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.     

Effect of FTY720 and ICAM-1 mAb mono and combination therapy in cardiac allo-transplantation in rats

Objective To observe the effect of FTY720 and ICAM-1 mAb mono and combination therapy in cardiac silo-transplantation in rats. Methods Rats were randomly assigned to 9 groups, heart allo-transplantation were performed in abdominal site with micro-surgical technique. Recipients with allografts were treated with different doses of FTY720 and(or) ICAM-1 mAb. Graft survival, histopathology andlevel of serum IL-2, IFN-γ, IL-4, IL-10were investigated. Results Low doses of FTY720 (lmg/kg) combined with ICAM-1 mAb achieved synergistic effect in the prolongation of cardiac graft survival, combination index(CD =0.67. Conclusion Concomitant therapy of FTY720 and ICAM-1 mAb achieved a synergistic effect in the prolongation of heart allograft survival in rats.     

Surveillance and privacy – Beyond the panopticon. An exploration of 720-degree observation in level 3 and 4 vehicle automation

On the path to high-level vehicle automation, the degree of surveillance both inside and outside the car increases significantly. Consequently, ethical considerations are becoming central to questions around surveillance regimes and data privacy implicit in level 3 and 4 vehicle automation. In this paper, we focus on outputs from the EU Horizon 2020 project Vision Inspired Driver Assistance Systems (VI-DAS). In particular, we assess the VI-DAS 720-degree observation technology, critical to ensuring a safe Human Machine Interaction (HMI), from multiple theoretical perspectives to contribute to a better understanding of the phenomena of privacy. As a synonym for surveillance, we started our evaluation with Bentham's ideation of the panopticon. From there, it is a relatively short step to radical Foucauldian critiques that offered more dystopian technologies of power. However, both theorems demonstrate a limited understanding of the issue of data privacy in the context of safe transportation along the evolution of highly automated vehicles. Thus, to allow the debate to move beyond more binary discussions on privacy versus control/power and to a certain degree escape the shadow of the panopticon, we applied the Nissenbaum four theses framework of Contextual Integrity (CI). Her decision heuristic allowed us to introduce structure and a degree of precision in our thinking on the matter of privacy that represents a step forward to phenomena of privacy in a specific context. Our approach concludes that the VI-DAS 720-degree observation technology can respect the user's privacy through an appropriate flow of personal information. However, the flows of personal data must be strongly regulated to ensure that data is seen as a value in terms of a commodity to protect human life and not seen as an asset that needs to be turned into value in terms of capital or the facilitation of asymmetric power-relations.     

三峡输电工程用ACSR-720/50导线制造的几个关键技术的探讨

三峡输电工程龙泉至政平± 5 0 0 k V直流输电线路用 ACSR- 72 0 /5 0 (钢芯铝绞线 )导线是迄今为止我国最大截面的输电用导线。本文介绍了在制造该导线时的几项关键技术。     

晶粒尺寸对GH720Li镍基合金蠕变-疲劳寿命的影响

为探明晶粒尺寸对涡轮盘材料—GH720Li镍基高温合金的蠕变-疲劳寿命的影响机理,开展了650℃下不同晶粒尺寸的GH720Li高温合金圆棒蠕变-疲劳试验研究。GH720Li高温合金的蠕变-疲劳寿命随着晶粒尺寸的减小而降低。而后,通过断口的SEM分析研究晶粒尺寸对GH720Li高温合金的蠕变-疲劳损伤影响机制。其失效机制主要为晶界的氧化起裂,而晶界长度随晶粒尺寸变小而增加。最后,对基于迟滞能量的损伤方程和机械功密度2种方法进行了修正,GH720Li合金的蠕变-疲劳寿命预测与试验结果吻合较好,验证了方法的准确性。     

High temperature low cycle fatigue behaviour of UDIMET 720 Li superalloy

The low cycle fatigue behaviour of UDIMET 720 Li has been investigated at 700 °C in vacuum and air environments under strain control tests. Hold times (HTs) have been introduced at peak tensile strain in order to determine the effects of creep and fatigue interactions. The fatigue life of the alloy is practically independent of HT in both environments at high strain ranges while HT has beneficial effect at low strain ranges. The main factor that adversely affects the life of the alloy is oxidation, as the fatigue life is reduced in air compared to vacuum especially at high strain ranges. The increase in fatigue due to HT at lower strain ranges is attributed to stress relaxation. A life prediction model has shown that nucleation occurs after few cycles at high strain ranges whereas a large proportion of the fatigue life is consumed in the nucleation process at low strain ranges.     

GH720Li合金的铸态组织和均匀化工艺

对GH720Li合金的铸态组织及均匀化工艺进行了研究,采用物理化学相分析的方法确定了该合金析出相的类型、数量和γ′相的粒径分布。结果表明：该合金在铸造状态下的析出相是γ′、Ti(C,N)、TiC和M2B2(痕),其中γ′相的质量分数高达34．187％。均匀化的结果表明：GH720Li合金适宜的均匀化温度为1190℃。     

Anti-Inflammatory Treatment with FTY720 Starting after Onset of Symptoms Reverses Synaptic Deficits in an AD Mouse Model

Therapeutic approaches providing effective medication for Alzheimer’s disease (AD) patients after disease onset are urgently needed. Previous studies in AD mouse models suggested that physical exercise or changed lifestyle can delay AD-related synaptic and memory dysfunctions when treatment started in juvenile animals long before onset of disease symptoms, while a pharmacological treatment that can reverse synaptic and memory deficits in AD mice was thus far not identified. Repurposing food and drug administration (FDA)-approved drugs for treatment of AD is a promising way to reduce the time to bring such medication into clinical practice. The sphingosine-1 phosphate analog fingolimod (FTY720) was approved recently for treatment of multiple sclerosis patients. Here, we addressed whether fingolimod rescues AD-related synaptic deficits and memory dysfunction in an amyloid precursor protein/presenilin-1 (APP/PS1) AD mouse model when medication starts after onset of symptoms (at five months). Male mice received intraperitoneal injections of fingolimod for one to two months starting at five to six months. This treatment rescued spine density as well as long-term potentiation in hippocampal cornu ammonis-1 (CA1) pyramidal neurons, that were both impaired in untreated APP/PS1 animals at six to seven months of age. Immunohistochemical analysis with markers of microgliosis (ionized calcium-binding adapter molecule 1; Iba1) and astrogliosis (glial fibrillary acid protein; GFAP) revealed that our fingolimod treatment regime strongly down regulated neuroinflammation in the hippocampus and neocortex of this AD model. These effects were accompanied by a moderate reduction of Aβ accumulation in hippocampus and neocortex. Our results suggest that fingolimod, when applied after onset of disease symptoms in an APP/PS1 mouse model, rescues synaptic pathology that is believed to underlie memory deficits in AD mice, and that this beneficial effect is mediated via anti-neuroinflammatory actions of the drug on microglia and astrocytes.     

Effect of interstitial content on high- temperature fatigue crack propagation and low- cycle fatigue of alloy 720

Alloy 720 is a high-strength cast and wrought turbine disc alloy currently in use for temperatures up to about 650 °C in Allison’s T800, T406, GMA 2100, and GMA 3007 engines. In the original composition in-tended for use as turbine blades, large carbide and boride stringers formed and acted as preferred crack initiators. Stringering was attributed to relatively higher boron and carbon levels. These interstitials are known to affect creep and ductility of superalloys, but the effects on low-cycle fatigue and fatigue crack propagation have not been studied. Recent emphasis on the total life approach in the design of turbine discs necessitates better understanding of the interactive fatigue crack propagation and low-cycle fatigue behavior at high temperatures. The objective of this study was to improve the damage tolerance of Alloy 720 by systematically modifying boron and carbon levels in the master melt, without altering the low-cy-cle fatigue and strength characteristics of the original composition. Improvement in strain-controlled low-cycle fatigue life was achieved by fragmenting the continuous stringers via composition modifica-tion. The fatigue crack propagation rate was reduced by a concurrent reduction of both carbon and bo-ron levels to optimally low levels at which the frequency of brittle second phases was minimal. The changes in composition have been incorporated for production disc forgings.