Immune Checkpoint and Tumor Therapy

Cancer immunotherapy employing immune checkpoint inhibitors (ICI) has revolutionized the tumor therapy far beyond their impressing clinical effects. Immune checkpoint therapy (ICT), which is directly involved in different immunosuppressive mechanisms at tumor sites, has been thoroughly studied. Nevertheless, the “off-target” effects of ICIs following systemic administration is still challenging. In addition, the clinical response rate of ICT is still unsatisfactory in that only a few patients hold lasting benefits. In this chapter, the mechanism of most widely used ICIs, including those based on CTLA-4 and PD-1/PD-L1, has been introduced. The approaches to enhancing the efficacy of ICT have been highlighted, namely improving targeted delivery of ICI by employing nanotechnology, modulating the immunosuppressive tumor microenvironment (TME), and combining ICT with other therapies. We hope advanced strategies summarized in this chapter would further inspire the development of ICT to boost their effectiveness while minimize unwanted side effects

Identification of novel immune-related targets mediating disease progression in acute pancreatitis

IntroductionAcute pancreatitis (AP) is an inflammatory disease with very poor outcomes. However, the order of induction and coordinated interactions of systemic inflammatory response syndrome (SIRS) and compensatory anti-inflammatory response syndrome (CARS) and the potential mechanisms in AP are still unclear.MethodsAn integrative analysis was performed based on transcripts of blood from patients with different severity levels of AP (GSE194331), as well as impaired lung (GSE151572), liver (GSE151927) and pancreas (GSE65146) samples from an AP experimental model to identify inflammatory signals and immune response-associated susceptibility genes. An AP animal model was established in wild-type (WT) mice and Tlr2-deficient mice by repeated intraperitoneal injection of cerulein. Serum lipase and amylase, pancreas impairment and neutrophil infiltration were evaluated to assess the effects of Tlr2 in vivo.ResultsThe numbers of anti-inflammatory response-related cells, such as M2 macrophages (P = 3.2 × 10–3), were increased with worsening AP progression, while the numbers of pro-inflammatory response-related cells, such as neutrophils (P = 3.0 × 10–8), also increased. Then, 10 immune-related AP susceptibility genes (SOSC3, ITGAM, CAMP, FPR1, IL1R1, TLR2, S100A8/9, HK3 and MMP9) were identified. Finally, compared with WT mice, Tlr2-deficient mice exhibited not only significantly reduced serum lipase and amylase levels after cerulein induction but also alleviated pancreatic inflammation and neutrophil accumulation.DiscussionIn summary, we discovered SIRS and CARS were stimulated in parallel, not activated consecutively. In addition, among the novel susceptibility genes, TLR2might be a novel therapeutic target that mediates dysregulation of inflammatory responses during AP progression

Conformational Transition Pathway in the Inhibitor Binding Process of Human Monoacylglycerol Lipase

Human monoacylglycerol lipase (MGL) catalyzes the hydrolysis of 2-arachidonoylglycerol to arachidonic and glycerol, which plays a pivotal role in the normal biological processes of brain. Co-crystal structure of the MGL in complex with its inhibitor, compound 1, shows that the helix α4 undergoes large-scale conformational changes in response to the compound 1 binding compared to the apo MGL. However, the detailed conformational transition pathway of the helix α4 in the inhibitor binding process of MGL has remained unclear. Here, conventional molecular dynamics (MD) and nudged elastic band (NEB) simulations were performed to explore the conformational transition pathway of the helix α4. Conventional MD simulations unveiled that the compound 1 induced the closed conformation of the active site of MGL, reduced the conformational flexibility of the helix α4, and elicited the large-scale conformational rearrangement of the helix α4, leading to the complete folding of the helix α4. Moreover, NEB simulations revealed that the conformational transition pathway of helix α4 underwent an almost 180° counter-clockwise rotation of the helix α4. Our computational results advance the structural and mechanistic understanding of the inhibitory mechanism

Reducing energy consumption of heat pumps by introducing a thermal energy storage system

We proposed a short-term thermal energy storage system by applying Phase Change Materials (PCMs) in air ducts connected to an indoor air conditioning unit within a ceiling space. PCM tubes were arranged in a staggered layout in the air duct and cooled by chilled air from the air conditioning unit during “charging” mode, whereas the PCM tubes released cold energy to the room space without operation of the compressor during “discharging” mode. The charging mode allowed for an increase in the partial load ratio of the heat pump to prevent low-efficiency operation at <20% load, which can increase seasonal energy efficiency. We constructed an energy simulation program, where the heat exchange coefficient between the PCM tubes and air was varied with airflow rate and the temperature difference between the PCM and air, in accordance with results from CFD analysis. Switching between the charging and discharging modes was based on the outlet temperature (Tout) and 30% of the rated capacity of the indoor unit (Lr). The heat balance between the charging and discharging modes was improved by this change to the system control. A higher load factor and higher COP resulted in a 7.6% reduction in energy consumption

Effect of the pore length and orientation upon the electrochemical capacitive performance of ordered mesoporous carbons

By utilizing hard template method to adjust the mesopore length, and alkali activation to generate micro pores, two hierarchical porous carbons (HPCs) were prepared. With controlling of their mesopore length and the activation conditions, the complex system composed by HPCs and electrolyte was simplified and the effect of mesopore length on the performance of HPCs as electrodes in supercapacitors was investigated. It is found that with the mesopore length getting smaller, the ordered area gets smaller and the aggregation occurs, which is caused by the high surface energy of small grains. HPC with long pores (HPCL) exhibits a donut-like morphology with well-defined ordered mesopores and a regular orientation while in HPC with short pores (HPCS), short mesopores are only orderly distributed in small regions. Longer ordered channels form unobstructed ways for ions transport in the particles while shorter channels, only orderly distributed in small areas, results in blocked paths, which may hinder the electrolyte ions transport. Due to the unobstructed structure, HPCL exhibits good rate capability with a capacitance retention rate over 86% as current density increasing from 50 mA/g to 1000 mA/g. The specific capacitance of HPCL derived from the cyclic voltammetry test at 10 mV/s is up to 201.72 F/g, while the specific capacitance of HPCS is only 193.65 F/g. (C) 2016 Science Press and Dalian Institute of Chemical Physics, Chinese Academy of Sciences. Published by Elsevier B.V. and Science Press. All rights reserved

Effect of the pore length and orientation upon the electrochemical capacitive performance of ordered mesoporous carbons

By utilizing hard template method to adjust the mesopore length, and alkali activation to generate micropores, two hierarchical porous carbons (HPCs) were prepared. With controlling of their mesopore length and the activation conditions, the complex system composed by HPCs and electrolyte was simplified and the effect of mesopore length on the performance of HPCs as electrodes in supercapacitors was investigated. It is found that with the mesopore length getting smaller, the ordered area gets smaller and the aggregation occurs, which is caused by the high surface energy of small grains. HPC with long pores (HPCL) exhibits a donut-like morphology with well-defined ordered mesopores and a regular orientation while in HPC with short pores (HPCS), short mesopores are only orderly distributed in small regions. Longer ordered channels form unobstructed ways for ions transport in the particles while shorter channels, only orderly distributed in small areas, results in blocked paths, which may hinder the electrolyte ions transport. Due to the unobstructed structure, HPCL exhibits good rate capability with a capacitance retention rate over 86% as current density increasing from 50 mA mA mV F

Research on Continuous Error Compensation of a Sub-Arc-Second Macro/Micro Dual-Drive Rotary System

In this paper, a sub-arc-second macro/micro dual-drive rotary system is designed, and the continuous compensation of the system error and its experimental research are completed. First, the macro-drive system is driven by a direct-drive motor, and the micro-drive system uses a piezoelectric ceramic to drive the micro-drive rotary mechanism; the system uses a micro-drive system to compensate the motion error of the macro-drive system, and uses circular grating to feedback the displacement of the macro/micro total output turntable to form a macro/micro dual-drive closed-loop control system. Second, based on the establishment of the system error model, the design of the system’s continuous error compensation scheme is completed. Finally, the positioning accuracy testing of the system, direct error compensation of the macro-drive, manual error compensation of the macro-drive, error compensation performance of the micro-drive part and macro/micro compensation of the system are carried out in the study. The results show that the repeated positioning error and the positioning error of the system are reduced by 78.8% and 95.2%, respectively, after macro/micro compensation. The correctness and effectiveness of the designed system design, error compensation and control method are verified through performance tests, and its positioning accuracy is verified to the sub-arc-second (0.1 arcsecond) level. The research in this paper has important reference value for the development of ultra-precision macro/micro dual-drive technology

A Novel Control Strategy for DC-Link Voltage Balance and Reactive Power Equilibrium of a Single-Phase Cascaded H-Bridge Rectifier

The dc-link voltage balance and reactive power equilibrium of the cascaded H-bridge rectifier (CHBR) are the prerequisites for the safe and stable operation of the system. However, the conventional PI (Proportional-Integral) control strategy only puts emphasis on the CHBR dc-link voltage balance without taking into account its reactive power equilibrium under capacitive and inductive working conditions. For this reason, this paper has proposed a novel control strategy for the CHBR that can not only balance dc-link voltage, but also achieve reactive power equilibrium and eliminate the coupling effect between the voltage-balancing controller (VBC) and original system controller (OSC). The control strategy can achieve dc-link voltage balance and the reactive power equilibrium of the CHBR through modifying the active duty cycle by closed loop control, and adjusting the reactive duty cycle relatively according to the modifiable amount of the active duty cycle. Moreover, the strategy can eliminate the coupling effect between the VBC and OSC by the open loop control modification of the active and reactive duty cycle of any H-bridge module in CHBR. Simulations and experiments have shown that the proposed control strategy is feasible and effective in performing the CHBR dc-link voltage balance and reactive power equilibrium under all working conditions and load variations