Multi-channel current electro-optic isolated measurement and discharge current characteristics in a parallel plate transmission line driver.

In this paper, a 96 kJ compact synchronous discharge driver is designed. The issue of the current measurement of the six parallel gas spark switches is resolved by a multi-channel isolated current measuring system, and the driver's circuit simulation model is constructed. Then, the discharge current characteristics of each branch and load are investigated, and the results show that when the operating voltage is at least 50 kV, the parallel switches are conducted synchronously. The designed multi-channel isolated current measuring system meets the use requirements at a maximum operating voltage of 80 kV, the peak current measured by a single channel is 500 kA at this time, which corresponds to the load current of 3 MA, and the current rise time (0%-100% rise time) is about 1.15 µs. However, the asynchronous conduction of these switches will increase the branch circuit's peak current by a maximum of 25%, and the maximum value of the inverse peak current ratio of the branch will increase to 1.16, which will threaten the safe operation of the components. At this time, there is a redistribution of charge between the already conducting branches, so the impact of the load current is less than that of the basic branch current. When the conduction dispersion of the switchers is less than 452 ns, the peak current of the load reduction is less than 3%, and the current waveform meets the application requirements. The research is essential for understanding the operating status of the driver and assessing the through-current capability of the device's components, such as gas switches and capacitors.

Hepatitis B antibody levels after different doses of hepatitis B vaccination: a retrospective study based on hospitalized children.

Many studies have investigated the positivity rate of hepatitis B surface antibody (HBsAb) after hepatitis B vaccine (HepB) immunization. However, the antibody level, assessed monthly or at more frequent intervals after each of the three doses, particularly within the first year after birth, has not been previously reported. To elucidate the level of antibody formation at various times after vaccination, the current study used the available detection data of HBsAb in hospitalized children to analyze the HBsAb level after immunization combined with their vaccination history. Both the positivity rate and geometric mean concentration (GMC) increased sequentially with immunization doses, reaching their peaks earlier after the third dose than after the first two doses, and the rate of HBsAb positivity was able to reach 100% between 11 and 90 days after completing the three doses of HepB. Within one year after receiving the three doses, the antibody positivity rate and GMC were maintained above 90% and 100 mIU/mL, respectively, and subsequently steadily declined, reaching the lowest value in the 9th and 10th years. The current findings reveal, in more detail, the level of antibody formation at different times following each dose of HepB in hospitalized children, particularly in the age group up to one year after vaccination. For the subjects of this study, we prefer to believe that the proportion of HBsAb non-response should be less than 5% after full immunization with HepB, provided that the appropriate time for blood collection is chosen.

Development of a repetitive plasma source for simulation of mitigated edge localized mode transient heat load.

A repetitive plasma source for simulation of mitigated edge localized mode transient heat load is developed. The repetitive plasma source consists of a repetitive pulsed power supply and a pulsed plasma accelerator. The pulsed plasma accelerator is composed of a coaxial cathode, an anode, and an insulator. The inner electrode is the cathode with a diameter of 5 mm, and the outer electrode is the anode with a diameter of 15 mm. An angular magnetic field is generated by the discharge current and acts with the radial current to generate Lorentz force, which drives the plasma ejecting to the outlet. The repetitive pulsed power supply can be divided into three parts, the primary charge circuit, the resonant charge circuit, and the discharge circuit. The time interval between resonant charge and discharge is 4 ms. The repetitive discharge components include ten modules running in parallel. There are four working modes for discharge components, depending on the number of simultaneously discharged modules. For Mode A, the maximum repetitive frequency is 50 Hz, and the transient heat load is 0.06 MJ/m2 when the discharge current is 10.5 kA. For Mode D, the maximum repetitive frequency is 5 Hz, and the transient heat load is 0.45 MJ/m2 when the discharge current is 66 kA. This is of great significance for the study of the interaction between plasma and plasma-facing materials in tokamak.

Oxidation and ordering of fine structure of corn starch under an ultrahigh magnetic field.

In this study, corn starch (40 % moisture content) was placed in an ultra-high magnetic field(UMF)(5-20 T) to investigate the ordering and stabilization process under the magnetic field. With the increase of the intensity of UMF, C-OH and O-C-O were oxidized to O = C-OH and cross-linked to form ester bonds. When the UMF intensity was 15 T, the effect was the most significant with the ordered short-range structures formed; since the O = C-OR enhanced carbon skeleton structure, the crystallinity increased comparatively and amylose content reached the minimum value (15.32 ± 0.04 %). Additionally, UMF has a compressive effect on the void structure of A-type starch, and the average particle size decreased. RVA and DSC demonstrated that the UMF-treated starch had better thermal stability and shear resistance. This study suggested that UMF could serve as a prospective technique for starch product processing.

Invention of MK-8262, a Cholesteryl Ester Transfer Protein (CETP) Inhibitor Backup to Anacetrapib with Best-in-Class Properties.

Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.

Dielectric Surface Flashover under Long-Term Repetitive Microsecond Pulses in Compressed Gas Environment.

As a key component of a high-power microwave (HPM) system, a multi-gap gas switch (MGS) has recently developed insulation failure due to surface flashover. Although design criteria for surface insulation have been put forward, it is still not clear how the insulation in this case deteriorated under long-term repetitive microsecond pulses (RMPs). In this paper, flashover experiments under RMPs were carried out on various dielectric surfaces between parallel-plane electrodes in SF6 and air atmospheres, respectively. Based on tests of the surface insulation lifetime (SIL), an empirical formula for SIL prediction is proposed with variations of insulator work coefficient λ, which is a more suitable parameter to characterize SIL under RMPs. Due of the accumulation effect, the relationship between E/p and ptdelay varies with the pulse repetitive frequency (PRF) and SIL recovery capability decreases with an increase in PRF and surface deterioration is exacerbated during successive flashovers. It is concluded that the flashover path plays a crucial role in surface insulation performance under RMPs due to the photoemission induced by ultraviolet (UV) radiation, signifying the necessity of reducing surface paths in future designs as well as the improvement of surface insulation.

From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9.

Proprotein convertase substilisin-like/kexin type 9 (PCSK9) is a serine protease involved in a protein-protein interaction with the low-density lipoprotein (LDL) receptor that has both human genetic and clinical validation. Blocking this protein-protein interaction prevents LDL receptor degradation and thereby decreases LDL cholesterol levels. Our pursuit of small-molecule direct binders for this difficult to drug PPI target utilized affinity selection/mass spectrometry, which identified one confirmed hit compound. An X-ray crystal structure revealed that this compound was binding in an unprecedented allosteric pocket located between the catalytic and C-terminal domain. Optimization of this initial hit, using two distinct strategies, led to compounds with high binding affinity to PCSK9. Direct target engagement was demonstrated in the cell lysate with a cellular thermal shift assay. Finally, ligand-induced protein degradation was shown with a proteasome recruiting tag attached to the high-affinity allosteric ligand for PCSK9.

Variable self-powered light detection CMOS chip with real-time adaptive tracking digital output based on a novel on-chip sensor.

This paper provides a solution for a self-powered light direction detection with digitized output. Light direction sensors, energy harvesting photodiodes, real-time adaptive tracking digital output unit and other necessary circuits are integrated on a single chip based on a standard 0.18 µm CMOS process. Light direction sensors proposed have an accuracy of 1.8 degree over a 120 degree range. In order to improve the accuracy, a compensation circuit is presented for photodiodes' forward currents. The actual measurement precision of output is approximately 7 ENOB. Besides that, an adaptive under voltage protection circuit is designed for variable supply power which may undulate with temperature and process.

Active tracking system for visible light communication using a GaN-based micro-LED and NRZ-OOK.

Visible light communication (VLC) holds the promise of a high-speed wireless network for indoor applications and competes with 5G radio frequency (RF) system. Although the breakthrough of gallium nitride (GaN) based micro-light-emitting-diodes (micro-LEDs) increases the -3dB modulation bandwidth exceptionally from tens of MHz to hundreds of MHz, the light collected onto a fast photo receiver drops dramatically, which determines the signal to noise ratio (SNR) of VLC. To fully implement the practical high data-rate VLC link enabled by a GaN-based micro-LED, it requires focusing optics and a tracking system. In this paper, we demonstrate an active on-chip tracking system for VLC using a GaN-based micro-LED and none-return-to-zero on-off keying (NRZ-OOK). Using this novel technique, the field of view (FOV) was enlarged to 120° and data rates up to 600 Mbps at a bit error rate (BER) of 2.1×10-4 were achieved without manual focusing. This paper demonstrates the establishment of a VLC physical link that shows enhanced communication quality by orders of magnitude, making it optimized for practical communication applications.

Optical properties of highly polarized InGaN light-emitting diodes modified by plasmonic metallic grating.

We implement finite-difference time-domain (FDTD) method to simulate the optical properties of highly polarized InGaN light emitting diodes (LEDs) coupled with metallic grating structure. The Purcell factor (Fp), light extraction efficiency (LEE), internal quantum efficiency (IQE), external quantum efficiency (EQE), and modulation frequency are calculated for different polarized emissions. Our results show that light polarization has a strong impact on Fp and LEE of LEDs due to their coupling effects with the surface plasmons (SPs) generated by metallic grating. Fp as high as 34 and modulation frequency up to 5.4 GHz are obtained for a simulated LED structure. Furthermore, LEE, IQE and EQE can also be enhanced by tuning the coupling between polarized emission and SPs. These results can serve as guidelines for the design and fabrication of high efficiency and high speed LEDs for the applications of solid-state lighting and visible-light communication.

CMOS self-powered monolithic light-direction sensor with digitalized output.

We present a novel self-powered chip to detect the direction of incident light. This chip directly provides digitized output without the need of any off-chip power supply or optical or mechanical components. The chip was implemented in a standard 0.5 µm CMOS process. A microscale metal baffle was created by stacking all metal layers, contacts, and vias available in the process to produce on-chip shadowing. N-well/p+ photodiode arrays are located on both sides of the baffle to sense light. The photocurrent generated by a photodiode depends on the size of the photodiode and the shadowing. The shadowed area depends on the incident angle of the light. A current mirror circuit is used to compare the currents generated by the photodiodes on the opposite sides of the baffle and, consequently, provide a digital signal to indicate the incident light angle. Compared with the ideal linear digital light-angle detector with the same resolution, the presented sensor achieved the maximum error of only 2 deg over 110 deg test range.

A self-powered 2-dimensional motion detection chip.

We demonstrate a self-powered chip to detect motion which enables constant, non-invasive monitoring. The chip was implemented in a standard 0.18 µm CMOS process. A P-N junction photodiode array was fabricated in the chip to detect when light is blocked by the movement of a hand or finger. The interface circuit detects the change between the shadowing and the exposure to determine the specific movement. This entire chip operates without any off-chip power supply and provides digitized outputs including 1 bit direction output and an 8 bits output indicative of the velocity in two dimensions.

Enhanced 5-fluorouracil cytotoxicity in high COX-2 expressing hepatocellular carcinoma cells by wogonin via the PI3K/Akt pathway.

Combination therapies may increase the antitumor effects and reduce the adverse effects for the treatment of hepatocellular carcinoma. In this study, we determined the effects of 5-fluorouracil alone or in combination with wogonin in vitro and in vivo, and we investigated the possible mechanisms. The combination of these 2 drugs led to a decrease in survival and a significant synergistic inhibitory effect on high COX-2 expression in SMMC-7721 hepatocellular carcinoma (HCC) cells. Furthermore, the results show that this combination inhibits COX-2 expression and increases sensitivity to chemotherapeutic agents partly through regulating the PI3K/Akt signaling pathway. Moreover, the combination treatment caused a significant growth inhibition of human tumor xenografts in vivo. In conclusion, wogonin may increase the cytotoxicity of some antineoplastic agents and it can be used in combination with these agents as a novel therapeutic regimen for HCC treatment.

VI-14, a novel flavonoid derivative, inhibits migration and invasion of human breast cancer cells.

It has been well characterized that flavonoids possess pronounced anticancer potentials including anti-angiogenesis, anti-metastasis, and pro-apoptosis. Herein, we report, for the first time, that VI-14, a novel flavonoid derivative, possesses anti-cancer properties. The purpose of this study is to investigate the anti-migration and anti-invasion activities of VI-14 in breast cancer cells. Our data indicate that VI-14 inhibits adhesion, migration and invasion of MDA-MB-231 and MDA-MB-435 human breast cancer cells. MDA-MB-231 cells treated with VI-14 display reduced activities and expressions of ECM degradation-associated proteins including matrix metalloproteinase 2 (MMP-2) and 9 (MMP-9) at both the protein and mRNA levels. Meanwhile, VI-14 treatment induces an up-regulated expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) and 2 (TIMP-2) in MDA-MB-231 cells. Western blotting results show that phosphorylation levels of critical components of the MAPK signaling pathway, including ERK, JNK and P38, are dramatically decreased in VI-14-treated MDA-MB-231 cells. Furthermore, treatment of VI-14 significantly decreases the nuclear levels and the binding ability of nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1). Taken together, our data suggest that VI-14 treatment suppresses migration and motility of breast cancer cells, and VI-14 may be a potential compound for cancer therapy.

Oroxylin A inhibits matrix metalloproteinase-2/9 expression and activation by up-regulating tissue inhibitor of metalloproteinase-2 and suppressing the ERK1/2 signaling pathway.

Matrix metalloproteinases (MMPs) play important roles in the invasion and migration of cancer cells. In this study, we used in vitro and in vivo assays to examine the inhibitory effects of oroxylin A, one of the main bioactive flavonoid extracted from Scutellaria radix, on the human breast carcinoma cell MDA-MB-231 invasion and migration. We found that oroxylin A can suppress cell adhesion, invasion and migration in a concentration-dependent manner. Moreover, oroxylin A led to the reduction of the activity and expression levels of MMP-2 and MMP-9 in gelatin zymography, real-time PCR and western blotting analysis. Further elucidation of the mechanism revealed that oroxylin A increased the expression of tissue inhibitor of metalloproteinase-2 (TIMP-2), the endogenous inhibitor of MMP-2, and repressed the phorbol-12-myristate-13-acetate (PMA)-induced translocation of protein kinase Cδ (PKCδ), phosphorylation of extracellular signal-regulated kinase (ERK1/2) and binding activity of the transcription factor activator protein-1 (AP-1) which are upstream signaling molecules in MMP-9 expression. Our results also indicated that oroxylin A inhibited the lung metastasis of murine melanoma cell B16-F10 in vivo. Therefore, we proposed that oroxylin A might be developed as a therapeutic potential candidate for the treatment of cancer metastasis.

Frontier of therapeutic antibody discovery: The challenges and how to face them.

Therapeutic monoclonal antibodies have become an important class of modern medicines. The established technologies for therapeutic antibody discovery such as humanization of mouse antibodies, phage display of human antibody libraries and transgenic animals harboring human IgG genes have been practiced successfully so far, and many incremental improvements are being made constantly. These methodologies are responsible for currently marketed therapeutic antibodies and for the biopharma industry pipeline which are concentrated on only a few dozen targets. A key challenge for wider application of biotherapeutic approaches is the paucity of truly validated targets for biotherapeutic intervention. The efforts to expand the target space include taking the pathway approach to study the disease correlation. Since many new targets are multi-spanning and multimeric membrane proteins there is a need to develop more effective methods to generate antibodies against these difficult targets. The pharmaceutical properties of therapeutic antibodies are an active area for study concentrating on biophysical characteristics such as thermal stability and aggregation propensity. The immunogenicity of biotherapeutics in humans is a very complex issue and there are no truly predictive animal models to rely on. The in silico and T-cell response approaches identify the potential for immunogenicity; however, one needs contingency plans for emergence of anti-product antibody response for clinical trials.

SAR studies on the central phenyl ring of substituted biphenyl oxazolidinone-potent CETP inhibitors.

SAR studies of the substitution effect on the central phenyl ring of the biphenyl scaffold were carried out using anacetrapib (9a) as the benchmark. The results revealed that the new analogs with substitutions to replace trifluoromethyl (9a) had a significant impact on CETP inhibition in vitro. In fact, analogs with some small groups were as potent or more potent than the CF(3) derivative for CETP inhibition. Five of these new analogs raised HDL-C significantly (>20mg/dL). None of them however was better than anacetrapib in vivo. The synthesis and biological evaluation of these CETP inhibitors are described.

Biphenyl-substituted oxazolidinones as cholesteryl ester transfer protein inhibitors: modifications of the oxazolidinone ring leading to the discovery of anacetrapib.

The development of the structure-activity studies leading to the discovery of anacetrapib is described. These studies focused on varying the substitution of the oxazolidinone ring of the 5-aryloxazolidinone system. Specifically, it was found that substitution of the 4-position with a methyl group with the cis-stereochemistry relative to the 5-aryl group afforded compounds with increased cholesteryl ester transfer protein (CETP) inhibition potency and a robust in vivo effect on increasing HDL-C levels in transgenic mice expressing cynomolgus monkey CETP.