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Microcystin-leucine arginine (MC-LR) has been reported to exhibit placental toxicity, leading to potential adverse pregnancy outcomes. Placental abnormalities often coincide with congenital heart defects (CHD). However, the extent to which MC-LR-induced placental abnormalities contribute to CHD and the cellular mechanisms underlying this association remain unknown. In this study, we observed abnormal polarization of placental macrophages in pregnant mice exposed to MC-LR during pregnancy, and the embryos developed cardiac developmental defects that persisted into adulthood. Trophoblast-derived extracellular vesicles (T-EVs) increase in number during pregnancy and act as a critical signal in macrophage polarization. However, MC-LR significantly affected the miRNA expression profile of T-EVs. Upon internalization into macrophages, T-EV-derived miR-377-3p specifically targets the 3'UTR region of NR6A1 to inhibit gene expression. Silencing of transcription suppressor NR6A1 leads to abnormal activation of the downstream mTOR/S6K1/SREBP pathway, inducing metabolic reprogramming and ultimately leading to M1 polarization of macrophages. This study elucidated the placental mechanism underlying MC-LR-induced CHD for the first time, providing insights into the environmental risks associated with CHD., Competing Interests: Declaration of competing interest The authors declare they have no competing financial interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

6:2 Fluorotelomer alcohol (6:2 FTOH) is a raw material used in the manufacture of short-chain poly- and perfluoroalkyl substances. Our previous study revealed that gestational exposure to 6:2 FTOH can impair blood‒brain barrier (BBB) function in offspring, accompanied by anxiety-like behavior and learning memory deficits. The aim of this study was to further investigate the specific mechanism by which maternal exposure to 6:2 FTOH resulted in impaired BBB function in offspring mice. Pregnant mice were orally administered different doses of 6:2 FTOH (0, 5, 25, and 125 mg/kg/day) from gestation day 8.5 until delivery. These results confirmed that maternal 6:2 FTOH exposure impaired BBB function and disrupted the brain immune microenvironment. Subsequent investigations revealed that endothelial-to-mesenchymal transition (EndMT) in the cerebral microvascular endothelium of offspring may be the mechanism mediating functional disruption of the BBB. Mechanistic studies revealed that exposure to 6:2 FTOH upregulated ETS proto-oncogene 1 (ETS1) expression via the tumor necrosis factor-α/extracellular signal-regulated kinase 1/2 signaling pathway, which mediated disturbances in energy metabolism, leading to impaired actin dynamics and subsequently triggering the EndMT phenotype. This is the first finding indicating that gestational 6:2 FTOH exposure caused functional impairment of the BBB through ETS1-mediated EndMT in cerebral microvascular endothelial cells, potentially providing novel insight into the environmental origins of neurodevelopmental disorders., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Underwater shock wave technology can realize dynamic rock fracture, which is helpful to increase oil and gas reservoir permeability. It can realize the efficient exploitation of medium and low maturity oil and gas resources. In practical application, the shock wave parameters require not only high intensity but also safety and controllability. To meet these requirements, insensitive composite energetic materials driven by electrical wire explosion plasma were proposed, which is one of the most promising methods. However, when in use, the load assembly process containing wires and energetic materials is complex. In this paper, a new type of energetic material load is proposed, using non-penetrating wire to drive composite energetic material. It can simplify the production process of the energetic load and produce acceptable shock wave parameters. The test results show that both the energy deposition of the wire and the shock wave intensity decrease under a non-penetrating wire structure. However, the shock wave intensity is still higher than that of the underwater electrical wire explosion. Based on schlieren diagnosis, it is found that the composite energetic material is gradually driven, and the energy release is not concentrated. In addition, the "non-wire" structure driving condition was discussed in contrast. Under this condition, the process of ionization channel establishment in composite energetic materials is random. The shock wave intensity is weak because the composite energetic material is in the process of slow detonation., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Förster resonance energy transfer (FRET)-based homogeneous immunoassay obviates tedious washing steps and thus is a promising approach for immunoassays. However, a conventional FRET-based homogeneous immunoassay operating in the visible region is not able to overcome the interference of complex biological samples, thus resulting in insufficient detection sensitivity and poor accuracy. Here, we develop a near-infrared (NIR)-to-NIR FRET platform (Ex = 808 nm, Em = 980 nm) that enables background-free high-throughput homogeneous quantification of various biomarkers in complex biological samples. This NIR-to-NIR FRET platform is portable and easy to operate and is mainly composed of a high-performance NIR-to-NIR FRET pair based on lanthanide-doped nanoparticles (LnNPs) and a custom-made microplate reader for readout of NIR luminescence signals. We demonstrate that this NIR-to-NIR FRET platform is versatile and robust, capable of realizing highly sensitive and accurate detection of various critical biomarkers, including small molecules (morphine and 1,25-dihydroxyvitamin D), proteins (human chorionic gonadotropin), and viral particles (adenovirus) in unprocessed complex biological samples (urine, whole blood, and feces) within 5-10 min. We expect this NIR-to-NIR FRET platform to provide low-cost healthcare for populations living in resource-limited areas and be widely used in many other fields, such as food safety and environmental monitoring.

A pulsed power supply with a short rise time and high repetition frequency is favorable to driving diffusive plasma for strongly oxidizing radical (O3, OH) generation and increasing the system's energy efficiency. In this paper, a 10-stage solid-state linear transformer driver (LTD) with a nanosecond rise time is developed to drive plasma for wastewater treatment. To decrease the rise time, a control system with low jitter is developed to improve the synchronization of pulses using an optocoupler isolation chip. A 10-stage LTD with a rise time of 6.2 ns is realized in the case that the rise time of the single-stage LTD is 5.4 ns. The results show that the LTD can generate pulses on a 300 Ω resistive load with a repetition frequency of 10 kHz, an amplitude of 8.80 kV, an overshoot less than 3.97%, and a reverse overshoot less than 4.82%. The rise time (6.2-33.0 ns), the pulse width (35.9-200.0 ns), and the fall time (10.5-27.6 ns) can be adjusted flexibly and independently by controlling the drive signals of metal oxide semiconductor field effect transistors. The pulsed generator is utilized to drive plasma in the needle-water electrode system. The preliminary experimental results show that the plasma includes abundant oxygen atoms and hydroxyl radicals with high activity, and it is suitable for wastewater treatment., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Emerging tumor immunotherapy methods encompass bispecific antibodies (BSABs), immune checkpoint inhibitors (ICIs), and adoptive cell immunotherapy. BSABs belong to the antibody family that can specifically recognize two different antigens or epitopes on the same antigen. These antibodies demonstrate superior clinical efficacy than monoclonal antibodies, indicating their role as a promising tumor immunotherapy option. Immune checkpoints are also important in tumor immunotherapy. Programmed cell death protein-1 (PD-1) is a widely acknowledged immune checkpoint target with effective anti-tumor activity. PD-1 inhibitors have demonstrated notable therapeutic efficacy in treating hematological and solid tumors; however, more than 50% of patients undergoing this treatment exhibit a poor response. However, ICI-based combination therapies (ICI combination therapies) have been demonstrated to synergistically increase anti-tumor effects and immune response rates. In this review, we compare the clinical efficacy and side effects of BSABs and ICI combination therapies in real-world tumor immunotherapy, aiming to provide evidence-based approaches for clinical research and personalized tumor diagnosis and treatment., (© 2024. The Author(s).)

The Blumlein pulse forming network (PFN) has widely been used in pulsed power technology to generate square waves with short pulse widths. In this paper, we developed a repetitive frequency square wave generator based on Blumlein PFN and pseudospark switch (PSS). A Blumlein PFN with unequal capacitances has been proposed, and the PFN parameters have been optimized for better output waveforms. A single-gap PSS with a withstand voltage of 40 kV and a repetitive frequency of 100 Hz has been designed to switch the Blumlein PFN. The experiment results show that the square wave generator can output pulses with a voltage of 26 kV, a rise time of 25 ns, and a pulse width of 90 ns on a matched load of 11 Ω. It has operated steadily for 10 h with a repetitive frequency of 100 Hz, and the jitter remains at around 1 ns after 1.05 × 106 shots., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Large-scale linear transformer drivers (LTDs) are composed of numerous high-power gas switches, and switch prefire is a frequent operational fault. To detect and locate the faulty switch accurately and efficiently, a two-terminal location method is proposed. A B-dot sensor is integrated on the gas switch's shell to collect the discharging signal. All the B-dot sensors are connected in parallel through cables of equal length. The fault position can be determined by the time delay of the signals at the two terminals. A diode is inserted between the B-dot sensor's coil and the cable core to ensure low-loss transmission of the signal. Two methods are applied in fault location, including time-of-arrival (TOA) and time reversal (TR). For the TOA method, an energy criterion and a phase criterion are applied and compared. The accuracy of the energy criterion is greatly influenced by the signal-to-noise ratio, while the phase criterion requires a reasonable estimate of the actual delay to account for the impact of phase periodicity. The TR method based on a precise simulation model is established, which demonstrates high precision in location. The TR method has been tested and validated on a single stage LTD module. Moreover, the location method for double switches prefire is discussed theoretically. The method proposed in this paper will be helpful to improve the efficiency of the commissioning, operation, and maintenance of the large-scale LTD devices., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Microcystin-leucine-arginine (MC-LR) is widespread in the water and food, which has suspected to be associated with adverse pregnancy outcomes. In the present study, we aim to assess the interaction between MC-LR exposure and preeclampsia development and elucidate the molecular events involved. After exposure to MC-LR during pregnancy, the mice developed hypertension and proteinuria, the typical symptoms of preeclampsia. This was associated with decreased invasiveness of placental trophoblast and vascular dysplasia caused by MC-LR through down-regulating VEGFA and TGF-β expression via AKT/m-TOR/HIF-1α pathway. In addition, this conclusion has been confirmed in a case-control study. Significantly, the addition of Deferoxamine (DFM), a phosphorylated serine-threonine protein kinases (p-AKT) specific agonist, can antagonize the inhibitory effect of MC-LR on the expression of related proteins, which further ameliorate the migration and invasion ability of HTR-8/Svneo cells. To sum up, our study revealed the pathologic mechanism by which MC-LR lead to preeclampsia and emphasized the importance of pregnancy management., Competing Interests: Declaration of competing interest The authors declare they have no actual or potential competing financial interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The use of linear transformer drivers (LTDs) is widely considered the most promising technological approach for the development of future pulsed-power accelerators. In large-scale pulsed-power accelerators, abnormal conditions like switch prefire can occur frequently during tests and normal operations due to the presence of a large number of switches. The diagnosis of such faults based on signature waveforms requires further investigation. According to previous research, the characteristics of the magnetic cores greatly influence the fault waveforms. In this paper, a full-cycle mathematical model of the magnetic core is established utilizing a classical Preisach model based on experimental results. This model is coupled with the LTD circuit model in simulations, and simulation results are obtained under the condition of switch prefire. The simulation results are in good agreement with the experimental results from a four-stage LTD module with a sharing shell and de-ionized water insulated transmission line. The magnetization process of the cores is also determined under prefire conditions. Analyses of the magnetization process indicate that the completely demagnetized core shows high permeability under positive excitation and that the permeability abruptly decreases as the excitation is reversed. The hysteresis characteristics result in a phenomenon in which the output voltage in the prefired stage is almost unipolar. Finally, the features of the fault voltages captured in the experiments are also explained., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

Lateral flow assays (LFAs) are promising points-of-care tests, playing a vital role in diseases screening, diagnosis and surveillance. However, development of portable, cheap, and smart LFAs platform for sensitive and accurate quantification of disease biomarkers in complex media is challenging. Here, a cheap handheld device was developed to realize on-site detection of disease biomarkers by Nd 3+ /Yb 3+ co-doped near-infrared (NIR)-to-NIR downconversion nanoparticles (DCNPs) based LFA. Its sensitivity is at least 8-fold higher for detecting NIR light signal from Nd 3+ /Yb 3+ co-doped nanoparticles than conventional expensive InGaAs camera based detection platform. Additionally, we enhance NIR quantum yield of Nd 3+ /Yb 3+ co-doped nanoparticles up to 35.5% via simultaneous high dopant of sensitizer ions Nd 3+ and emitter ions Yb 3+ . Combination of NIR-to-NIR handheld detection device and ultra-bright NIR emitting NaNbF 4 :Yb60%@NaLuF 4 nanoparticle probe allows the detection sensitivity of SARS-CoV-2 ancestral strain and Omicron variants specific neutralizing antibodies LFA up to the level of commercial enzyme linked immunosorbent assay kit. Furthermore, by this robust method, enhanced neutralizing antibodies against SARS-CoV-2 ancestral strain and Omicron variants are observed in healthy participants with Ad5-nCoV booster on top of two doses of inactivated vaccine. This NIR-to-NIR handheld platform provides a promising strategy for on-site evaluating protective humoral immunity after SARS-CoV-2 vaccination or infection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Environmental hypoxia is becoming more prevalent in aquatic environments of mandarin fish (Siniperca chuatsi) aquaculture because of eutrophication and climate change. Little information is available on the molecular mechanisms of the detrimental effects of hypoxia in this species. In this study, the authors assembled a transcriptome for mandarin fish exposed to lower oxygen conditions at different times (24 and 96 h). The antioxidant enzymatic activities of catalase, glutathione, superoxide dismutase, glutamic pyruvic transaminase and malondialdehyde significantly increased at 6 or 12 h but decreased after reaching a climax during 96 h hypoxia stress. The gene ontology study revealed 27,616 transcripts, whereas the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed 25 linked pathways. Significant changes in the expression of certain genes involved in protein processing in the endoplasmic reticulum, the calcium signalling system and inositol phosphate metabolism were discovered using the KEGG pathway analysis. In the liver, 97 genes were differentially expressed between the control and experimental groups. The expression level of 28 differentially expressed genes (DEGs) under different hypoxic stress conditions was detected using real-time PCR and compared to transcriptome sequencing results. The result showed that some genes in the experimental group associated with hypoxic stress, such as hif, ho-1a, ho-1b, igfbp1, hsp90α and hsp90 β, were significantly upregulated compared with those in the control group. The large amount of transcriptome data from this research has enlarged the mandarin fish gene and genome bioinformation. The identified DEGs and pathways are useful in further studies of biological responses to hypoxia., (© 2023 Fisheries Society of the British Isles.)

Astragaloside IV (ASIV) has effects of antioxidation and immunologic enhancement. However, there are few reports on the application and potential mechanism of ASIV in aquaculture. In this study, we investigated the effect of ASIV on growth, antioxidation, and immune function of tilapia. Tilapia were fed a diet containing 0.1, 0.2, and 0.5 g·kg -1 ASIV for 60 days, followed by an intrapleural injection of 50 mg·kg -1 cyclophosphamide (CTX) to induce oxidative damage and immunosuppression. Then tilapia were weighed and blood, liver, spleen, kidney, and intestinal were collected. The results showed ASIV increased the final weight, relative weight rate, and specific growth rate of tilapia, reduce conversion ratio, and reduced the morphological lesions of tissues. Meanwhile, ASIV alleviated CTX-induced oxidative damage by improving antioxidant activity in serum and tissues and inhibiting lipid peroxidation. Additionally, ASIV attenuated the immunosuppression of tilapia caused by CTX, regulated immunochemical indexes in serum, increased the viability of peripheral blood leukocytes and head kidney macrophages, and restored respiratory burst activity (O 2 - ) in head kidney macrophages and splenocytes. Furthermore, qPCR data showed ASIV up-regulated antioxidant-related gene expression of nrf2, ho-1, gpx3, and cat and immune-related gene expression including C3 and igm. In conclusion, ASIV as a feed additive can not only improve the growth performance but also enhance the antioxidant capacity and immune function of tilapia, which may be associated with the ability of ASIV to scavenge free radicals, reduce lipid peroxidation levels, and stabilize numbers of immune cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

With the development of technology, low-temperature plasma plays an increasingly important role in industrial applications. The industrial application of low-temperature plasma has the following requirements for plasma, high electron energy, low macroscopic temperature, and uniformity. Low-temperature plasma driven by nanosecond pulses reflects more significant advantages in these aspects compared to direct current plasma and alternating current plasma. In this paper, a simple topology is proposed, which is based on the pseudospark switch and the diode opening switch. A pulse generator is developed, which can eventually output pulses with an amplitude of 106 kV, a rise time of 15.5 ns, a pulse width of 46 ns, and a maximum repetition rate of 1 kHz on a 260 Ω resistive load. The pulse generator can successfully drive needle-plate discharge plasma in ambient air. It has excellent parameters, stability, compactness, and a long lifetime. The proposed topology may be helpful for nanosecond pulse generators with amplitude ranging from tens to hundreds of kilovolts, which could be widely used in industry.

Salvianolic acid B (Sal B), as one of the main water-soluble components of Salvia miltiorrhizae , has significant pharmacological activities, including antioxidant, free radical elimination and biofilm protection actions. However, the protective effect of Sal B on Nile tilapia and the underlying mechanism are rarely reported. Therefore, the aim of this study was to evaluate the effects of Sal B on antioxidant stress, apoptosis and autophagy in Nile tilapia liver. In this experiment, Nile tilapia were fed diets containing sal B (0.25, 0.50 and 0.75 g·kg -1 ) for 60 days, and then the oxidative hepatic injury of the tilapia was induced via intrapleural injection of 50 g·kg -1 cyclophosphamide (CTX) three times. After the final exposure to CTX, the Nile tilapia were weighed and blood and liver samples were collected for the detection of growth and biochemical indicators, pathological observations and TUNEL detection, as well as the determination of mRNA expression levels. The results showed that after the CTX treatment, the liver was severely damaged, the antioxidant capacity of the Nile tilapia was significantly decreased and the hepatocyte autophagy and apoptosis levels were significantly increased. Meanwhile, dietary Sal B can not only significantly improve the growth performance of tilapia and effectively reduce CTX-induced liver morphological lesions, but can also alleviate CTX-induced hepatocyte autophagy and apoptosis. In addition, Sal B also significantly regulated the expression of genes related to antioxidative stress, autophagy and apoptosis pathways. This suggested that the hepatoprotective effect of Sal B may be achieved through various pathways, including scavenging free radicals and inhibiting hepatocyte apoptosis and autophagy.

Diffuse large B-cell lymphoma (DLBCL) is the most common invasive type of non-Hodgkin lymphoma. Cell-of-origin (COO) classification is related to patients' prognoses. Primary drug resistance in treatment for DLBCL has been observed. The specific serum biomarkers in these patients who suffer from relapsed and refractory (R/R)-DLBCL remains unclear. In the current study, using single-cell RNA sequencing (scRNA-seq) and mass cytometry (CyTOF), we determined and verified immune cell biomarkers at the mRNA and protein levels in single-cell resolution from 18 diagnostic PBMC specimens collected from patients with R/R DLBCL. As controls, 5 PBMC specimens from healthy volunteers were obtained. We identified a panel of 35 surface marker genes for the features of R/R DLBCL unique cell cluster by scRNA-seq of 8 R/R DLBCL patient samples and validated its efficiency in an external cohort consisting of 10 R/R DLBCL patients by CyTOF. The cell clustering and dimension reduction were compared among R/R DLBCL samples in CyTOF Space with COO as well as the C-MYC expression designation. Immune cells from each patient occupied unique regions in the 32-dimensional phenotypic space with no apparent clustering of samples into discrete subtypes. Significant heterogeneity observed in subgroups was mainly attributed to individual differences among samples and not to expression differences in a single, homogeneous immune cell subpopulation. The marker panel showed reliability in labeling R/R DLBCL without any influence from COO stratification and C-MYC expression designation. Furthermore, we compared all the markers between R/R DLBCL and normal samples. A total of 12 biomarkers were significantly overexpressed in R/R DLBCL relative to the normal samples. Therefore, we further optimized the diagnostic biomarker panel of R/R DLBCL comprising CD82, CD55, CD36, CD63, CD59, IKZF1, CD69, CD163, CD14, CD226, CD84, and CD31. In summary, we developed a novel set of biomarkers for the diagnoses of patients with R/R DLBCL. Detections procedures at single-cell resolution provide precise biomarkers, which may substantially overcome intertumoral and intratumoral heterogeneity among primary samples. The findings confirmed that each case was unique and may comprise multiple, genetically distinct subclones., (©2022 Society for Leukocyte Biology.)

Microcystin-leucine-arginine (MC-LR) reduces the fertility of female mice, but the mechanism is unknown. We studied the effect of MC-LR on early pregnancy and elucidated its possible mechanism. The number of embryo beds and embryo volume decreased in pregnant mice at 6 or 8 days after fertilization after acute exposure to MC-LR. The corpus luteum secretes estrogen and progesterone, which are involved in embryo implantation and maintenance of early pregnancy. MC-LR exposure reduced luteal blood vessel branches and inhibited hormone synthesis. Functional blood vessels are essential to the maintenance of luteal structure and function. Reduced migration and tube-forming were also detected in human umbilical vascular endothelial cells (HUVECs) treated with MC-LR. MC-LR significantly decreased the expression of vascular endothelial growth factor receptor 2 (VEGFR2) in vivo and in vitro, which was responsible for the inhibited construction of the vascular network. The MEK/ERK/SP1 signal pathway mediated the decrease in VEGFR2 expression, and the agonists of phosphorylated extracellular regulated protein kinases (p-ERK) alleviated the anti-angiogenic effect of MC-LR. In conclusion, we demonstrated the toxicity of MC-LR on construction of vascular network in corpus luteum, which could provide a new perspective on female infertility or miscarriage caused by environmental factors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Electrical wire explosions have many applications in scientific research and industry. Optical diagnosis is a powerful method to clarify the evolutionary process of such explosions. In this paper, an experimental platform was established to diagnose the optical radiation of electrical wire explosions. A low-jitter trigatron switch and its trigger generator were designed to ensure accurate synchronization. The spatial-temporal evolution process and the self-emission spectrum of electrical explosion plasmas from different wires (copper and tantalum) were obtained and analyzed. The optical diagnosis results indicated that the electrical explosion of copper wire was mainly characterized by the inhomogeneity of partial ionization and the rapid expansion of the discharge channel. The spectrum in the early discharge stage of the copper wire electrical explosion was a continuum, and most of the self-radiation spectral lines belonged to Cu I or Cu II. At the later stage of the plasma dissipation process, the continuous spectrum gradually transformed into a line spectrum. The development of the tantalum wire discharge channel was relatively uniform, and the plasma was mainly established in the gas-liquid mixed phase channel of the tantalum wire. The self-emission spectrum of the tantalum wire was always continuous, and the absorption process of line spectrum radiation was distinct.

To reduce the commutation loss of the pseudospark switch, we connect a magnetic switch in series to the anode of the pseudospark switch. Herein, the typical discharge process and switching characteristics of a pseudospark switch in series with a magnetic switch are experimentally investigated at a different number of magnetic cores, gas pressures, and applied voltages. The results show that the addition of the magnetic switch extends the duration of the hollow cathode discharge of the pseudospark. Moreover, the rapid increase of the loop current and the fast decrease of the discharge voltage are separated, which is beneficial for reducing the commutation loss. With an increasing number of magnetic cores, the magnetic delay time increases and the commutation loss significantly decreases. However, the trigger delay time hardly changes since the magnetic switch does not affect the development of the pre-breakdown phase. At a fixed applied voltage, the trigger delay, magnetic delay time, and commutation loss decrease with increasing gas pressure. Furthermore, at a fixed gas pressure, the trigger delay of the pseudospark switch in series with a magnetic switch first decreases and then remains unchanged with increasing applied voltage, which is similar to that of a pseudospark switch without a magnetic switch because of the strong enough trigger injection. The magnetic delay time decreases and the commutation loss almost linearly increases with increasing applied voltage.

In recent years, several novel avalanche transistor-based power synthesis topologies have been proposed to improve the output performance of pulse generators based on avalanche transistors. The most promising is the topology based on avalanche transistors Marx Bank Circuits (MBCs) and linear transformer driver (LTD). However, it suffers from the same problems as other semiconductor switch-based LTD generators. The greater the number of LTD modules, the higher the requirements for synchronization and drive capability of the trigger system. This paper proposes a new self-triggering topology for pulse generators based on avalanche transistors MBCs and LTD, which significantly simplifies the entire generator's requirement for trigger system synchronization and driving capability. First, the circuit topology and its operation principle are introduced. Then, three prototypes with one trigger LTD module and three self-triggering LTD modules are developed. The output characteristics are experimentally investigated. The results verify the feasibility of the proposed topology. Finally, the output amplitude and the rise time are 3.35 kV/3.7 ns, 4.12 kV/3.7 ns, and 4.88 kV/4.0 ns on a 25 Ω resistive load, respectively. All generators can operate at 1 kHz. The topology proposed in the article maximally simplifies the requirements for synchronization and drive capability of the trigger system for generators based on avalanche transistor MBCs and LTD.

Pulsed power technology is gradually forming a development trend of civil-military integration, which puts forward more requirements for pulsed power generators. This paper takes magnetic switches (MSs) as the starting point and reviews recent advancements in pulse generators based on MSs. First, the working mechanism of the MS "rapid inductance drop after magnetic core saturation" is analyzed. Second, the basic uses of MSs are introduced with specific examples, namely, magnetic compression unit, saturated pulse transformer, and magnetic delay switches. Then, the typical topologies of pulse generators based on MSs are discussed, including transmission line, Marx, Fitch, linear transformer driver, and semiconductor opening switch pumping circuits. These circuits' technical characteristics and parameter levels are highlighted. Finally, the existing problems and future development trends of MS-based solid-state pulse generators are discussed.

Cyclophosphamide (CTX) is a common immunosuppressant, and it can also results in liver injury in human and animals. In this study, the CTX-induced liver injury mechanism in tilapia (Oreochromis niloticus) was investigated by studying alteration of endoplasmic reticulum stress (ERS), inflammation and anti-oxidative status. Tilapia was intraperitoneally injected CTX at the doses of 10, 25, 50, 75 and 100 mg·kg -1 , and the blood and liver tissues were collected. The results showed that CTX administration had a significant cytotoxicity on hepatocytes, and increased the liver index. The extensive vacuolar degeneration, unclear cell outline and other histological lesions were also observed. CTX administration markedly decreased the antioxidant ability and enhanced lipid peroxidation in liver. Furthermore, qPCR data showed that CTX administration at 50-100 mg·kg -1 up-regulated gene expressions of cyp1a, cyp2k1 and cyp3a, and inflammatory response-related genes including rel, relb, nfκb1, il-6, il-8, il-10 and tnf-α. CTX significantly promoted the mRNA levels of ERS-related genes (eif2α, crt, parp1, grp78, ire1, xbp1s and chop) in a dose dependent manner. Additionally, CTX injection at 75-100 mg·kg -1 could down-regulate gene expressions of anti-oxidative status including nrf2, ucp2, ho-1, gpx3, gstα and cat. Overall results suggested CTX injection induced liver damage which was related to the cytotoxic effect on hepatocytes, decrease of antioxidant capacity, inflammatory response and ERS., (Copyright © 2022. Published by Elsevier Inc.)

The plasma bridge neutralizer (PBN) based on a tungsten filament is a promising technique of a thermionic DC electron source where a hot filament is immersed in an inert gas flow and electrons are "bridged" from a small orifice to the ion beam. PBNs have been widely used in space propulsion and industrial applications due to their relatively simple structure and low power consumption. However, they have well-known disadvantages, namely, low emission current density and short lifetime. In this article, we propose a novel ring-cusp magnetically confined PBN (RCM-PBN) to address these issues. In the RCM-PBN, electrons are confined by a ring-cusp magnetic field, which improves the ionization efficiency and reduces the discharge chamber wall losses. Electrical insulation of the orifice plate from the chamber wall prevents a large number of electrons from being collected by the orifice plate, which greatly improves the extracted electron current. The effects of different operating parameters on the extracted electron current were studied through experiments. It was found that the increase in the extracted electron current with the extraction voltage was related to the anode spot formation. Analysis of the gas utilization factor and electron extraction cost shows that the optimal operating condition was obtained at an argon mass flow rate of 1.2 SCCM and a heater power of 45 W. At its optimum, a stable electron current of 1.1 A was extracted from the RCM-PBN with a gas utilization factor of 12.8 and an electron extraction cost of 143 W/A.

Purpose: This study aimed to combine the clinical data of acute myeloid leukaemia (AML) from The Cancer Genome Atlas (TCGA) database to obtain prognosis-related biomarkers, construct a prognostic risk model using long non-coding RNAs (lncRNAs) in AML and help patients with AML make clinical treatment decisions. Methods: We analysed the transcriptional group information of 151 patients with AML obtained from TCGA and extracted the expressions of lncRNAs. According to the mutation frequency, the patients were divided into the high mutation group (genomic unstable group, top 25% of mutation frequency) and low mutation group (genomic stable group, 25% after mutation frequency). The 'limma' R package was used to analyse the difference in lncRNA expressions between the two groups, and the "survival," "caret," and "glmnet" R packages were used to screen lncRNAs that are related to clinical prognosis. Subsequently, a prognosis-related risk model was constructed and verified through different methods. Results: According to the lncRNA expression data in TCGA, we found that seven lncRNAs (i.e. AL645608.6, LINC01436, AL645608.2, AC073534.2, LINC02593, AL512413.1, and AL645608.4) were highly correlated with the clinical prognosis of patients with AML, so we constructed a prognostic risk model of lncRNAs based on LINC01436, AC073534.2, and LINC02593. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses of differentially expressed lncRNA-related target genes were performed, receiver operating characteristic (ROC) curves were created, the applicability of the model in children was assessed using the TARGET database and the model was externally verified using the GEO database. Furthermore, different expression patterns of lncRNAs were validated in various AML cell lines derived from Homo sapiens. Conclusions: We have established a lncRNA prognostic model that can predict the survival of patients with AML. The Kaplan-Meier analysis showed that this model distinguished survival differences between patients with high- and low-risk status. The ROC analysis confirmed this finding and showed that the model had high prediction accuracy. The Kaplan-Meier analysis of the clinical subgroups showed that this model can predict prognosis independent of clinicopathological factors. Therefore, the proposed prognostic lncRNA risk model can be used as an independent biomarker of AML., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ding, Ling, Shi and Zheng.)

Observation of a melting layer using a 1.55 µm coherent Doppler lidar (CDL) is first presented during a stratiform precipitation event. Simultaneous radar measurements are also performed by co-located 1.24 cm micro rain radar (MRR) and 10.6 cm Doppler weather radar (DWR). As a well-known bright band in radar reflectivity appears during precipitation, an interesting dark band about 160 m below that in lidar backscattering is observed. Due to the absorption effect, the backscattering from raindrops at 1.55 µm is found much weaker than that at short wavelengths usually used in direct detection lidars. However, the CDL provides additional Doppler information which is helpful for melting layer identification. For example, a spectrum bright band with broadened width and sign conversion of skewness is detected in this case. After a deep analysis of the power spectra, the aerosol and precipitation components are separated. The fall speed of hydrometeors given by CDL is found smaller than that of MRR, with the differences of approximately 0.5 m/s and 1.5 m/s for the snow and rainfall, respectively. To illustrate the influence of absorption effect, simulations of the backscatter coefficient and extinction coefficient of aerosol and rainfall are also performed at the wavelength range of 0.3 ∼ 2.2 µm using the Mie theory.

All-solid-state linear transformer drivers (LTDs) are widely used in high-voltage repetitive nanosecond-pulsed generators, and only a few LTD generators can output bipolar rectangular waves currently. Furthermore, owing to the large reverse overshoot when the output pulse width is long, fewer LTD generators can achieve a rectangular wave output with a microsecond pulse width. In this study, a bipolar LTD circuit topology based on a push-pull circuit is proposed for irreversible electroporation. In this topology, a single-stage LTD module has four push-pull branches in its primary winding to achieve a bipolar output and a short-circuited winding with two resistor-capacitor-diode snubbers to suppress forward/reverse overshoot. A single-stage LTD module and a 12-stage LTD have been tested, and the results show that they can output bipolar rectangular pulses with variable parameters. When the output pulse width is 100 ns to 1 µs, the maximum output voltage amplitude is 5.74 kV, the rise time is 29.1 ns, and the reverse overshoot at 1 µs is 2.9%. When the output pulse width is 1-8 µs, the maximum output voltage amplitude is 2.93 kV, the rise time is 24.3 ns, and the reverse overshoot at 8 µs is 11.3%.

The mandarin fish, Siniperca chuatsi , is an economically important perciform species with widespread aquaculture practices in China. Its special feeding habit, acceptance of only live prey fishes, contributes to its delicious meat. However, little is currently known about related genetic mechanisms. Here, we performed whole-genome sequencing and assembled a 758.78 Mb genome assembly of the mandarin fish, with the scaffold and contig N50 values reaching 2.64 Mb and 46.11 Kb, respectively. Approximately 92.8% of the scaffolds were ordered onto 24 chromosomes (Chrs) with the assistance of a previously established genetic linkage map. The chromosome-level genome contained 19,904 protein-coding genes, of which 19,059 (95.75%) genes were functionally annotated. The special feeding behavior of mandarin fish could be attributable to the interaction of a variety of sense organs (such as vision, smell, and endocrine organs). Through comparative genomics analysis, some interesting results were found. For example, olfactory receptor (OR) genes (especially the beta and delta types) underwent a significant expansion, and endocrinology/vision related npy , spexin , and opsin genes presented various functional mutations. These may contribute to the special feeding habit of the mandarin fish by strengthening the olfactory and visual systems. Meanwhile, previously identified sex-related genes and quantitative trait locis (QTLs) were localized on the Chr14 and Chr17, respectively. 155 toxin proteins were predicted from mandarin fish genome. In summary, the high-quality genome assembly of the mandarin fish provides novel insights into the feeding habit of live prey and offers a valuable genetic resource for the quality improvement of this freshwater fish., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ding, Zhang, Zhao, Jing, Cao, Li, Huang, You, Wang, Shi and Bing.)

Low-temperature plasma technology is widely used in various industrial fields, which require the plasma to be of large volume, diffuse, and stable. Furthermore, previous studies have shown that better plasma performance has been obtained by using generators with a high voltage, a high repetition rate, a fast rise time, and a short pulse duration. In this paper, a novel topology is proposed for such generators, which is based on magnetic switches and diode opening switches. A prototype is developed, and its output characteristics are investigated by varying essential parameters, such as the load resistance and the power supply voltage. The experimental results show that it can generate pulses with a voltage of 30.6 kV, a rise time of 7.1 ns, a pulse duration of 8.2 ns, and a maximum repetition rate of 12 kHz on a 300 Ω resistive load. The prototype has been successfully used to drive uniform plasma in ambient air. In the proposed topology, a diode is added to make the magnetic cores independent of each other, significantly simplifying the design calculation. It may help develop nanosecond solid-state generators.

The fast linear transformer driver (FLTD) utilizes a water-insulated transmission line as its secondary. To monitor the fast pulsed current and locate the fault, a compact self-integrating current sensor is developed. Print circuit board (PCB) coils and PCB integrating resistors are used to form the current sensor. By soldering a large number of chip resistors, PCB integrating resistors with various resistance and low inductance can be obtained. The current sensor is designed in a coaxial structure to reduce its inductance and size and can be installed on the inner conductor of the FLTD's secondary water-insulated transmission line with a small opening. The principle and matching schemes for the current sensor are theoretically analyzed with the circuit principle. Both simple matching and two-stage division can be used to obtain signals without oscillation. The time constant of the two schemes is the same. However, the sensitivity of the current sensor with two-stage division is lower than that with simple matching. A 100 kV step pulse generator is used as the pulsed high current generator to verify the properties of the current sensor. The designed current sensor could respond to the step current pulse with the rise time of 4 ns. The matching scheme is verified to be effective with step response experiments. Finally, the influence of the parameters, which are the coil type, the angle between the PCB coil and the magnetic flux, the resistance of the integrating resistor, and the length of the measuring cable, on the output signal of the current sensor is studied.

In this paper, a 60-stage Marx circuit with the two-phase immersion cooling technique is presented. The performance parameters of the pulse generator with phase change immersion cooling and forced air cooling are compared. The results show that the maximum repetition rate is increased from 80 to 260 kHz, the pulse drift is significantly reduced from 900 to 200 ps, and the temperature rise of transistors is controlled effectively to enhance the stability of the amplitude. We also studied the influence of temperature on the turn-on and turn-off processes of the transistors to show the importance of heat management under high repetition conditions. Finally, a pulse generator is developed with the repetition rate of 200 kHz, the rise time of 180 ps, and the amplitude of 2350 V on a matched 50 Ω resistive load, which can work for more than 30 min.

Avalanche transistor Marx bank circuits (MBCs) are widely used in high voltage repetitive nanosecond pulse generators, but problems exist with respect to increasing the output voltage due to the limited pulsed current. Accordingly, a novel topology based on an avalanche transistor MBC combined with a linear transformer driver is proposed, the latter of which exhibits advantageous stress distribution and modular structure. A four-module prototype with four units in each module is developed in the laboratory. The output characteristics are investigated by varying important parameters such as the main capacitance, the number of conducting units, the number of cascaded modules, and the trigger signal time delay. The test results verify the validity of the proposed topology. For a 50 Ω resistive load, the prototype can generate pulses with an amplitude of 10.9 kV, a rise time of 3.3 ns, and a voltage superposition efficiency of 89%. The topology proposed in this paper may help to provide a method to further improve the output performance of avalanche transistor MBCs.

The blood acts as a transfer channel for a variety of factors in the whole body. The ricefield eel (Monopterus albus) is a protogynous hermaphrodite vertebrate. Until now, no research has reported an analysis of the blood transcriptome during the process of sexual development in the ricefield eel. In this study, the transcriptome sequencing of blood samples from male and female ricefield eels was completed with a total of 34.70 Gb clean data. The clean data of each sample all reached 5.23 GB, and the percent of the Q30 basic group was 88.62% and above. A total of 106,369 unigenes were obtained after assembly, including 13,296 unigenes with a length of more than 1 kb. Further functional annotation analysis showed that there are 28,522 unigenes that can be annotated. The annotations of genes with differential expression revealed that there were 563 genes with significant differential expression in the blood of male and female ricefield eels, including 91 upregulated genes and 472 downregulated genes. Among which, 14 genes may be closely related to sex differentiation, the qPCR was used to confirmed the expression pattern of those genes and result shown that 11 genes were downregulated and 3 genes were upregulated, consistent with the results of our RNA-Seq analysis. This blood transcript dataset will open future research avenues on ricefield eel sex development and differentiation.

8-oxoguanine (8-oxoG) is one of the most prevalent genotoxic lesions, and it is generated in DNA attacked by reactive oxygen species (ROS). Adenine misincorporated opposite to 8-oxoG during replication is excised by MutY homolog (MUTYH), an important protein of the base excision repair (BER) system. Mutyh plays an important role in the maintenance of genomic integrity, but the functional consequences of Mutyh deficiency are not fully understood. In the current study, we investigated the histological and functional changes of five tissues (hippocampus, heart, liver, kidney and lung) and their molecular basis in Mutyh -/- and wild-type mice exposed to D-galactose (D-gal). Our data indicated that Mutyh deficiency hindered the weight gain of experimental mice and induced substantial alterations of 8-oxoG content and superoxide dismutase (SOD) activity, but no significant histological and functional impairment appeared in the investigated tissues of Mutyh- deficient mice without D-gal exposure. Under low-dose D-gal exposure, Mutyh deficiency altered expression of genes involved in mitochondrial unfolded protein response (UPR mt ) in the heart, liver and lung, and caused an enhanced expression of mitochondrial dynamics proteins (MDPs) in hippocampus and liver. The stress responses could maintain mitochondrial proteostasis and function. However, such responses were not noted when experiencing excessive damage burden induced by high-dose D-gal exposure, in which Mutyh deficiency increased accumulation of 8-oxoG and aggravated mitonuclear protein imbalance, as well as histological lesions in heart, liver and kidney. A higher sensitivity to ROS-induced cardiotoxicity with high-dose D-gal exposure was noticed in Mutyh -/- mice. However, no differences in learning and memory impairments were observed between Mutyh -/- and wild-type mice with high-dose D-gal exposure. In conclusion, our data demonstrated that Mutyh deficiency has different impacts on various tissues based on the degree of oxidative stress., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In this paper, a torsional thrust balance with an asymmetrical arm is designed and tested which is effective for the microthruster performance evaluation in the vacuum facilities with limited space. An optimization design method for the key parameters of the thrust balance has been developed. By utilizing the asymmetrical arm, a great resolution can be obtained with a restrained arm length. A novel printed circuit board electrostatic comb has been applied to the thrust balance calibration. Experimental results show that the comb is capable of producing steady force in the range of about 30 μN-3300 μN and an impulse bit of 7 µNs-777 µNs which can be further extended to nano-Newton second range with a shorter pulse width and a lower voltage. The calibration results show that the thrust balance has a great repeatability and reliability. The total uncertainty of the thrust stand is estimated to be 3.33% in the 1 µNs range.

To monitor fast pulsed voltage in the transmission line of the fast linear transformer driver, a compact and self-integrating capacitive sensor is developed. A printed circuit board (PCB) with multi-layer ceramic capacitors (MLCCs) serves as a low-voltage arm. Given the reflow structure of the PCB and a parallel arrangement of MLCCs, the residual inductance of the PCB low-voltage arm can be effectively reduced. Moreover, its capacitance can be easily adjusted. The capacitive sensor is designed using a coaxial structure, suitable for installation on the inner high voltage electrode of the secondary water-insulated transmission line. Three matching schemes for the measuring cable are discussed, showing that two-stage division with matching at the end of the cable is more suitable for fast pulsed voltage measurement due to its high dividing ratio and flat frequency response. A square wave with a rise time of ∼1.5 ns and a pulse width of ∼200 ns is used to verify the properties of the capacitive sensor. The results show that the rise time of the designed capacitive sensor can reach 1.5 ns when a short cable is used. Increasing capacitance of the low-voltage arm or resistance at the cable entrance will increase the time constant of the capacitive sensor, which improves its low-frequency properties. A long cable will significantly reduce the high-frequency response and the magnitude of the signal from the capacitive sensor.

A potent class of DNA-damaging agents, natural product bis-intercalator depsipeptides (NPBIDs), was evaluated as ultrapotent payloads for use in antibody-drug conjugates (ADCs). Detailed investigation of potency (both in cells and via biophysical characterization of DNA binding), chemical tractability, and in vitro and in vivo stability of the compounds in this class eliminated a number of potential candidates, greatly reducing the complexity and resources required for conjugate preparation and evaluation. This effort yielded a potent, stable, and efficacious ADC, PF-06888667, consisting of the bis-intercalator, SW-163D, conjugated via an N-acetyl-lysine-valine-citrulline- p-aminobenzyl alcohol- N, N-dimethylethylenediamine (AcLysValCit-PABC-DMAE) linker to an engineered variant of the anti-Her2 mAb, trastuzumab, catalyzed by transglutaminase.

Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that simultaneously bind to a target protein and an E3 ligase, thereby leading to ubiquitination and subsequent degradation of the target. They present an exciting opportunity to modulate proteins in a manner independent of enzymatic or signaling activity. As such, they have recently emerged as an attractive mechanism to explore previously "undruggable" targets. Despite this interest, fundamental questions remain regarding the parameters most critical for achieving potency and selectivity. Here we employ a series of biochemical and cellular techniques to investigate requirements for efficient knockdown of Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase essential for B cell maturation. Members of an 11-compound PROTAC library were investigated for their ability to form binary and ternary complexes with BTK and cereblon (CRBN, an E3 ligase component). Results were extended to measure effects on BTK-CRBN cooperative interactions as well as in vitro and in vivo BTK degradation. Our data show that alleviation of steric clashes between BTK and CRBN by modulating PROTAC linker length within this chemical series allows potent BTK degradation in the absence of thermodynamic cooperativity., Competing Interests: Conflict of interest statement: All authors are or were employees of Pfizer, Inc.

An electrostatic calibration technique is highly flexible in producing a wide range of force and it is widely applied for nano-newton to micro-newton thrust stand calibration. This paper proposes a novel method for electrostatic comb implementation and related experiments have been carried out. Based on the printed circuit board and commercial fins, the comb can be realized flexibly with the output force conveniently extended. The force generated by this kind of comb is theoretically analyzed. Different from the traditional comb structure, the conductive area of the comb fixed plate is minimized to improve the force consistency over engagement. The influence of fin length, fin number, applied voltage, and engagement on the output force has been studied experimentally. The final comb system is capable of producing steady force in the range 13-5040 μN with the relative error within 5%. With a high voltage pulse generator, this system could produce calibration impulse bit in the range 1-1000 μN s for which the lowest level can be far more extended to the nanonewton range with a shorter pulse width, a lower voltage, and a reduced number of fins. Moreover, the calibrator has a rather flat force-engagement characteristic when the engagement is in the range of 6 mm-16 mm, while the variation of electrostatic force is within 5%. This calibrator has a wide output range and great consistency, and it is beneficial for the thrust stand calibration.

Aberrant miRNA expression has been detected in various tumor tissues, which may be considered as a marker for early cancer diagnosis. One miRNA has multiple downstream target genes, which can be regulated by multiple upstream other miRNAs. Hence, this dynamic regulation is likely characterized by volatility, and thus, finding the appropriate time point for tests becomes essential for the use of miRNAs as an early marker of tumor diagnosis. In this study, we established a chronic liver cancer progression model in mice by using low doses of the harmful substance microcystin-LR (MC-LR). On the basis of miRNAs microarray assay, we further tested seven miRNAs that showed characteristic expression changes in pre-hepatocarcinogenesis. Our results showed that the levels of four miRNAs (miR-122-5p, miR-125-5p, miR-199a-5p, and miR-503-5p) decreased dramatically, whereas those of two miRNAs (miR-222-5p and miR-590-5p) increased significantly in the early stages, which were all accompanied by an increase in atypia of hepatocytes. MiR-490-5p was a sensitive molecular, suitable only for evaluation of pathological changes in young mice. Therefore the combination the seven of miRNAs for a set may prove to be an effective method in healthy assessment of environmental toxicants for detection of hepatocarcinogenesis caused by hazardous materials., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This paper presents the design and development of a trigger with a high repetition rate, low jitter, and compact structure for the pseudospark switch (PSS), which includes an improved Marx generator based on avalanche transistors and a corona-plasma trigger unit. The generator adopted a novel 3 × 12-stage Marx circuit based on avalanche transistors in which the failure rate of transistors in the first and second stages was significantly reduced by connecting the parallel capacitors compared to the previous similar generator. The reason for the improved performance was also discussed. The main parameters of output pulses were an amplitude of -7 kV, rise time of 6 ns, jitter of 0.2 ns, and repetition rate of 2 kHz. The corona-plasma trigger unit adopted BaTiO 3 ceramics with high ε r as the dielectric and was arranged in the hollow cathode of the PSS. The experiments of triggering a PSS prototype were conducted. The influence of anode voltage and pressure on the trigger delay and jitter was studied, and the minimum trigger jitter achieved <1 ns. This trigger worked for 10 7 shots at the repetition rate of 2 kHz continuously without obvious performance degradation and any failure of the generator. The main advantage of this trigger is the simultaneous combination of the high repetition rate, low jitter, long lifetime, and great simplicity in a compact structure.

Fatty liver is an increasingly serious disease of fish in aquaculture. However, the mechanisms responsible for the occurrence of fatty liver remain unclear, and no effective methods for the prevention and treatment of this disease have yet been found. In the present study, we aimed to develop an in vitro model of hepatocyte injury using oleic acid as hepatotoxicant and evaluate the protective effects of Rhizoma Alismatis extract (RAE) in Jian carp using this model. Primary hepatocytes from Jian carp were isolated and purified and cultured in vitro. The result indicated that 0.4 mmol L -1 oleic acid and 48 h could be the optimal conditions to induce hepatocyte injury model in cultured hepatocytes. Hepatocytes were exposed to oleic acid, followed by the addition of RAE at 0, 1, 5, 10, 20, or 50 μg mL -1 . The hepatocytes and supernatant were then analyzed. RAE suppressed oleic acid-induced elevations in aspartate aminotransferase, alanine aminotransferase, triglycerides, total cholesterol, lactate dehydrogenase, alkaline phosphatase, cholinesterase, malondialdehyde, γ-glutamyl transferase, cytochrome P450 1A, cytochrome P450 2E1, liver-type fatty acid binding protein, free fatty acid, fatty acid synthetase, and tumor necrosis factor-α (P < 0.01 or P < 0.05); reduced protein levels of cytochrome P450 1A, nuclear factor (NF)-κB p65, and NF-κB c-Rel; and inhibited cytochrome P4503A, NF-κB c-Rel, nuclear factor erythroid-related factor 2, peroxisome proliferator-activated receptor-α, and cytochrome P4501A mRNA levels. In conclusion, RAE exhibited a protective effect against hepatocyte injury in Jian carp. Further in vivo studies are needed to provide more evidence for the use of RAE as a hepatoprotective agent for the treatment of hepatocyte injury.

Many diseases are believed to be driven by pathological levels of reactive oxygen species (ROS) and oxidative stress has long been recognized as a driver for inflammatory disorders. Apoptosis signal-regulating kinase 1 (ASK1) has been reported to be activated by intracellular ROS and its inhibition leads to a down regulation of p38-and JNK-dependent signaling. Consequently, ASK1 inhibitors may have the potential to treat clinically important inflammatory pathologies including renal, pulmonary and liver diseases. Analysis of the ASK1 ATP-binding site suggested that Gln756, an amino acid that rarely occurs at the GK+2 position, offered opportunities for achieving kinase selectivity for ASK1 which was applied to the design of a parallel medicinal chemistry library that afforded inhibitors of ASK1 with nanomolar potency and excellent kinome selectivity. A focused optimization strategy utilizing structure-based design resulted in the identification of ASK1 inhibitors with low nanomolar potency in a cellular assay, high selectivity when tested against kinase and broad pharmacology screening panels, and attractive physicochemical properties. The compounds we describe are attractive tool compounds to inform the therapeutic potential of ASK1 inhibition., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

A pair of W-Ni-Fe and W-Cu electrodes were tested under 100 kA level pulsed currents for 10 000 shots, respectively. Surface roughness and morphology characteristics of the two pairs of electrodes were obtained and compared. Experimental results indicated cracks divided the W-Cu electrode surface to polygons while the W-Ni-Fe electrode surface remained as a whole with pits and protrusions. Accordingly, the surface roughness of W-Ni-Fe electrodes increased to ∼3 μm while that of W-Cu electrodes reached ∼7 μm at the end of the test. The results reveal that the W-Ni-Fe alloy has a better erosion resistance and potential to be further applied in spark gaps.

A platform SWE-2 used for single wire explosion experiments has been designed, established, and commissioned. This paper describes the design and initial experiments of SWE-2. In summary, two pulsed current sources based on pulse capacitors and spark gaps are adopted to drive sub-microsecond and microsecond time scale wire explosions in a gaseous/liquid medium, respectively. In the initial experiments, a single copper wire was exploded in air, helium, and argon with a 0.1-0.3 MPa ambient pressure as well as tap water with a 283-323 K temperature, 184-11 000 μS/cm conductivity, or 0.1-0.9 MPa hydrostatic pressure. In addition, the diagnostic system is introduced in detail. Energy deposition, optical emission, and shock wave characteristics are briefly discussed based on experimental results. The platform was demonstrated to operate successfully with a single wire load. These results provide the potential for further applications of this platform, such as plasma-matter interactions, shock wave effects, and reservoir simulations.

In order to evaluate the antioxidant and anti-inflammatory effects of glycyrrhetinic acid (GA) on carbon tetrachloride (CCl 4 )-induced damage in precision-cut liver slices (PCLS) from Jian carp (Cyprinus carpio. Jian), an acute liver damage model was established in this study. The viability of PCLS, levels of anti-oxidases in liver homogenates, expression of inflammation-related genes including nuclear factor-κB (nf-κB)/c-rel, inducible nitric oxide synthase (inos), interleukin-1β (il-1β), interleukin-6 (il-6) and interleukin-8 (il-8), and protein levels of (nf-κB)/c-rel in liver tissues were measured. The results showed that pretreatment of PCLS with GA at 5 and 10 μg/mL for 6 h significantly inhibited the cytotoxicity of CCl 4 . GA attenuated CCl 4 -induced oxidative stress in PCLS through promoting the recovery of superoxide dismutase (SOD) and glutathione (GSH) levels, and inhibiting malondialdehyde (MDA) synthesis. In inflammatory response, GA at both 5 and 10 μg/mL significantly inhibited the increase in mRNA levels of inflammatory cytokines including nf-kƁ/c-rel, inos, il-1β, il-6 and il-8, and the protein level of Nf-kƁ/C-rel induced by CCl 4 . Furthermore, treatment with pyrrolyl dithiocarbamate (PDTC, 4 μg/mL), an inhibitor of nuclear transcription factor nf-kB, significantly inhibited nf-kB levels, and transcription of downstream cytokines inos, il-1β, il-6 and il-8, also the viability of PCLS was significantly increased. These results indicated that GA suppressed inflammation and reduced cytotoxicity by inhibiting the nf-kƁ signaling pathway, and plays a role in liver protection., (Copyright © 2017. Published by Elsevier Ltd.)

To understand the molecular mechanism of estrogen and to evaluate the role of the estrogen receptor in mediating estrogen action, the full-length cDNA of estrogen receptor α (ERα) was cloned from Monopterus albus, and its expression pattern and distribution were investigated. The ERα cDNA of M. albus includes an open reading frame of 1863 bp, a 140-bp 5'-untranslated region and a 797-bp 3'-untranslated region. Amino acid sequence homology analysis showed that the Monopterus albus ERα has a moderate degree of similarity with Sebastes schlegelii, Zoarces viviparus and Haplochromis burtoni (81.1%, 80.7% and 80.4%, respectively). Quantitative PCR results showed that the highest level of ERα expression was in the liver; the next highest level of expression was observed in the gonads, where it was expressed at high levels particularly in the ovary in developmental stages IV and V and in the testis in developmental stage II/III. Immunohistochemistry analysis showed that ERα was present as slender particles distributed mainly in the membranes of spermatocytes and oocytes in the testis and ovary, whereas no positive signal was observed in the cytoplasm of sperm cells. This report describes the first molecular characterization of full-length ERα and its tissue-specific distribution in M. albus.

A Ty3/gypsy-retrotransposon-type transposon was found in the genome of the Jian carp (Cyprinus carpio var. Jian) in a previous study (unpublished), and was designated a JRE retrotransposon (Jian retrotransposon). The full-length JRE retrotransposon is 5126 bp, which includes two long terminal repeats of 470 bp at the 5' end and 453 bp at the 3' end, and two open reading frames between them: 4203 bp encoding the group-specific antigen (GAG) and polyprotein (POL). The pol gene has a typical Ty3/gypsy retrotransposon structure, and the gene order is protease, reverse transcriptase, RNase H, and integrase (PR-RT-RH-IN). A phylogenetic analysis of the pol gene showed that it has similarities of 40.7, 40, and 32.8 %, to retrotransposons of Azumapecten farreri, Mizuhopecten yessoensis, and Xiphophorus maculatus, respectively. Therefore, JRE might belong to the JULE retrotransposon family. The copy number of the JRE transposon in the genome of the Jian carp is 124, determined with real-time quantitative PCR. The mRNA of the JRE retrotransposon is expressed in five Jian carp tissues, the liver, kidney, blood, muscle, and gonad, and slightly higher in the kidney and liver than in the other tissues.

Underwater shock waves (SWs) generated by underwater electrical wire explosions (UEWEs) have been widely studied and applied. Precise measurement of this kind of SWs is important, but very difficult to accomplish due to their high peak pressure, steep rising edge and very short pulse width (on the order of tens of μs). This paper aims to analyze the signals obtained by two kinds of commercial piezoelectric pressure probes, and reconstruct the correct pressure waveform from the distorted one measured by the pressure probes. It is found that both PCB138 and Müller-plate probes can be used to measure the relative SW pressure value because of their good uniformities and linearities, but none of them can obtain precise SW waveforms. In order to approach to the real SW signal better, we propose a new multi-exponential pressure waveform model, which has considered the faster pressure decay at the early stage and the slower pressure decay in longer times. Based on this model and the energy conservation law, the pressure waveform obtained by the PCB138 probe has been reconstructed, and the reconstruction accuracy has been verified by the signals obtained by the Müller-plate probe. Reconstruction results show that the measured SW peak pressures are smaller than the real signal. The waveform reconstruction method is both reasonable and reliable.

Irreversible electroporation (IRE) is a novel ablation method that has been tested in humans with lung, prostate, kidney, liver, lymph node and presacral cancers. As a new non-thermal treatment, the use of IRE to ablate tumors in the musculoskeletal system might reduce the incidence of fractures. We aimed to determine the ablation threshold of cortical bone and to evaluate the medium- and long-term healing process and mechanical properties of the femur in a rabbit model post-IRE ablation. The ablation threshold of cortical bone was between 1090 V/cm and 1310 V/cm (120 pulses). IRE-ablated femurs displayed no detectable fracture but did exhibit signs of recovery, including osteoblast regeneration, angiogenesis and bone remodeling. In the ablation area, revascularization appeared at 4 weeks post-IRE. Osteogenic activity peaked 8 weeks post-IRE and remained high at 12 weeks. The mechanical strength decreased briefly 4 weeks post-IRE but returned to normal levels within 8 weeks. Our experiment revealed that IRE ablation preserved the structural integrity of the bone cortex, and the ablated bone was able to regenerate rapidly. IRE may hold unique promise for in situ bone tissue ablation because rapid revascularization and active osteogenesis in the IRE ablation area are possible.

Background: To evaluate the potential effects of irreversible electroporation ablation on the Achilles tendon in a rabbit model and to compare the histopathological and biomechanical changes between specimens following electroporation ablation and radiofrequency ablation., Methods: A total of 140 six-month-old male New Zealand rabbits were used. The animals were randomly divided into two groups, 70 in the radiofrequency ablation group and 70 in the electroporation group. In situ ablations were applied directly to the Achilles tendons of rabbits using typical electroporation (1800 V/cm, 90 pulses) and radiofrequency ablation (power control mode) protocols. Histopathological and biomechanical evaluations were performed to examine the effects of electroporation ablation and radiofrequency ablation over time., Results: Both electroporation and radiofrequency ablation produced complete cell ablation in the target region. Thermal damage resulted in tendon rupture 3 days post radiofrequency ablation. In contrast, electroporation-ablated Achilles tendons preserved their biomechanical properties and showed no detectable rupture at this time point. The electroporation-ablated tendons exhibited signs of recovery, including tenoblast regeneration and angiogenesis within 2 weeks, and the restoration of their integral structure was evident within 12 weeks., Conclusions: When applying electroporation to ablate solid tumors, major advantage could be that collateral damage to adjacent tendons or ligaments is minimized due to the unique ability of electroporation ablation to target the cell membrane. This advantage could have a significant impact on the field of tumor ablation near vital tendons or ligaments.