Idiosyncratic Drug-Induced Liver Injury: Mechanistic and Clinical Challenges

Idiosyncratic drug-induced liver injury (IDILI) remains a significant problem for patients and drug development. The idiosyncratic nature of IDILI makes mechanistic studies difficult, and little is known of its pathogenesis for certain. Circumstantial evidence suggests that most, but not all, IDILI is caused by reactive metabolites of drugs that are bioactivated by cytochromes P450 and other enzymes in the liver. Additionally, there is overwhelming evidence that most IDILI is mediated by the adaptive immune system; one example being the association of IDILI caused by specific drugs with specific human leukocyte antigen (HLA) haplotypes, and this may in part explain the idiosyncratic nature of these reactions. The T cell receptor repertoire likely also contributes to the idiosyncratic nature. Although most of the liver injury is likely mediated by the adaptive immune system, specifically cytotoxic CD8+ T cells, adaptive immune activation first requires an innate immune response to activate antigen presenting cells and produce cytokines required for T cell proliferation. This innate response is likely caused by either a reactive metabolite or some form of cell stress that is clinically silent but not idiosyncratic. If this is true it would make it possible to study the early steps in the immune response that in some patients can lead to IDILI. Other hypotheses have been proposed, such as mitochondrial injury, inhibition of the bile salt export pump, unfolded protein response, and oxidative stress although, in most cases, it is likely that they are also involved in the initiation of an immune response rather than representing a completely separate mechanism. Using the clinical manifestations of liver injury from a number of examples of IDILI-associated drugs, this review aims to summarize and illustrate these mechanistic hypotheses.     

Bioinspired Triboelectric Soft Robot Driven by Mechanical Energy

A sustainable power source is a key technical challenge for practical applications of electrically responsive soft robots, especially the required voltage is over several thousand volts. Here, a practicable new technology, triboelectric soft robot (TESR) system with the primary characteristics of power source from mechanical energy, is developed. At its heart is TESR with bioinspired architectures made of soft-deformable body and two triboelectric adhesion feet, which is driven and accurately controlled through triboelectric effect, while reaching maximum crawling speeds of 14.9 mm s⁻¹ on the acrylic surface. The characteristics of the TESR, including displacement and force, are tested and simulated under the power of a rotary freestanding triboelectric nanogenerator (RF-TENG). Crawling of TESR is successfully realized on different materials surfaces and different angle slopes under the driven of RF-TENG. Furthermore, a real-time visual monitoring platform, in which TESR carries a micro camera to transmit images in a long narrow tunnel, is also achieved successfully, indicating that it can be used for fast diagnosis in an area inaccessible to human beings in the future. This study offers a new insight into the sustainable power source technologies suitable for electrically responsive soft robots and contributes to expanding the applicability of TENGs.     

Thermodynamic properties of sodium hexatitanate (Na2Ti6O13) at high temperature (298.15–1573 K)

Sodium hexatitanate (Na₂Ti₆O₁₃) was reported as an anode side material for Sodium ion batteries owing to low material cost, high energy efficiency, good thermal stability and long cycle life. Therefore, studies pertaining to the thermodynamic properties of Na₂Ti₆O₁₃ are indispensable for improving its service performance. However, a significant number of literature reviews concerning thermodynamic properties indicated that heat capacity of Na₂Ti₆O₁₃ at high temperatures should be confirmed. In this study, the 99.5% purity of Na₂Ti₆O₁₃ sample was successfully prepared via solid-state reaction using TiO₂ and Na₂CO₃ as initial materials. Heat capacity of the as-synthesized samples in the temperature range of 573–1523 K was measured using a multi-high temperature calorimeter 96 line. Heat capacity, Cp, from 298.15 to 1573 K was modeled as a polynomial formula with a prediction error of 3%: Cp = 474.08143 + 0.06286T-8.04068 × 10⁶ T⁻² (J⋅mol⁻¹⋅K⁻¹). In combination with the low-temperature data, heat capacity of Na₂Ti₆O₁₃ from 0 to 1573 K was given in present study. Values of changes in enthalpy, Gibbs free energy and entropy in the temperature range of 298.15–1573 K were calculated based on the temperature dependence of heat capacity.     

Biodegradable Polymeric Nanoparticles Containing an Immune Checkpoint Inhibitor (aPDL1) to Locally Induce Immune Responses in the Central Nervous System

Immunotherapy is an efficient approach to clinical oncology. However, the immune privilege of the central nervous system (CNS) limits the application of immunotherapeutic strategies for brain cancers, especially glioblastoma (GBM). Tumor resistance to immune checkpoint inhibitors is a further challenge in immunotherapies. To overcome the immunological tolerance of brain tumors, a novel multifunctional nanoparticle (NP) for highly efficient synergetic immunotherapy is reported. The NP contains an anti-PDL1 antibody (aPDL1), upconverting NPs, and the photosensitizer 5-ALA; the surface of the NP is conjugated with the B1R kinin ligand to facilitate transport across the blood-tumor-barrier. Upon irradiation with a 980 nm laser, 5-ALA is transformed into protoporphyrin IX, generating reactive oxygen species. Photodynamic therapy (PDT) further promotes intratumoral infiltration of cytotoxic T lymphocytes and sensitizes tumors to PDL1 blockade therapy. It is demonstrated that combining PDT and aPDL1 can effectively suppress GBM growth in mouse models. The proposed NPs provide a novel and effective strategy for boosting anti-GBM photoimmunotherapy.     

Gd2Zr2O7 ceramics synthesized by solid-state reactive sintering: Effects of starting powders with different-scale particle sizes

In this work, the effects of starting oxide powders with different-scale particle sizes on the synthesis of gadolinium zirconate pyrochlore (Gd₂Zr₂O₇, GZO) and its physical properties were studied. Micron Gd₂O₃ (μG), micron ZrO₂ (μZ), nano Gd₂O₃ (nG), and nano ZrO₂ (nZ) powders were used. GZO ceramics were prepared by employing solid-state reactive sintering at 1300 °C, 1400 °C, 1500 °C and 1600 °C with mixed powders of different sizes (μGμZ, μGnZ, nGμZ and nGnZ). X-ray diffraction and Raman analyses of the ceramics revealed that nG has a more significant impact on the crystallization process than nZ. All ceramics synthesized with different sized oxide powders crystallized into pyrochlore phases except for those synthesized with μGnZ mixed powders, which resulted in a fluorite phase. The results indicated that decreasing the particle size of only ZrO₂ to synthesize pyrochlore-phase Gd₂Zr₂O₇ with high crystallinity may not be effective. Samples obtained at 1500 °C were further analyzed. Scanning electron microscopy results revealed that all four ceramics have a non-homogeneous grain size and that the average grain size ranges from 5.40 to 8.30 μm. In addition, the density and Vickers hardness measurements showed that the use of nanopowders significantly improves the mechanical properties.     

井下供电监控及防越级跳闸系统运用分析

以井下供电监控及防越级跳闸运用为对象开展探究。在分析矿井供电系统运行中现存主要问题的基础上,对供电监控与防越级跳闸系统整体应用的积极意义进行了分析和总结,希望能够让更多矿井技术人员了解供电监控及防越级跳闸系统的优越性,为其在矿井中的广泛推广普及提供便利,为煤矿行业更加高效地发展提供帮助。     

低功耗高性能的全MOS电压基准源设计

设计了一种基于亚阈值技术的全MOS电压基准源,采用共源共栅结构来增大PSRR,使用MOS管代替电阻,优化温度特性,使电路中大部分MOS管工作于亚阈值区。基于0.18μm CMOS工艺进行设计、版图绘制、和前、后仿真,在后仿真中得出相关参数值。对各参数做出详细分析,包括:一定温度范围内的温度系数;常温下基准输出电压;不同电源电压条件下的线性调整率、基准源静态电流及功耗,并对不同频率下的电源电压抑制比进行了对比。实验结果表明达到了低功耗高性能的设计目标。     

Polynomial filtering for nonlinear stochastic systems with state‐ and disturbance‐dependent noises

This article is concerned with the polynomial filtering problem for a class of nonlinear stochastic systems governed by the Itô differential equation. The system under investigation involves polynomial nonlinearities, unknown‐but‐bounded disturbances, and state‐ and disturbance‐dependent noises ((x,d)‐dependent noises for short). By expanding the polynomial nonlinear functions in Taylor series around the state estimate, a new polynomial filter design method is developed with hope to reduce the conservatism of the existing results. In virtue of stochastic analysis and inequality technique, sufficient conditions in terms of parameter‐dependent linear matrix inequalities (PDLMIs) are derived to guarantee that the estimation error system is input‐to‐state stable in probability. Moreover, the desired polynomial matrix can be obtained by solving the PDLMIs via the sum‐of‐squares approach. The effectiveness and applicability of the proposed method are illustrated by two numerical examples with one concerning the permanent magnet synchronous motor.     

Computer‐aided design methodology for linearity enhancement of multiwatt GaN HEMT amplifiers using multiple parallel devices

This article presents a design methodology for linearizing GaN HEMT amplifiers based on splitting a large FET into multiple parallel FETs with same total gate periphery and by biasing them individually. By varying the biases, the magnitude and the phase of the IMD3 components at the output of FET changes. A detailed simulation methodology using commercial microwave CAD software is presented. Simulation results show that by biasing one device in Class AB and other(s) in deep Class AB mode, IMD3 components of parallel FETs can be made out of phase to each other leading to cancellation and improvement in linearity. Three prototype circuits were simulated using (a) a single 5 mm FET (1 × 5 mm), (b) two parallel 2.5 mm FETs (2 × 2.5 mm), and (c) four parallel 1.25 mm FETs (4 × 1.25 mm), for a total gate periphery of 5 mm, over the frequency range of 0.8 to 1.0 GHz. IMD3 improvement up to 20 dBc was achieved with the 4 × 1.25 mm circuit when the FET biases were optimized. Measurement results show improvement in linearity up to 20 dBc for 4 × 1.25 mm circuit. The proposed method improves linearity without a substantial penalty on the power consumption and is straightforward to implement.     

Benchmark value determination of energy efficiency indexes for coal-fired power units based on data mining methods

The operational optimisation of coal-fired power units is important for saving energy and reducing losses in the electric power industry. One of the key issues is how to determine the benchmark values of the energy efficiency indexes of the units. Therefore, a new framework for determining these benchmark values is proposed, based on data mining methods. First, the energy efficiency key performance indicators (KPIs) associated with the net coal consumption rate (NCCR) were selected based on the domain knowledge. Second, the decision-making samples with minimal NCCR were acquired with the fuzzy C-means (FCM) clustering algorithm, and the corresponding clustering centres were employed as the benchmark values. Finally, based on the support vector regression (SVR) algorithm, the target values of the NCCR were obtained with the KPIs as input, and the energy saving potential was evaluated by comparing the target values with the historical values of the NCCR. An actual on-duty 1000 MW unit was taken as study unit, and the results show that the energy saving potential is remarkable when the operators adjust the KPIs based on the calculated benchmark values.