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.     

Colossal dielectric response and relaxation behavior in novel system of Zr4+ and Nb5+ co-substituted CaCu3Ti4O12 ceramics

In this work, we developed a novel system of isovalent Zr⁴⁺ and donor Nb⁵⁺ co-doped CaCu₃Ti₄O₁₂ (CCTO) ceramics to enhance dielectric response. The influences of Zr⁴⁺ and Nb⁵⁺ co-substituting on the colossal dielectric response and relaxation behavior of the CCTO ceramics fabricated by a conventional solid-phase synthesis method were investigated methodically. Co-doping of Zr⁴⁺ and Nb⁵⁺ ions leads to a significant reduction in grain size for the CCTO ceramics sintered at 1060 °C for 10 h. XRD and Raman results of the CaCu₃Ti_3.8-xZr_xNb_0.2O₁₂ (CCTZNO) ceramics show a cubic perovskite structure with space group Im-3. The first principle calculation result exhibits a better thermodynamic stability of the CCTO structure co-doped with Zr⁴⁺ and Nb⁵⁺ ions than that of single-doped with Zr⁴⁺ or Nb⁵⁺ ion. Interestingly, the CCTZNO ceramics exhibit greatly improved dielectric constant (~10⁵) at a frequency range of 10²–10⁵ Hz and at a temperature range of 20–210 °C, indicating a giant dielectric response within broader frequency and temperature ranges. The dielectric properties of CCTZNO ceramics were analyzed from the viewpoints of defect-dipole effect and internal barrier layer capacitance (IBLC) model. Accordingly, the immensely enhanced dielectric response is primarily ascribed to the complex defect dipoles associated with oxygen vacancies by co-doping Zr⁴⁺ and Nb⁵⁺ ions into CCTO structure. In addition, the obvious dielectric relaxation behavior has been found in CCTZNO ceramics, and the relaxation process in middle frequency regions is attributed to the grain boundary response confirmed by complex impedance spectroscopy and electric modulus.     

浅渍法发酵豇豆的工艺优化

以具有降解亚硝酸盐功能的植物乳杆菌（Lactobacillus plantarum）SD-7和具有优良抗氧化能力的植物乳杆菌（Lactobacillus plantarum）FM-LP-9为复合发酵剂（1∶1），采用浅渍法发酵豇豆。以硬度和感官评分为考察指标，通过单因素试验及响应面试验研究复合发酵剂接种量、发酵温度和发酵时间对浅渍法发酵豇豆品质的影响。结果表明，最佳发酵工艺条件为发酵温度25 ℃，接种量5%，发酵时间125 h，在此优化条件下，得到的浅渍法发酵豇豆硬度为47.31 N，感官评分为90.98分，香气浓郁、口感脆嫩。     

High performance H2 sensor based on rGO-wrapped SnO2–Pd porous hollow spheres

Hydrogen (H₂) sensors based on metal oxide semiconductors (MOS) are promising for many applications such as a rocket propellant, industrial gas and the safety of storage. However, poor selectivity at low analyte concentrations, and independent response on high humidity limit the practical applications. Herein, we designed rGO-wrapped SnO₂–Pd porous hollow spheres composite (SnO₂–Pd@rGO) for high performance H₂ sensor. The porous hollow structure was from the carbon sphere template. The rGO wrapping was via self-assembly of GO on SnO₂-based spheres with subsequent thermal reduction in H₂ ambient. This sensor exhibited excellently selective H₂ sensing performances at 390 °C, linear response over a broad concentration range (0.1–1000 ppm) with recovery time of only 3 s, a high response of ～8 to 0.1 ppm H₂ in a minute, and acceptable stability under high humidity conditions (e. g. 80%). The calculated detection limit of 16.5 ppb opened up the possibility of trace H₂ monitoring. Furthermore, this sensor demonstrated certain response to H₂ at the minimum concentration of 50 ppm at 130 °C. These performances mainly benefited from the special hollow porous structure with abundant heterojunctions, the catalysis of the doped-PdO_x, the relative hydrophobic surface from rGO, and the deoxygenation after H₂ reduction.     

咖啡渣活性炭的制备、表征及其对Cr(Ⅵ)的吸附机制研究

以碘吸附值为评价指标，活化时间、活化温度和浸渍比为影响因素，采用响应面法试验设计对磷酸活化法制备咖啡渣活性炭的工艺条件进行优化，并通过静态吸附试验研究了不同吸附时间、溶液pH值和吸附温度条件下，活性炭对水溶液中Cr（Ⅵ）吸附性能的影响，最后利用Langmuir、Freundlich吸附等温方程、准一级动力学方程、准二级动力学方程和颗粒内部扩散方程进行拟合。试验结果表明，制备咖啡渣活性炭的最佳工艺条件为活化时间1 h、活化温度498℃、浸渍比1.72；在此条件下活性炭得率为30.4%，碘吸附值为（799±16）mg/g，比表面积为1 006 m²/g，孔容为0.779 cm³/g、微孔孔容为0.051 cm³/g、平均孔径为3.088 nm。较低pH值和较高温度能够促进活性炭对Cr（Ⅵ）的吸附；Langmuir等温方程能够更好地描述活性炭对Cr（Ⅵ）的吸附效果；活性炭对Cr（Ⅵ）的吸附分3个阶段：快速吸附阶段、慢速吸附阶段和吸附平衡阶段，10 min内可完成吸附总量的79%，360 min内达到吸附平衡，该吸附过程符合准二级吸附动力学方程。分析表明咖啡渣活性炭对Cr（Ⅵ）的吸附主要为单分子层的化学吸附。     

Development of a statistical model to classify driving stress levels using galvanic skin responses

Many studies have demonstrated the strong relationships between physiological responses and driving stress, but they have done little to build a model that could be used to identify a driver's stress accurately in real time. The objective of this study is to develop a model that accurately classifies driving stress by monitoring physiological responses—specifically galvanic skin response (GSR). GSR data were collected from nine drivers with licenses obtained in the US in real road driving situations with two stress conditions—rest period (low stress) and highway or city driving (high stress). The validation drive was performed by one driver with licenses obtained in South Korea in real long‐term road driving situations with two stress conditions—rural area (low stress) and highway or highway under construction (high stress). Those two conditions were used to build a binary logistic regression model to classify low stress or high stress based on a driver's measured hand GSR. The overall classification accuracy of the developed model was found to be 85.3%, and the accuracy of cross validation, with a testing dataset, was found to be 83.2%. A simple logit model was developed to identify drivers' stress by incorporating their GSR data. The developed model can be embedded in a wearable device equipped with GSR sensors for drivers to detect their stress level in real time.     

Hollow mesoporous silica nanoparticles as nanocarriers employed in cancer therapy: A review

Hollow mesoporous silica nanoparticles (HMSNs) have become an attractive drug carrier because of their unique characteristics including stable physicochemical properties, large specific surface area and facile functionalization, especially made into intelligent drug delivery systems (DDSs) for cancer therapy. HMSNs are employed to transport traditional anti-tumor drugs, which can solve the problems of drugs with instability, poor solubility and lack of recognition, etc., while significantly improving the anti-tumor effect. And an unexpected good result will be obtained by combining functional molecules and metal species with HMSNs for cancer diagnosis and treatment. Actually, HMSNs-based DDSs have developed relatively mature in recent years. This review briefly describes how to successfully prepare an ordinary HMSNs-based DDS, as well as its degradation, different stimuli-responses, targets and combination therapy. These versatile intelligent nanoparticles show great potential in clinical aspects.     

Neosporosis: An Overview of Its Molecular Epidemiology and Pathogenesis

Neospora caninum (N. caninum), a cyst-forming protozoan parasite, is a major cause of bovine abortions and neonatal mortality worldwide. N. caninum has a broad intermediate host range, and its sexual cycle occurs exclusively in canids. Another species of Neospora, Neospora hughesi (N. hughesi), has been identified and causes myeloencephalitis in horses. Although molecular epidemiology studies are in their infancy, the 18S ribosomal RNA (rRNA) and ITS1 regions within the small subunit ribosomal RNA (ssuRNA) and an N. caninum species-specific DNA probe (pNc5) have been used extensively to differentiate Neospora from other closely related apicomplexan parasites. While these repetitive regions have higher sensitivity and specificity than housekeeping or antigen genes, they suffer from low discriminatory power and fail to capture intra-species diversity. Similarly, although multiple minisatellite or microsatellite marker studies have shown clear geographic substructures within Neospora, strains are often misclassified due to a convergence in the size of different alleles at microsatellite loci, known as homoplasy. Only one strain, N. caninum Liverpool (Nc-Liv), has been genome sequenced and compared with its closest relative, Toxoplasma gondii (T. gondii). Hence, detailed population genomics studies based on whole-genome sequences from multiple strains worldwide are needed in order to better understand the current population genetic structure of Neospora, and ultimately to determine more effective vaccine candidates against bovine neosporosis. The aim of this review is to outline our current understanding of the molecular epidemiology and genomics of Neospora in juxtaposition with the closely related apicomplexan parasites Hammondia hammondi and T. gondii.     

Simulation and energy optimization of the stabilizer tower of a pyrolysis gasoline hydrogenation unit

Energy optimization of second distillation tower of a pyrolysis gasoline hydrogenation unit has been studied by the thermal cycle of vapor recompression method. The mentioned cycle is connected to the second distillation tower of the stabilizer of pyrolysis gasoline, and the results are found promising. The composite pinch curve for both the current and the optimized methods are shown. Moreover, an increase in the heat transfer rate in heat exchanger E-1014 causes energy recovery in reboiler. According to simulation results, by vapor recompression to 1970 kPa and using this heat source for thermal integration, condenser and reboiler’s energies are decreased by 56.93 and 30.4 percentage, respectively.     

Selection of risk response actions with consideration of secondary risks

Secondary risk in project risk management refers to the risk that arises as a direct result of implementing a risk response action (RRA). It is important for project managers (PMs) to consider the effects caused by the secondary risks in the process of RRA selection. The purpose of this paper is to propose an optimization method to address the problem of selecting risk response actions (RRAs) with consideration of secondary risk which is seldom considered in the existing studies. The optimization model aims to minimize the total risk costs with time constraint being placed on the project makespan. By solving the model, an optimal set of RRAs along with the earliest start time for each activity can both be obtained. The results show that secondary risk plays an important role in the process of RRA selection. Project managers should allocate more budget for responding the project risk when the secondary risk is considered, and consider all factors relating to both time and cost so as to select appropriate RRAs to mitigate primary risk and secondary risk.