Search

Supplementary Table S1. List of methylated histone proteins identified from in vitro HMT assay on calf thymus extracts followed by LC-MS/MS analysis

SMYD3 methyltransferase is nearly undetectable in normal human tissues but highly expressed in several cancers, including breast cancer, although its contributions to pathogenesis in this setting are unclear. Here we report that histone H2A.Z.1 is a substrate of SMYD3 that supports malignancy. SMYD3-mediated dimethylation of H2A.Z.1 at lysine 101 (H2A.Z.1K101me2) increased stability by preventing binding to the removal chaperone ANP32E and facilitating its interaction with histone H3. Moreover, a microarray analysis identified cyclin A1 as a target coregulated by SMYD3 and H2A.Z.1K101me2. The colocalization of SMYD3 and H2A.Z.1K101me2 at the promoter of cyclin A1 activated its expression and G1–S progression. Enforced expression of cyclin A1 in cells containing mutant H2A.Z.1 rescued tumor formation in a mouse model. Our findings suggest that SMYD3-mediated H2A.Z.1K101 dimethylation activates cyclin A1 expression and contributes to driving the proliferation of breast cancer cells. Cancer Res; 76(20); 6043–53. ©2016 AACR. more...

Fig. S1. Representative mass spectrometry data of methylated H2A.Z. Fig. S2. Methylation activity of SMYD3 on histones in the context of nucleosome and evaluation of the H2A.ZK101me2 antibody. Fig. S3. Dimethylation of H2A.Z is critical for its protein interaction. Fig. S4. Dimethylation of H2A.Z is critical for promoting cell growth. Fig. S5. Genes affected by SMYD3 knockdown and H2A.ZK101Q expression. Fig. S6. Cyclin A1 is one of the downstream targets co-regulated by SMYD3 and H2A.ZK101me2. more...

Supplementary Materials and Methods, Supplementary Figure Legends and Supplementary Tables

The Arl4 small GTPases participate in a variety of cellular events, including cytoskeleton remodeling, vesicle trafficking, cell migration, and neuronal development. Whereas small GTPases are typically regulated by their GTPase cycle, Arl4 proteins have been found to act independent of this canonical regulatory mechanism. Here, we show that Arl4A and Arl4D (Arl4A/D) are unstable due to proteasomal degradation, but stimulation of cells by fibronectin (FN) inhibits this degradation to promote Arl4A/D stability. Proteomic analysis reveals that FN stimulation induces phosphorylation at S143 of Arl4A and at S144 of Arl4D. We identify Pak1 as the responsible kinase for these phosphorylations. Moreover, these phosphorylations promote the chaperone protein HYPK to bind Arl4A/D, which stabilizes their recruitment to the plasma membrane to promote cell migration. These findings not only advance a major mechanistic understanding of how Arl4 proteins act in cell migration but also achieve a fundamental understanding of how these small GTPases are modulated by revealing that protein stability, rather than the GTPase cycle, acts as a key regulatory mechanism. more...

Ovarian cancer has a high recurrence rate after platinum‐based chemotherapy. To improve the treatment of ovarian cancer and identify ovarian cancer‐specific antibodies, we immunized mice with the human ovarian carcinoma cell line, SKOV‐3, and generated hybridoma clones. Several rounds of screening yielded 30 monoclonal antibodies (mAbs) with no cross‐reactivity to normal cells. Among these mAbs, OV‐Ab 30‐7 was found to target integrin α3 and upregulate p53 and p21, while stimulating the apoptosis of cancer cells. We further found that binding of integrin α3 by OV‐Ab 30‐7 impaired laminin‐induced focal adhesion kinase phosphorylation. The mAb alone or in combination with carboplatin and paclitaxel inhibited tumor progression and prolonged survival of tumor‐bearing mice. Moreover, immunohistochemical staining of ovarian patient specimens revealed higher levels of integrin α3 in cancer cells compared with normal cells. By querying online clinical databases, we found that elevated ITGA3 expression in ovarian cancer is associated with poor prognosis. Taken together, our data suggest that the novel mAb, OV‐Ab 30‐7, may be considered as a potential therapeutic for ovarian cancer., The novel mAb, OV‐Ab 30‐7, can induce ovarian cancer cell apoptosis, and blockage integrin‐laminin signaling, and may be considered as a potential therapeutic for ovarian cancer. more...

Background DNA mismatch repair (MMR) proteins form 2 heterodimers-MutSα formed by MSH2 and MSH6, and MutLα by MLH1 and PMS2. In endometrial endometrioid adenocarcinomas, cases with MMR protein defect also usually harbor other recurrent genetic mutations of the neoplasm. However, it remains unknown whether defects of the 2 functionally different heterodimers are linked to mutations in different genes. We aimed to study the MMR protein expression, microsatellite instability (MSI), and other common genetic mutations of endometrial endometrioid adenocarcinoma. Materials and methods We investigated the MSI status of 107 endometrial endometrioid adenocarcinoma patients. MMR protein expression, and mutation of KRAS, CTNNB1, and PIK3CA were also evaluated by immunohistochemistry and sequencing. Results An overall 34.6% (37/107) of endometrial endometrioid adenocarcinomas were MSI-H. All MSI-H tumors exhibited loss of MMR protein expression (loss of MLH1, PMS2, MSH6, and MSH2 was noted in 22, 25, 12, and 7 cases, respectively). CTNNB1, PIK3CA, and KRAS mutation were present in 9, 7, and 7 MSI-H tumors. Compared with patients with loss of PMS2 and/or MLH1 expression, patients with loss of MSH6 and/or MSH2 expression were associated with higher frequencies of CTNNB1 mutation (P=0.036) and PIK3CA mutation (P=0.025). Conclusions In MSI-H endometrial endometrioid adenocarcinomas, different types of MMR protein deficiency indicate different molecular genetic alterations. more...

Background and aims The itemization difference of patient-reported outcome (PRO) in hepatitis patients with different etiologies remains elusive in Asia. We aimed to assess the characteristics and the difference of health-related quality of life (HRQoL) in chronic hepatitis B (CHB), chronic hepatitis C (CHC), and non-alcoholic fatty liver disease (NAFLD) patients. Methods We conducted the study in an outpatient setting. The 36-Item Short Form Health Survey (SF-36) was completed by the patients upon the initial diagnosis and recruitment for a long-term follow-up purpose. The PRO results were also assessed by disease severity. Results There were 244 patients (198 males) of CHB, 54 patients (29 males) of CHC, and 129 patients (85 males) of NAFLD, respectively. CHC patient had the mean score of 67.1 ± 23.3 in physical component summary (PCS) of the SF-36 health survey, which was significantly lower than CHB patients (76.4 ± 19.5), and NAFLD patients (77.5 ± 13.7), respectively (p = 0.001). The significantly lower performance of PCS in CHC patients was mainly attributed to the lower performance in physical functioning and bodily pain components. Higher fibrosis 4 index scores were significantly associated with lower PCS scores in all patient groups. There was no significant difference of mean mental component summary (MCS) between groups. However, NAFLD patients had significantly lower mental health scores than other groups (p = 0.02). Conclusions The significant difference of HRQoL exists in hepatitis patients with different etiologies. Disease severity leads to a lower PCS performance. more...

Solid thin films developed by a microwave plasma-enhanced chemical vapor deposition (MPECVD) system have excellent electrical properties, good substrate adhesion, and excellent step coverage. Due to these advantages, MPECVD films have been widely used in very large-scale integrated circuit technology, optoelectronic devices, MEMS, and other fields. The MPECVD method is one of the promising candidates for synthetic CNTs due to low temperature and large area growth. Recently, this technique has gained popularity in graphene and diamond film fabrication. This paper discusses the design of an MPECVD chamber operated at 2.45 GHz of frequency using a finite element method simulation. The design consists of a coaxial waveguide and a cylindrical chamber at the center connected using 4 identical slots in each direction. For the magnetic coupling, slots placed at the bottom of the central cavity. TM 011 mode in the inner chamber is employed to generate the plasma at 2.45GHz. In addition, we consider the effects of input power and gas pressure on plasma density. more...

An RF waveguide circulator is a ferromagnetic passive device with three or four ports, which is used to protect other RF components from excessive signal reflection. The previous studies on the design and development of the circulators deal with achieving broad bandwidth and high transmission efficiency using finite element method (FEM) simulations with a homogenous applied bias field. This work takes a step further and presents a novel self-consistent approach to modeling a ferrite waveguide circulator by solving electromagnetic and magnetostatic equations simultaneously. The comparison between the homogenous and the non-homogenous field models shows the importance of coupling a magnetic circuit to an electromagnetic simulation. The more realistic circulator design presented here still has a broad bandwidth of 180 MHz, insertion loss less than 0.24 dB, reflection, and isolation better than 20 dB operated at the center frequency of 2.45 GHz. It can be used to replace an industrial waveguide circulator, which has only a 50 MHz bandwidth. Hence, by increasing the bandwidth of a circulator, one can reduce the number of units for a dual-frequency magnetrons operating concurrently at 2,430 and 2,480 MHz with a working power of 3 kW each employed in the microwave plasma system. more...

The ferrite waveguide circulator available on the market nowadays has a rigid housing made up of metal and connected with several mechanical joints. The parts are assembled by molding, brazing, metallization, silver, or conventional soldering. These traditional techniques usually increase the production cost of one unit. The testing of these devices and the corresponding fine-tuning for the desired frequency and bandwidth lead to further increase of the cost and time. Hence, we propose to use the 3D printing technology to prototype the ferrite waveguide circulator. The metal circulators commonly used in industries are generally more expensive. Therefore, the experimental prototype of a WR340 ferrite waveguide circulator can be built using a cost-effective 3D printing technology for validating the design and comparing with the simulation results. The said circulator has a simple structure; hence by using the Lego method, the unit can be quickly produced and assembled. This paper presents how to 3D print a circulator housing, which is then metal coated. the ferrite discs are then fixed at the chamfer center enclosed by the magnets on both sides to complete the magnetic circuit. The circulator developed by this additive manufacturing is expected to have a bandwidth of 150 MHZ or higher with a transmission of 93% operated at 2.45GHz frequency. more...

A Marx generator generates a high-voltage pulse by charging lots of capacitors in parallel, then suddenly connecting them in series. In principles, a comparatively lower voltage DC power supply can be used for the charging to achieve the desired high voltage. However, a moderate DC high-voltage power supply is still quite expensive and bulky but not in full-time charging. In this work, a mini-Marx generator powered by a Cockcroft-Walton (CW) voltage multiplier has been proposed to form a more efficient but affordable choice of pulsed high-voltage power sources. For generating a high voltage in a range of 70-100 kV, the mini-Marx generator consists of 8 stages. Therefore, a CW multiplier operating up to 10-15 kV is required. For demonstration, a 22-stage CW multiplier with an AC supply voltage of 220V at 60 Hz is chosen so that it can be driven by household electricity to generate a DC voltage of over 13 kV to charge the mini-Marx generator. Numerical simulations using PSpice have been performed for validating the concept. A prototype is developed. After setting a suitable time-controlled switch for releasing CW multiplier and a trigger for the spark gaps of the mini-Marx generator, the preliminary simulation results predicting a pulsed open-circuit voltage up to 85 kV from the mini-Marx generator can be achieved while being charged by the CW generator operating at 11 kV. Detailed simulation and experimental results will be presented. more...

Beam Optics Analyzer (BOA) is a finite element, particle-in-cell, charged particle code. We will present its recent advances including methodologies and numerical results to simulate a gridded magnetron, study surface coating by investigating backscattered electron penetration depth, and use permanent magnets to focus doubly converged electron beams. more...

The effects of strain on the work functions of tungsten surfaces covered with a monolayer of adsorbates have been studied systematically using ab initio density functional theory. It has been found that the strain on tungsten surfaces due to different atomic coverages exhibits very interesting influences on the surface work function. For a clean tungsten surface, a compressive strain more profoundly increases the work function than a tensile strain, and the strain dependence of the work function shows a concave trend. With an atomic coverage of adsorbates, the strain dependence of the work function on the tungsten surface can be dramatically changed or modulated to a linearly increasing, linearly decreasing, convex, or sinusoidal behaviour, depending on the types of atoms. Using the framework of the well-developed surface dipole model [Phys. Rev. B, 2003, 68, 195408], the result of modulation of strain effects on the work function induced by different adsorbates can be well understood and attributed to two contributions, one from the relaxation of the substrate induced by the overlayer and the other from the surface dipole moment. These contributions are strongly correlated with the interlayer distances modulated by the adsorbates and strains. It is found that the O adsorbate-induced modulation of the strain effect on the work function exhibits a strong linear dependence on a uniaxial strain, and this may have applications in reducing the work function of cathodes by applying an external strain. more...

We discuss first-principles topological electronic structure of noncentrosymmetric SrSi$_2$ materials class based on the hybrid exchange-correlation functional. Topological phase diagram of SrSi$_2$ is mapped out as a function of the lattice constant with focus on the semimetal order. A tunable double-Weyl Fermion state in Sr$_{1-x}$Ca$_{x}$Si$_2$ and Sr$_{1-x}$Ba$_{x}$Si$_2$ alloys is identified. Ca doping in SrSi$_2$ is shown to yield a double-Weyl semimetal with a large Fermi arc length, while Ba doping leads to a transition from the topological semimetal to a gapped insulator state. Our study indicates that SrSi$_2$ materials family could provide an interesting platform for accessing the unique topological properties of Weyl semimetals., Comment: 21 pages (Text file including 5 figures), Accepted in Nature Scientific Reports more...

The possibility of dynamic after cavity interaction (ACI) in a down-scaled gyrotron model has been studied using a 3-D conformal finite-difference time-domain particle-in-cell simulation. The purpose has been to benchmark this type of simulation against previous numerical results obtained by other methods and tools and to obtain additional physical insight on the effect of dynamic ACI. The benchmarking has been successful, as a good agreement with the older results has been achieved. Thus, the algorithms developed and validated can be used for studying the issue in a larger scale or more realistic model with affordable computational resources in the near future. more...

// Ruey-Jien Chen 1 , Chia-Tung Shun 2 , Men-Luh Yen 1 , Chia-Hung Chou 1 and Ming-Chieh Lin 2 1 Department of Obstetrics and Gynecology, National Taiwan University, Taipei 100, Taiwan 2 Department of Pathology, National Taiwan University, Taipei 100, Taiwan Correspondence to: Ruey-Jien Chen, email: rjchen@ntuh.gov.tw Keywords: G9a, angiogenesis, cancer cell proliferation, xenograft, patient survival Received: April 09, 2016 Accepted: May 12, 2017 Published: July 07, 2017 ABSTRACT Research suggests that the epigenetic regulator G9a, a H3K9 histone methyltransferase, is involved in cancer invasion and metastasis. Here we show that G9a is linked to cancer angiogenesis and poor patient survival. Invasive cervical cancer has a higher G9a expression than cancer precursors or normal epithelium. Pharmacological inhibition and genetic silencing of G9a suppresses H3K9 methylation, cancer cell proliferation, angiogenesis, and cancer cell invasion/migration, but not apoptosis. Microarray and quantitative reverse transcription polymerase chain reaction analyses reveal that G9a induces a cohort of angiogenic factors that include angiogenin, interleukin-8, and C-X-C motif chemokine ligand 16. Depressing G9a by either pharmacological inhibitor or gene knock down significantly reduces angiogenic factor expression. Moreover, promoting G9a gene expression augments transcription and angiogenic function. A luciferase reporter assay suggests that knockdown of G9a inhibits transcriptional activation of interleukin-8. G9a depletion suppresses xenograft tumor growth in mouse model, which is linked to a decrease in microvessel density and proliferating cell nuclear antigen expression. Clinically, higher G9a expression correlates with poorer survival for cancer patients. For patients’ primary tumors a positive correlation between G9a expression and microvessel density also exists. In addition to increasing tumor cell proliferation, G9a promotes tumor angiogenesis and reduces the patient survival rate. G9a may possess great value for targeted therapies. more...

Tungsten, the common choice for vacuum tube filaments, can survive under high temperatures and provide thermionic emission of electrons. However, the emission is largely limited due to its relatively high work function (approximately 4.5 eV). First principles or ab initio calculations are used to study the local work functions of tungsten (W) clean (100), (110), and (111) surfaces under external electric fields. The authors have systematically tested the convergence of density-functional-theory (DFT) calculations in the local-density approximation (LDA) and generalized-gradient approximation (GGA) with a planewave basis set the projector-augmented wave method as implemented in the Vienna Ab-initio Simulation Package (VASP). Several pseudo-potentials have been tested for comparison. With the tungsten model under electric fields applied on both sides, we can investigate the dependence of the local work function and effective work function on field strength. In addition to thermionic emission, tungsten has been considered for use as a field emission (FE) electron source. more...

3-D time-domain modeling of beam wave interaction in a fusion gyrotron is very challenging due to the open-end features of cavity structure and higher-order mode excitation employed to achieve high efficiency. In a previous project, namely GyroPIC, funded by DOE, several required capabilities or algorithms had been developed in a 3-D particle-in-cell (PI C) simulation code in order to simulate the beam wave interaction in a high-order mode gyrotron. In past decades, it has been considered as an impossible mission to simulate a fusion gyrotron in 3-D using a PIC based method. The preliminary results showed that the 3-D electromagnetic (EM) PIC method could provide an alternative modeling tool for studying the gyrotron cavity interaction and mode competition for gaining more physics insight and further improving the efficiency. Upon finishing the code development, a research effort has been continued in recent years to study the beam wave interaction and mode competition using the well-developed 3-D EM PIC simulation. more...

Magnetite is a mineral and one of the main iron ores. With the chemical formula Fe 3 O 4 , it is one of the oxides of iron. Magnetite is the earliest discovered magnet, around 1500 B.C. It crystallizes in the inverse cubic spinel structure (Fd3m) above the so-called Verwey transition temperature which is about 120 K. In this work, we study the electronic properties of magnetite (100), (110), and (111) surfaces under external electric fields using first principles or ab initio calculations based on density functional theory. With an electric field applied, the effective work function changes under different field strength. By calculating the local work function, we can know the distribution of work function on a certain surface. The effective work functions of magnetite Fe 3 O 4 on different surfaces have been determined. The local work function has been found to have the correspondences with the atoms' positions and charge densities. In addition, the deviation in local work function $(\pmb{\Delta\varphi})$ increases proportionally to an increasing electric field up to 0.2 V/A. It is proposed that the magnetite as a half-metal can possibly be used as a spin-polarized electron source. more...

in this work, a three-dimensional conformal finite-difference time-domain simulation is employed to study the time dependent output properties of horn antennas for high power microwave (HPM) applications. As a benchmark, fundamental modes in standard rectangular and circular horn antennas are studied and compared with those simulated in frequency domain using HFSS. For steady state operation, the output characteristics shows similar behaviors in both frequency and time domains while in transient regime the time dependent characteristics demonstrates very interesting phenomena which might be better considered for a short pulse HPM operation. The final goal is to study the output characteristics of higher order modes for a specific application. Preliminary results obtained including near field and far field patterns and corresponding antenna parameters will be presented. more...

The research and development of a microwave plasma jet chemical vapor deposition for diamond film growth have been carried out in this study. This three-dimensional microwave plasma model helps understanding the operating conditions for the growth of diamond film. This mathematical modeling uses an adaptive finite element numerical method based on different parameters. Plasma simulation has been considered as a numerically stiff problem because of the strong nonlinearity and multi scales crossing. The whole system has been modeled soundly. Also, the thin diamond film has been successfully fabricated according to the identical condition. The SEM image shows that the deposited diamond particles are uniformly distributed on the substrate with the size of $1\mu\mathrm{m}$ which might find application in surface hardening and field electron emission. more...

In a previous study, it was found that not only magnetic compression profile but initial thermal velocities of electrons play an important role in causing a low frequency oscillation (LFO) in the operation of a magnetron injection gun (MIG) employed in an MIT fusion gyrotron. An unphysical particle boundary condition, i.e., large initial thermal velocities of electrons, had to be assumed to produce the LFO in the 3-D electromagnetic (EM) particle-in-cell (PIC) simulation. In this work, we have included the gyrotron cavity along with the MIG as well as a large vacuum envelope representing the vacuum chamber similar to that employed in the MIT experiments. In the EM PIC simulation, it is found that the momentum of electrons is suppressed by the space charge due to the vacuum envelope. For the first time, without unphysical approximations, the LFO could be reproduced in the $\pmb{3}\mathbf{D}$ time domain EM PIC simulations. The initial velocity spread at the cathode temperature is assumed in this simulation in contrast to an unphysical larger velocity spread formerly used. more...

The industrial L-band WR975 circulators operating at a frequency range from 900 to 930 MHz have been designed and simulated. Commercially, an L-band circulator at $\pmb{896\pm 10}$ MHz is available. However, for a wider bandwidth (~ 30 MHz) application, we would need two units operated in dual frequencies between 896 MHz and 915 MHz to cover the frequency range required. Through a Finite Element Method (FEM) simulation study, it was found that by reducing the height of the waveguide circulator in half a broader bandwidth can be obtained and this also leads to a reduction of overall fabrication cost. This paper discusses a detailed design and modeling of the L-broadband circulator operating at 915 MHz with a bandwidth of 43.5 MHz (892MZ to 935.5 MHz), an insertion loss of 0.25 dB for the entire bandwidth, and 0.22 dB at frequency of 915 MHz. For the entire bandwidth, the transmission efficiency is over 94.3% and it is more than 95% from 900 to 930 MHz of operating region which reduces power reflections for improving the performance and reliability of magnetrons. In addition, different ferrite materials are studied for optimizing this L-band waveguide circulator. more...

In this work, a numerical simulation has been conducted to investigate the effect of superbiphilic surface on boiling using the volume of fluid (VOF) method. The boiling curve has been used to study the heat transfer efficiency and boiling dynamics which gain more physical insights into the underlying mechanisms. By adjusting the mixed hydrophilic and hydrophobic surface, two types of surface prpoerties have been investigated in this work: the superhydrophilic and superhydrophobic networks. The superhydrophilic network is found to achieve a larger critical heat flux and delay the occurrence of film boiling, while the superhydrophobic network can reach the critical heat flux at a comparatively lower superheat. The superbiphilic surface can enhance the heat transfer efficiency, and the critical heat flux obtained is 55 % greater than the hydrophilic/hydrophobic surface with a uniform contact angle. For the first time, the effect of superbiphilic contact angle on the complete boiling curve is shown. The numerical predictions demonstrate good agreement with prior experimental and theoretical studies. This work provides a better understanding of contact angle effect in boiling dynamics, and it serves a good indicator for designing a smarter heat exchanger which might greatly benefit the whole energy industry. more...