Targeting S1PRs as a Therapeutic Strategy for Inflammatory Bone Loss Diseases—Beyond Regulating S1P Signaling

As G protein coupled receptors, sphingosine-1-phosphate receptors (S1PRs) have recently gained attention for their role in modulating inflammatory bone loss diseases. Notably, in murine studies inhibiting S1PR2 by its specific inhibitor, JTE013, alleviated osteoporosis induced by RANKL and attenuated periodontal alveolar bone loss induced by oral bacterial inflammation. Treatment with a multiple S1PRs modulator, FTY720, also suppressed ovariectomy-induced osteoporosis, collagen or adjuvant-induced arthritis, and apical periodontitis in mice. However, most previous studies and reviews have focused mainly on how S1PRs manipulate S1P signaling pathways, subsequently affecting various diseases. In this review, we summarize the underlying mechanisms associated with JTE013 and FTY720 in modulating inflammatory cytokine release, cell chemotaxis, and osteoclastogenesis, subsequently influencing inflammatory bone loss diseases. Studies from our group and from other labs indicate that S1PRs not only control S1P signaling, they also regulate signaling pathways induced by other stimuli, including bacteria, lipopolysaccharide (LPS), bile acid, receptor activator of nuclear factor κB ligand (RANKL), IL-6, and vitamin D. JTE013 and FTY720 alleviate inflammatory bone loss by decreasing the production of inflammatory cytokines and chemokines, reducing chemotaxis of inflammatory cells from blood circulation to bone and soft tissues, and suppressing RANKL-induced osteoclast formation.     

Ablative Radiotherapy Reprograms the Tumor Microenvironment of a Pancreatic Tumor in Favoring the Immune Checkpoint Blockade Therapy

The low overall survival rate of patients with pancreatic cancer has driven research to seek a new therapeutic protocol. Radiotherapy (RT) is frequently an option in the neoadjuvant or palliative settings for pancreatic cancer treatment. This study explored the effect of RT protocols on the tumor microenvironment (TME) and their consequent impact on anti-programmed cell death ligand-1 (PD-L1) therapy. Using a murine orthotopic pancreatic tumor model, UN-KC-6141, RT-disturbed TME was examined by immunohistochemical staining. The results showed that ablative RT is more effective than fractionated RT at recruiting T cells. On the other hand, fractionated RT induces more myeloid-derived suppressor cell infiltration than ablative RT. The RT-disturbed TME presents a higher perfusion rate per vessel. The increase in vessel perfusion is associated with a higher amount of anti-PD-L1 antibody being delivered to the tumor. Animal survival is increased by anti-PD-L1 therapy after ablative RT, with 67% of treated animals surviving more than 30 days after tumor inoculation compared to a median survival time of 16.5 days for the control group. Splenocytes isolated from surviving animals were specifically cytotoxic for UN-KC-6141 cells. We conclude that the ablative RT-induced TME is more suited than conventional RT-induced TME to combination therapy with immune checkpoint blockade.     

Enhanced electrochemical performance of LiNi0.8Co0.1Mn0.1O2 via titanium and boron co-doping

Titanium and boron are simultaneously introduced into LiNi_0.8Co_0.1Mn_0.1O₂ to improve the structural stability and electrochemical performance of the material. X-ray diffraction studies reveal that Ti⁴⁺ ion replaces Li⁺ ion and reduces the cation mixing; B³⁺ ion enters the tetrahedron of the transition metal layers and enlarges the distance of the [LiO₆] layers. The co-doped sample has spherical secondary particles with elongated and enlarged primary particles, in which Ti and B elements distribute uniformly. Electrochemical studies reveal the co-doped sample has improved rate performance (183.1 mAh·g^-1 at 1 C and 155.5 mAh·g^-1 at 10 C) and cycle stability (capacity retention of 94.7% after 100 cycles at 1 C). EIS and CV disclose that Ti and B co-doping reduces charge transfer impedance and suppresses phase change of LiNi_0.8Co_0.1Mn_0.1O_2.     

基于TRNSYS的茯砖茶生产工艺能源系统节能环保特性研究

茯砖茶发酵、干燥过程中，烘房内温湿度稳定性和能源系统低能耗是保证茯砖茶品质与成本的重要因素。本文采用TRNSYS仿真与实验研究相结合的方法，对咸阳某茯砖茶厂实际使用的空气源热泵系统进行建模，通过研究各季节典型代表月烘房温湿度的波动情况，确定该空气源热泵系统在全年的运行状态是否满足工艺要求，在此基础上，对比了该系统在全年可运行季节代表月与该生产厂房早期使用的燃气锅炉系统的能耗仿真结果，对空气源热泵系统的节能与环保特性进行研究。结果表明：由于夏季送风质量流量过大且室外空气含湿量较高，7月烘房温湿度不满足工艺要求。热泵系统在1、4、10月的总标煤消耗量的平均值是锅炉系统的44.42%，平均CO2、SO2、NOx排放量分别为锅炉系统的34.13%、44.1%、40.60%。在茯砖茶发酵、干燥的过程中，相比于燃气锅炉系统，空气源热泵系统具有更好的节能与环保特性。     

45 t门座起重机顶升方案设计

针对国内45 t门座起重机大车行走机构平衡梁裂缝问题。分析平衡梁裂缝产生原因并提出相应的维修方案,并对维修关键技术中的顶升方案设计,采用Ansys软件对其强度进行了有限元分析,同时对维修前后的平衡梁进行分析并对比。将维修方案应用于实际工程,取得了较好效果。该顶升机构修复方案设计符合工程实际,对工程实践具有一定的指导意义。     

国家治理的系统工程视角——民主与集中的张力

国家是一个开放的复杂巨系统,从系统工程视角探讨国家治理的一些学理问题。由统治到治理,国家治理体系如何保持民主与集中的张力是亟待解决的重要问题,意味着政府职能的重大转变及大众民主的深化与扩大。国家治理体系需要国家理论的指导,在回顾资产阶级国家理论及马克思主义国家理论的基础上,建议研究当代中国特色社会主义的国家理论,以回答国家治理实践中的诸多问题。"人民当家作主"应当是我国国家治理体系的最高价值目标,也是最根本的政治目标,有必要探讨这一目标的实现形式。在社会主义国家,官僚主义以及由此衍生的资产阶级法权是这一目标的最大障碍。基层社会治理应当是政府他组织与基层自组织的有机结合,是政府顶层设计、指导服务与基层组织承担责任的有机统一,以此实现社会良法善治。     

核电厂人因可靠性分析中的相关性分析方法研究

人因可靠性分析（HRA）是核电厂风险分析中的重要组成部分，其中人误事件的相关性分析是HRA中必不可少的内容，忽略人误事件间的相关性，将导致低估核电厂的风险水平。本文提出了一种基于D（邓）数和层次分析法-决策试行与评价实验室（AHP-DEMATEL）方法的相关性分析模型。首先，确定两事件间相关性的影响因素及其结构关系，并针对每个影响因素建立相关性等级的隶属度函数及其锚点；其次，利用AHP-DEMATEL方法来确定各影响因素的综合权重；最后，根据实际情况评估各因素的相关性等级并构建D数，并根据D数和综合权重计算出两人因事件的相关性程度及其可信度，通过算例验证了该模型及其方法的有效性。