RUFY4 deletion prevents pathological bone loss by blocking endo-lysosomal trafficking of osteoclasts

Mature osteoclasts degrade bone matrix by exocytosis of active proteases from secretory lysosomes through a ruffled border.However,the molecular mechanisms underlying lysosomal trafficking and secretion in osteoclasts remain largely unknown.Here,we show with GeneChip analysis that RUN and FYVE domain-containing protein 4(RUFY4)is strongly upregulated during osteoclastogenesis.Mice lacking Rufy4 exhibited a high trabecular bone mass phenotype with abnormalities in osteoclast function in vivo.Furthermore,deleting Rufy4 did not affect osteoclast differentiation,but inhibited bone-resorbing activity due to disruption in the acidic maturation of secondary lysosomes,their trafficking to the membrane,and their secretion of cathepsin K into the extracellular space.Mechanistically,RUFY4 promotes late endosome-lysosome fusion by acting as an adaptor protein between Rab7 on late endosomes and LAMP2 on primary lysosomes.Consequently,Rufy4-deficient mice were highly protected from lipopolysaccharide-and ovariectomy-induced bone loss.Thus,RUFY4 plays as a new regulator in osteoclast activity by mediating endo-lysosomal trafficking and have a potential to be specific target for therapies against bone-loss diseases such as osteoporosis.

“OCS”控制系统在原料药项目设计中的应用研究

针对目前原料药项目控制系统普遍存在的问题提出了一种新的“OCS”控制系统,通过对“OCS”控制系统基本原理的介绍,阐述了“OCS”控制系统较PLC系统及DCS系统的优势,并通过项目实例佐证了“OCS”控制系统的优越性。总之“OCS”控制系统主要通过组件iDTU和RJU的组合,将传输信号由传统的电信号转换成光信号,完美地解决了原料药项目控制系统设计中防爆、线缆过多等诸多难题。

应用OCS可编程控制器实现天然气计量核查

天然气计量现场需要对流量计算机进行计量核查,一次表流量计种类不同、组态参数配置复杂、受液晶显示窗口限制无法同步采集计量核查数据等问题制约了现场操作的可行性。本文研发了一种基于OCS可编程控制器的天然气计量网关,可针对不同厂家流量计算机的数据参数表,动态配置数据类型、从机地址、字节顺序、读写权限并映射到OCS的%R设备寄存器,解决了天然气计量核查数据预采集的难题;结合现场天然气介质组份、实时工况温度、实时工况压力值等数据,使用依据GB/T17747-2011《天然气压缩因子的计算》所研发的“天然气流量计算机压缩因子核查软件”,按流量计算机参数设置进行的计量核查;使用依据GB/T11062-2020《天然气发热量、密度、相对密度和沃泊指数的计算方法》所研发的“天然气流量能量计量核查软件”,进行天然气能量计量核查;针对天然气的现场计量核查,实现了硬件自动化采集预处理,软件自动化快速计算,有效提升了计量的工作效率和可靠性。

Transcriptional reprogramming during human osteoclast differentiation identifies regulators of osteoclast activity

Enhanced osteoclastogenesis and osteoclast activity contribute to the development of osteoporosis,which is characterized by increased bone resorption and inadequate bone formation.As novel antiosteoporotic therapeutics are needed,understanding the genetic regulation of human osteoclastogenesis could help identify potential treatment targets.This study aimed to provide an overview of transcriptional reprogramming during human osteoclast differentiation.Osteoclasts were differentiated from CD14+monocytes from eight female donors.RNA sequencing during differentiation revealed 8980 differentially expressed genes grouped into eight temporal patterns conserved across donors.These patterns revealed distinct molecular functions associated with postmenopausal osteoporosis susceptibility genes based on RNA from iliac crest biopsies and bone mineral density SNPs.Network analyses revealed mutual dependencies between temporal expression patterns and provided insight into subtype-specific transcriptional networks.The donor-specific expression patterns revealed genes at the monocyte stage,such as filamin B(FLNB)and oxidized low-density lipoprotein receptor 1(OLR1,encoding LOX-1),that are predictive of the resorptive activity of mature osteoclasts.The expression of differentially expressed G-protein coupled receptors was strong during osteoclast differentiation,and these receptors are associated with bone mineral density SNPs,suggesting that they play a pivotal role in osteoclast differentiation and activity.The regulatory effects of three differentially expressed G-protein coupled receptors were exemplified by in vitro pharmacological modulation of complement 5 A receptor 1(C5AR1),somatostatin receptor 2(SSTR2),and free fatty acid receptor 4(FFAR4/GPR120).Activating C5AR1 enhanced osteoclast formation,while activating SSTR2 decreased the resorptive activity of mature osteoclasts,and activating FFAR4 decreased both the number and resorptive activity of mature osteoclasts.In conclusion,we report the occurrence of transcriptional reprogramming during human osteoclast differentiation and identified SSTR2 and FFAR4 as antiresorptive G-protein coupled receptors and FLNB and LOX-1 as potential molecular markers of osteoclast activity.These data can help future investigations identify molecular regulators of osteoclast differentiation and activity and provide the basis for novel antiosteoporotic targets.

CD97 inhibits osteoclast differentiation via Rap1a/ERK pathway under compression

Acceleration of tooth movement during orthodontic treatment is challenging, with osteoclast-mediated bone resorption on the compressive side being the rate-limiting step. Recent studies have demonstrated that mechanoreceptors on the surface of monocytes/macrophages, especially adhesion G protein-coupled receptors (aGPCRs), play important roles in force sensing.However, its role in the regulation of osteoclast differentiation remains unclear. Herein, through single-cell analysis, we revealed that CD97, a novel mechanosensitive aGPCR, was expressed in macrophages. Compression upregulated CD97 expression and inhibited osteoclast differentiation;while knockdown of CD97 partially rescued osteoclast differentiation. It suggests that CD97 may be an important mechanosensitive receptor during osteoclast differentiation. RNA sequencing analysis showed that the Rap1a/ERK signalling pathway mediates the effects of CD97 on osteoclast differentiation under compression. Consistently, we clarified that administration of the Rap1a inhibitor GGTI298 increased osteoclast activity, thereby accelerating tooth movement. In conclusion,our results indicate that CD97 suppresses osteoclast differentiation through the Rap1a/ERK signalling pathway under orthodontic compressive force.

OCS在尿素装置中的应用

阐述了一种电子布线技术OCS在尿素装置中的应用,将电子布线技术与光网络技术相结合,搭建了现场仪表设备和远程分散控制系统的工控桥梁,并将电子布线技术与传统DCS技术进行了对比。结果显示:相比传统DCS技术,电子布线技术简化了回路结构,降低了投资成本。

基于深度学习的安顺电网调控OCS系统告警优化方法

为提升安顺电网调控OCS系统告警效果,研究提出了一种基于深度学习的安顺电网调控OCS系统告警优化方法。该方法先基于深度学习理论完成电网调控系统告警架构优化设计,然后基于LSTM模型完成电网调控OCS系统告警状态预测,最后以预测结果为基础,对其告警信号进行分类,完成电网调控OCS系统告警行为优化设计。实验结果表明,应用所提方法进行安顺电网调控OCS系统告警优化后,其告警准更高、响应时间更短,应用效果更好。

可重构OCS技术在大模型预训练中的应用(特邀)

【目的】相比于电子分组交换机(EPS),全光电路交换(OCS)在时延、功耗、成本和稳定性等各个方面都体现出了优势,文章通过分析大模型预训练中的并行切分策略、集合通信需求、流量模式和现今的网络架构,讨论了基于OCS在训练组网中的可行的应用方式,以在训练任务中充分利用OCS的优势。【方法】文章提出在故障快速恢复中采用多个小端口OCS进行网络设备冗余保护的机制,可在机顶(ToR)交换机故障时快速切换不中断训练任务。此外,文章还提出OCS只为数据并行(DP)服务,且仅在任务开始前进行配置。【结果】文章提出了多种可行的光电组网架构,以及在不同AllReduce算法下的具体配置,采用包括集合通信算法和架构设计联合优化的方式达到更优的带宽利用率。【结论】只要充分结合训练任务的流量模型,OCS可以很好地融入现有EPS网络架构,从成本、低功耗、低时延以及高稳定性等各方面对大模型预训练进行优化。

一种基于调度OCS系统的变电站N600接地线电流在线监测方法研发

变电站内如果发生保护用电压互感器二次回路多点接地则很容易导致距离保护和零序保护误动或者拒动,而电压互感器二次回路多点接地不易被发现。目前,继电保护用电压互感器的二次回路多点接地主要依靠运维人员按周期测量N600接地线电流大小来判断是否存在多点接地,现有方法不具备实时性,这将对电力电网的安全稳定运行造成一定的隐患。本文提出一种基于调度OCS系统的变电站N600接地线电流在线监测方法,解决了由于N600接地线电流人工测量周期过长导致电流值超标不能及时发现的情况,有效降低了电压互感器二次回路多点接地导致保护拒动、误动的风险,同时通过使用该方法就无须运维人员到变电站对N600一点接地线进行人工测量,提高了工作效率,降低了人工成本。

Effects of acupotomy on the activity of osteoclasts and osteoblasts in the subchondral bone of rabbits with early and mid-stage knee osteoarthritis models

Objective:To investigate whether acupotomy could inhibit subchondral bone remodeling in knee osteoarthritis(KOA)rabbits by regulating the activity of osteoblasts and osteoclasts.Methods:KOA rabbits were prepared by immobilization for 6 and 9 weeks by Videman method.Nine groups of rabbits(control,6 weeks and 9 weeks model,6 weeks and 9 weeks acupotomy,6 weeks and 9 weeks electroacupuncture,and 6 weeks and 9 weeks drug groups)received acupotomy,electroacupuncture and risedronate sodium intervention,respectively,for 3 weeks.Results:Acupotomy can inhibit the activity of osteoclasts and osteoblasts in subchondral bone by reducing the proteins expression of cathepsin K(CK)and tartrate-resistant acid phosphatase(TRAP)and decreasing the proteins expression of osteocalcin(OCN)and alkaline phosphatase(ALP),to intercept the abnormal bone resorption and bone formation of subchondral bone in 6-week and 9-week immobilization-induced KOA rabbits.Conclusion:These findings indicated that acupotomy may be more advantageous than risedronate sodium intervention in modulating subchondral bone remodeling in KOA rabbits,especially in 9-week immobilization-induced KOA rabbits.

血液高RDW和高N-MID OC/β-CTX比值在老年女性椎体骨折中的诊断价值

目的 探讨血液红细胞分布宽度(RDW)及骨钙素N段中分子片段(N-MID OC)/Ⅰ型胶原羧基端肽β特殊序列(β-CTX)比值联合检测对老年女性骨质疏松椎体骨折(OPVF)的诊断价值。方法 纳入2021年1月—2021年12月我院≥60岁女性骨质疏松住院患者786例,分为无骨折组(A组,378例)和OPVF组(B组,388例)。N-MID OC、β-CTX、NMID-OC/β-CTX比值、红细胞计数(RBC)、红细胞压积(HCT)、血红蛋白(Hb)、红细胞平均体积(MCV)、平均血红蛋白浓度(MCHC)、平均血红蛋白量(MCH)、红细胞分布宽度(RDW-CV)、钙(Ca)、磷(P)及镁(Mg)。结果 与A组相比,B组Ca、P、Hb、HCT、MCV、MCH、MCHC含量降低,RDW-CV、N-MID OC/β-CTX含量增加,差异有统计学意义(均P<0.05)。OPVF与β-CTX、Ca、P呈负相关,与RDW-CV、N-MID OC/β-CTX呈正相关(均P<0.05)。骨折患者RDW与N-MID OC、β-CTX、Ca、P、Mg呈负相关(均P<0.05)。RDW、N-MID-OC/β-CTX为OPVF的风险因素(均P<0.05),OR分别为1.38、1.005。二者含量越高,椎体骨折风险越高,最高层是最低层的约3倍和2倍,OR为2.818,1.734。二者联合检测可提高对OPVF的诊断性能,其AUC敏感性、特异性、阳性预示值、阴性预示值分别为0.64、42.78%、82.01%、70.9%、58.3%。结论 血液高RDW和高N-MID OC/β-CTX比值与老年女性骨质疏松性椎体骨折明显相关,是其危险因素,可用于辅助诊断及预测其发生。

A Simplified Method for Purifying Osteoclasts from Human Giant Cell Tumor of Bone

Objective: To purify and identify the osteoclasts from the tissue of humangiant cell tumor of bone. Methods: We have developed a new method that allows the purification oflarge numbers of authentic osteoclasts (OCs). The OCs were isolated from tissue of human giant celltumor of bone by 0.25% trypsin and collagenase. We characterized OCs in terms of the expression ofdifferent phenotypic markers of OCs. The phenotypic markers of OC included Tartrate-resistant acidphosphatase staining (TRAP). The expression of calcitonin receptor (CTR), cathepsin K and receptoractivator of necrosis factor κB (RANK) mRNA were examined by RT-PCR. Results: The OC cell purifiedby above method functioned normally in vitro. The purity was about 79.7%. They showed the normalosteoclast phenotypes markers of OC. Conclusion: The method provides a system for performingbiochemical and molecular studies of OCs. The study indicates that the method of purifying theosteoclasts from human GCT cell can be used for research of bone metabolism.

New insights into inflammatory osteoclast precursors as therapeutic targets for rheumatoid arthritis and periodontitis

Rheumatoid arthritis(RA)and periodontitis are chronic inflammatory diseases leading to increased bone resorption.Preventing this inflammatory bone resorption is a major health challenge.Both diseases share immunopathogenic similarities and a common inflammatory environment.The autoimmune response or periodontal infection stimulates certain immune actors,leading in both cases to chronic inflammation that perpetuates bone resorption.Moreover,RA and periodontitis have a strong epidemiological association that could be explained by periodontal microbial dysbiosis.This dysbiosis is believed to be involved in the initiation of RA via three mechanisms.(i)The dissemination of periodontal pathogens triggers systemic inflammation.(ii)Periodontal pathogens can induce the generation of citrullinated neoepitopes,leading to the generation of anti-citrullinated peptide autoantibodies.(iii)Intracellular danger-associated molecular patterns accelerate local and systemic inflammation.Therefore,periodontal dysbiosis could promote or sustain bone resorption in distant inflamed joints.Interestingly,in inflammatory conditions,the existence of osteoclasts distinct from“classical osteoclasts”has recently been reported.They have proinflammatory origins and functions.Several populations of osteoclast precursors have been described in RA,such as classical monocytes,a dendritic cell subtype,and arthritis-associated osteoclastogenic macrophages.The aim of this review is to synthesize knowledge on osteoclasts and their precursors in inflammatory conditions,especially in RA and periodontitis.Special attention will be given to recent data related to RA that could be of potential value in periodontitis due to the immunopathogenic similarities between the two diseases.Improving our understanding of these pathogenic mechanisms should lead to the identification of new therapeutic targets involved in the pathological inflammatory bone resorption associated with these diseases.

IgSF11-mediated phosphorylation of pyruvate kinase M2 regulates osteoclast differentiation and prevents pathological bone loss

Osteoclasts are primary bone-resorbing cells,and receptor-activated NF-k B ligand(RANKL)stimulation is the key driver of osteoclast differentiation.During late-stage differentiation,osteoclasts become multinucleated and enlarged(so-called“maturation”),suggesting their need to adapt to changing metabolic demands and a substantial increase in size.Here,we demonstrate that immunoglobulin superfamily 11(Ig SF11),which is required for osteoclast differentiation through an association with the postsynaptic scaffolding protein PSD-95,regulates osteoclast differentiation by controlling the activity of pyruvate kinase M isoform2(PKM2).By using a system that directly induces the activation of Ig SF11 in a controlled manner,we identified PKM2 as a major Ig SF11-induced tyrosine-phosphorylated protein.Ig SF11 activates multiple Src family tyrosine kinases(SFKs),including c-Src,Fyn,and Hc K,which phosphorylate PKM2 and thereby inhibit PKM2 activity.Consistently,Ig SF11-deficient cells show higher PKM2activity and defective osteoclast differentiation.Furthermore,inhibiting PKM2 activities with the specific inhibitor Shikonin rescues the impaired osteoclast differentiation in Ig SF11-deficient cells,and activating PKM2 with the specific activator TEPP46 suppresses osteoclast differentiation in wild-type cells.Moreover,PKM2 activation further suppresses osteoclastic bone loss without affecting bone formation in vivo.Taken together,these results show that Ig SF11 controls osteoclast differentiation through PKM2 activity,which is a metabolic switch necessary for optimal osteoclast maturation.

OCS系统权限管控提升的研究与应用

阐述了国际背景下网络攻击及内部人员恶意破坏事件对电网调度机构的警示。为深入贯彻落实国家对电力安全风险管控工作的总体部署,提出电网运行监控系统(以下简称OCS系统)权限管控提升研究的必要性。依托于某网级OCS系统,首先提出基于PCS9000可扩展因子服务框架及某网安全专业统一身份认证系统的双因子登录方案,接着提出一种全新的权限管控授权机制,对系统中账户的异常登录行为进行授权管控,并对系统运维中的关键操作采用多人授权、多次确认等方式进行管控。

Paracrine and endocrine actions of bone——the functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts

The skeleton is a dynamic organ that is constantly remodeled. Proteins secreted from bone cells, namely osteoblasts, osteocytes,and osteoclasts exert regulation on osteoblastogenesis, osteclastogenesis, and angiogenesis in a paracrine manner. Osteoblasts secrete a range of different molecules including RANKL/OPG, M-CSF, SEMA3A, WNT5A, and WNT16 that regulate osteoclastogenesis. Osteoblasts also produce VEGFA that stimulates osteoblastogenesis and angiogenesis. Osteocytes produce sclerostin（SOST） that inhibits osteoblast differentiation and promotes osteoclast differentiation. Osteoclasts secrete factors including BMP6, CTHRC1, EFNB2, S1P, WNT10B, SEMA4D, and CT-1 that act on osteoblasts and osteocytes, and thereby influencea A osteogenesis. Osteoclast precursors produce the angiogenic factor PDGF-BB to promote the formation of Type H vessels, which then stimulate osteoblastogenesis. Besides, the evidences over the past decades show that at least three hormones or ＂osteokines＂from bone cells have endocrine functions. FGF23 is produced by osteoblasts and osteocytes and can regulate phosphate metabolism. Osteocalcin（OCN） secreted by osteoblasts regulates systemic glucose and energy metabolism, reproduction, and cognition. Lipocalin-2（LCN2） is secreted by osteoblasts and can influence energy metabolism by suppressing appetite in the brain.We review the recent progresses in the paracrine and endocrine functions of the secretory proteins of osteoblasts, osteocytes, and osteoclasts, revealing connections of the skeleton with other tissues and providing added insights into the pathogenesis of degenerative diseases affecting multiple organs and the drug discovery process.

Osteoclasts:New Insights

Osteoclasts, the bone-resorbing cells, play a pivotal role in skeletal development and adult bone remodeling. They also participate in the pathogenesis of various bone disorders. Osteoclasts differentiate from cells of the monocyte/macrophage lineage upon stimulation of two essential factors, the monocyte/ macrophage colony stimulating factor （M-CSF） and receptor activation of NF-κB ligand （RANKL）. M-CSF binds to its receptor c-Fms to activate distinct signaling pathways to stimulate the proliferation and survival of osteoclast precursors and the mature cell. RANKL, however, is the primary osteoclast differentiation factor, and promotes osteoclast differentiation mainly through controlling gene expression by activating its receptor, RANK. Osteoclast function depends on polarization of the cell, induced by integrin avβ3, to form the resorptive machinery characterized by the attachment to the bone matrix and the formation of the bone-apposed ruffled border. Recent studies have provided new insights into the mechanism of osteoclast differentiation and bone resorption. In particular, c-Fms and RANK signaling have been shown to regulate bone resorption by cross-talking with those activated by integrin avβ3. This review discusses new advances in the understanding of the mechanisms of osteoclast differentiation and function.

OC渲染技术在C4D软件中的应用研究

随着计算机图形学的发展,渲染技术已经成为动画、电影、游戏等视觉艺术领域中的重要环节。在众多渲染技术中,OC(Octane Render)渲染技术以其高效、快速的性能在CINEMA 4D(简称C4D)软件中得到了广泛应用。随着云计算和虚拟现实技术的快速发展,OC渲染技术也将更多地应用于这些领域,为人们提供更加丰富、逼真的视觉体验。在文中对OC渲染技术在C4D软件中的应用进行了探讨。

Effect of Lanthanum(Ⅲ) on Cytosolic Free Calcium in Isolated Rabbit Mature Osteoclasts

The effect of lanthanum （ Ⅲ ） （La^3 ＋ ） on cytosolic free calcium （ [ Ca^2 ＋ ] i ） in isolated rabbit mature osteoclasts was studied with the employment of fluo-3/AM as an intracellular calcium-sensitive fluorescent probe by using a confocal laser scanning microscope. La^3＋ does not alter basal [Ca^2＋ ]i levels and cell spread area at the concentration of 1.00 × 10^- 8 mol· L ^- 1. However, La^3 ＋ at higher concentrations （ 1. 00 × 10^ - 5 and 1.00 × 10^- 7 mol· L^- 1 ） decreases [ Ca^2 ＋ ] i levels and cell spread area, and greater decreases are observed for the higher concentrations of La^3 ＋ . Since [Ca^2 ＋ ]i affects cytoskeleton and the adhesion properties of osteoclasts, our results seem to suggest that La^3 ＋ inhibit bone resorption by decreasing [Ca^2＋]i in rabbit mature osteoclasts.

银川市夏季VOCs污染特征及臭氧生成潜势分析

采用罐采样/气相色谱-氢离子火焰检测器/质谱检测器联用法对银川市2021年7-9月大气中116种VOCs进行手工监测,分析其污染特征、臭氧生成潜势和来源。结果表明:观测期间,银川市共检出81种VOCs,总挥发性有机物的平均体积浓度值为58.4×10-9,各主要组分浓度由大到小依次为:含氧挥发性有机物(OVOCs)(42.5%)、烷烃(32%)、卤代烃(7.7%)、芳香烃(6.8%)、烯烃(6.6%)。银川市主要非甲烷烃类体积浓度水平处于国内中等水平。加密观测期间,日变化规律呈双峰结构,高浓度主要出现在凌晨0:00-03:00和午后15:00-18:00,大气光化学反应二次生成对醛酮类有较大贡献,昼间醛酮类物质表现出与臭氧浓度一致的变化特征。臭氧生成潜势分析银川市夏季VOCs臭氧生成潜势为503.1μg/m3,其中醛酮类含氧VOCs(52.4%)和芳烃(19.1%)是主要贡献组分。利用示踪法和比值法推断,液化石油气(LPG)燃烧、机动车尾气和工业排放是非甲烷烃类的主要来源。