSS), and healthy controls (HCs). We used concanavalin A (Con A) affinity chromatography, 1-D SDS-PAGE, and label-free nano-LC-MS/MS to screen biomarker candidates (serum-derived Con A-captured proteins) and then identify PTMs of validated biomarkers (serum proteins) using pooled serum from 7 RA-sSS female patients and 7 age-matched HCs (the discovery set). Furthermore, the protein level and autoantibody isotype analyses were further validated against individual serum from 18 HCs, 18 RA, 18 pSS, and 18 RA-sSS patients (the validation set). Con A-bound ITIH3 was identified and validated as the only differentially expressed protein, which was elevated. Additionally, 2 novel PTMs in ITIH3 were identified and included citrullination at arginine-(546) and arginine-(556), and hexosamine at tryptophan-(558). Further, concentrations of anti-citrullinatd-ITIH3(542-556) peptide autoantibodies significantly increased in patients with RA, pSS, and RA-sSS compared to HCs. Especially, autoantibody IgM against the citrullinated-ITIH3(542-556) peptide showed better diagnostic performance in discriminating both RA versus pSS and pSS versus RA-sSS. SIGNIFICANCE: By using comparative proteomic analysis of serum samples, the current study discovered and validates differentially expressed Con A-bound ITIH3 as a potential biomarker for secondary Sjögren's syndrome (SS) in rheumatoid arthritis (RA) patients and healthy controls (HCs). Besides, hexosamine and citrullination on ITIH3 were further identified. Through analyzing autoantibody isotypes against the citrullinated ITIH3 peptide, patients with RA, primary SS, and RA-secondary SS, and HCs can be further discriminated. The current strategy can be applied for identifying potential diagnostic and pathologic markers for autoimmune diseases.

Reduced Subthreshold Characteristics and Flicker Noise of an AlGaAs/InGaAs PHEMT Using Liquid Phase Deposited TiO2 as a Gate Dielectric.

This study presents the fabrication and improved properties of an AlGaAs/InGaAs metal-oxide-semiconductor pseudomorphic high-electron-mobility transistor (MOS-PHEMT) using liquid phase deposited titanium dioxide (LPD-TiO2) as a gate dielectric. Sulfur pretreatment and postoxidation rapid thermal annealing (RTA) were consecutively employed before and after the gate dielectric was deposited to fill dangling bonds and therefore release interface trapped charges. Compared with a benchmark PHEMT, the AlGaAs/InGaAs MOS-PHEMT using LPD-TiO2 exhibited larger gate bias operation, higher breakdown voltage, suppressed subthreshold characteristics, and reduced flicker noise. As a result, the device with proposed process and using LPD-TiO2 as a gate dielectric is promising for high-speed applications that demand little noise at low frequencies.

Positive effects of cell-free porous PLGA implants and early loading exercise on hyaline cartilage regeneration in rabbits.

The regeneration of hyaline cartilage remains clinically challenging. Here, we evaluated the therapeutic effects of using cell-free porous poly(lactic-co-glycolic acid) (PLGA) graft implants (PGIs) along with early loading exercise to repair a full-thickness osteochondral defect. Rabbits were randomly allocated to a treadmill exercise (TRE) group or a sedentary (SED) group and were prepared as either a PGI model or an empty defect (ED) model. TRE was performed as a short-term loading exercise; SED was physical inactivity in a free cage. The knees were evaluated at 6 and 12 weeks after surgery. At the end of testing, none of the knees developed synovitis, formed osteophytes, or became infected. Macroscopically, the PGI-TRE group regenerated a smooth articular surface, with transparent new hyaline-like tissue soundly integrated with the neighboring cartilage, but the other groups remained distinct at the margins with fibrous or opaque tissues. In a micro-CT analysis, the synthesized bone volume/tissue volume (BV/TV) was significantly higher in the PGI-TRE group, which also had integrating architecture in the regeneration site. The thickness of the trabecular (subchondral) bone was improved in all groups from 6 to 12 weeks. Histologically, remarkable differences in the cartilage regeneration were visible. At week 6, compared with SED groups, the TRE groups manifested modest inflammatory cells with pro-inflammatory cytokines (i.e., TNF-α and IL-6), improved collagen alignment and higher glycosaminoglycan (GAG) content, particularly in the PGI-TRE group. At week 12, the PGI-TRE group had the best regeneration outcomes, showing the formation of hyaline-like cartilage, the development of columnar rounded chondrocytes that expressed enriched levels of collagen type II and GAG, and functionalized trabecular bone with osteocytes. In summary, the combination of implanting cell-free PLGA and performing an early loading exercise can significantly promote the full-thickness osteochondral regeneration in rabbit knee joint models. STATEMENT OF SIGNIFICANCE: Promoting effective hyaline cartilage regeneration rather than fibrocartilage scar tissue remains clinically challenging. To address the obstacle, we fabricated a spongy cell-free PLGA scaffold, and designed a reasonable exercise program to generate combined therapeutic effects. First, the implanting scaffold generates an affordable mechanical structure to bear the loading forces and bridge with the host to offer a space in the full-thickness osteochondral regeneration in rabbit knee joint. After implantation, rabbits were performed by an early treadmill exercise 15 min/day, 5 days/week for 2 weeks that directly exerts in situ endogenous growth factor and anti-inflammatory effects in the reparative site. The advanced therapeutic strategy showed that neo-hyaline cartilage formation with enriched collagen type II, higher glycosaminoglycan, integrating subchondral bone formation and modest inflammation.

Analysis of differentially expressed novel post-translational modifications of plasma apolipoprotein E in Taiwanese females with breast cancer.

APOE ε2 or ε4 alleles being used as indicators of breast cancer risk are controversial in Taiwanese females. We provide a concept for relative comparisons of post-translational modifications (PTMs) of plasma apolipoprotein E (ApoE) between normal controls and breast cancer patients to investigate the association of ApoE with breast cancer risk. APOE polymorphisms (ApoE isoforms) were not assessed in this study. The relative modification ratio (%) of 15 targeted and 21 modified peptides were evaluated by 1D SDS-PAGE, in-gel digestion, and label-free nano-LC/MS to compare normal controls with breast cancer patients. Plasma levels of the ApoE protein did not significantly differ between normal controls and breast cancer patients. Eleven sites with novel PTMs were identified from 7 pairs of differentially expressed targeted and modified peptides according to the relative modification ratio including methylation at the E3 (↑1.45-fold), E7 (↑1.45-fold), E11 (↑1.19-fold), E77 (↑2.02-fold), E87 (↑2.02-fold), and Q98 (↑1.62-fold) residues; dimethylation at the Q187 (↑1.44-fold) residue; dihydroxylation at the R92 (↑1.25-fold), K95 (↑1.25-fold), and R103 (↑1.25-fold) residues; and glycosylation at the S129 (↑1.14-fold) residue. The clustered methylation and dihydroxylation of plasma ApoE proteins may play a role in breast cancer.

Synergistic effect of natural compounds on the fatty acid-induced autophagy of activated hepatic stellate cells.

Autophagy, a lysosomal pathway to maintain cellular homeostasis, is mediated via the mammalian target of rapamycin (mTOR)-dependent pathways. Hepatic stellate cells (HSCs), previously termed fat- or vitamin A-storing cells, can transdifferentiate into myofibroblast-like cells and are the most relevant cell type for overproduction of extracellular matrix (ECM) and development of liver fibrosis during injury. However, the role of autophagy in fat metabolism of HSCs remains unclear. This study investigates the regulatory effect of natural compounds on fatty acid-induced autophagy pathways of nonchemical-induced HSC (NHSC) and thioacetamide-induced HSC. Oleic acid (OA) and palmitic acid (PA) have shown a significant effect on cell proliferation with oil red O staining and Western blot confirming that OA and PA induce fat storage ability and autophagy protein expression in NHSC. Natural compounds rutin, curcumin, antroquinonol and benzyl cinnamate treatment have shown no effect on the autophagy protein expression. Nevertheless, cells pretreated with OA and PA then treated with rutin, curcumin, antroquinonol and benzyl cinnamate could significantly induce the light chain I/II (LC3 I/II) protein expression. In mTOR-dependent pathway, the PI3K-Class I, Akt, and p-mTOR proteins were decreased with PA treatment. However, there were no significant changes in PI3K-Class III and Beclin-1 protein expressions found to imply that this autophagy is unrelated to the mTOR-independent pathway. Taken together, the present study unveils rutin and curcumin as a possible effective stimulation for fatty acid-induced autophagy via mTOR-dependent pathways in NHSC. We further suggest the benefits of these natural compounds for alleviating liver fibrosis.

Insulin and LiCl synergistically rescue myogenic differentiation of FoxO1 over-expressed myoblasts.

Most recent studies reported that FoxO1 transcription factor was a negative regulator of myogenesis under serum withdrawal condition, a situation not actually found in vivo. Therefore, the role of FoxO1 in myogenesis should be re-examined under more physiologically relevant conditions. Here we found that FoxO1 was preferentially localized to nucleus in proliferating (PMB) and confluent myoblasts (CMB) and its nuclear exclusion was a prerequisite for formation of multinucleated myotubes (MT). The nuclear shuttling of FoxO1 in PMB could be prevented by leptomycin B and we further found that cytoplasmic accumulation of FoxO1 in myotubes was caused by the blockade of its nuclear import. Although over-expression of wildtype FoxO1 in C2C12 myoblasts significantly blocked their myogenic differentiation under serum withdrawal condition, application of insulin and LiCl, an activator of Wnt signaling pathway, to these cells successfully rescued their myogenic differentiation and generated myotubes with larger diameters. Interestingly, insulin treatment significantly reduced FoxO1 level and also delayed nuclear re-accumulation of FoxO1 triggered by mitogen deprivation. We further found that FoxO1 directly repressed the promoter activity of myogenic genes and this repression can be relieved by insulin and LiCl treatment. These results suggest that FoxO1 inhibits myogenesis in serum withdrawal condition but turns into a hypertrophy potentiator when other myogenic signals, such as Wnt and insulin, are available.

Structure of native oligomeric Sprouty2 by electron microscopy and its property of electroconductivity.

Receptor tyrosine kinases (RTKs) regulate many cellular processes, and Sprouty2 (Spry2) is known as an important regulator of RTK signaling pathways. Therefore, it is worth investigating the properties of Spry2 in more detail. In this study, we found that Spry2 is able to self-assemble into oligomers with a high-affinity KD value of approximately 16nM, as determined through BIAcore surface plasmon resonance analysis. The three-dimensional (3D) structure of Spry2 was resolved using an electron microscopy (EM) single-particle reconstruction approach, which revealed that Spry2 is donut-shaped with two lip-cover domains. Furthermore, the method of energy dispersive spectrum obtained through EM was analyzed to determine the elements carried by Spry2, and the results demonstrated that Spry2 is a silicon- and iron-containing protein. The silicon may contribute to the electroconductivity of Spry2, and this property exhibits a concentration-dependent feature. This study provides the first report of a silicon- and iron-containing protein, and its 3D structure may allow us (1) to study the potential mechanism through the signal transduction is controlled by switching the electronic transfer on or off and (2) to develop a new type of conductor or even semiconductor using biological or half-biological hybrid materials in the future.

FoxO6 and PGC-1α form a regulatory loop in myogenic cells.

Transcription factors of the FoxO (forkhead box O) family regulate a wide range of cellular physiological processes, including metabolic adaptation and myogenic differentiation. The transcriptional activity of most FoxO members is inhibitory to myogenic differentiation and overexpression of FoxO1 inhibits the development of oxidative type I fibres in vivo. In this study, we found that FoxO6, the last discovered FoxO family member, is expressed ubiquitously in various tissues but with higher expression levels in oxidative tissues, such as brain and oxidative muscles. Both the expression level and promoter activity of FoxO6 were found to be enhanced by PGC-1α (peroxisome-proliferator-activated receptor γ co-activator 1α), thus explained its enriched expression in oxidative tissues. We further demonstrated that FoxO6 represses the expression of PGC-1α via direct binding to an upstream A/T-rich element (AAGATATCAAAACA,-2228-2215) in the PGC-1α promoter. Oxidative low-intensity exercise induced PGC-1α but reduced FoxO6 expression levels in hind leg muscles, and the binding of FoxO6 to PGC-1α promoter was also prevented by exercise. As FoxO6 promoter can be co-activated by PGC-1α and its promoter in turn can be repressed by FoxO6, it suggests that FoxO6 and PGC-1α form a regulatory loop for setting oxidative metabolism level in the skeletal muscle, which can be entrained by exercise.

Comparative proteomics, network analysis and post-translational modification identification reveal differential profiles of plasma Con A-bound glycoprotein biomarkers in gastric cancer.

In the study, we used Con A affinity chromatography, 1-D gel electrophoresis, and nano-LC-MS/MS to screen biomarker candidates in plasma samples obtained from 30 patients with gastric cancer and 30 healthy volunteers. First, we pooled plasma samples matched by age and sex. We identified 17 differentially expressed Con A-bound glycoproteins, including 10 upregulated proteins and 7 downregulated proteins; these differences were significant (Student's t-test, p-value<0.05). Furthermore, 2 of the upregulated proteins displayed expression levels that were increased by 2-fold or more in gastric cancer samples when compared with normal control samples. These proteins included leucine-rich alpha-2-glycoprotein (LRG1) and inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3), and the expression levels were validated by Western blot analysis. Pathway and network analysis of the differentially expressed proteins by Ingenuity Pathway Analysis revealed vital canonical pathways involving acute phase response signaling, the complement system, LXR/RXR activation, hematopoiesis from pluripotent stem cells, and primary immunodeficiency signaling. Our results suggest that Con A-bound LRG1 and ITIH3 may not be practically applicable as a robust biomarker for the early detection of gastric cancer. Additionally, three novel PTMs in ITIH3 were identified and include hexose-N-acetyl-hexosamine at asparagine-(41), trimethylation at aspartic acid-(290), and flavin adenine dinucleotide at histidine-(335). BIOLOGICAL SIGNIFICANCE: Our study was to describe a combinatorial approach of Con A affinity chromatography, 1-D SDS-PAGE, and nano-LC/MS/MS that provides a label-free, comparative glycoproteomic quantification strategy for the investigation of glycoprotein profiles in plasma from gastric cancer patients versus healthy volunteers and to identify glycoprotein biomarkers for the early clinical detection of gastric cancer. Three novel PTMs, HexHexNAc, trimethylation and FAD, in Con A-bound ITIH3 were identified and built in molecular modeling. The aspartic acid-(290) trimethylation site was located in a metal ion-dependent adhesion site (MIDAS motif; (290)-DXSXS…T…D-(313)) that may influence important function for binding protein ligands.