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.     

Distinct Roles of Soluble and Transmembrane Adenylyl Cyclases in the Regulation of Flagellar Motility in Ciona Sperm

Adenylyl cyclase (AC) is a key enzyme that synthesizes cyclic AMP (cAMP) at the onset of the signaling pathway to activate sperm motility. Here, we showed that both transmembrane AC (tmAC) and soluble AC (sAC) are distinctly involved in the regulation of sperm motility in the ascidian Ciona intestinalis. A tmAC inhibitor blocked both cAMP synthesis and the activation of sperm motility induced by the egg factor sperm activating and attracting factor (SAAF), as well as those induced by theophylline, an inhibitor of phoshodiesterase. It also significantly inhibited cAMP-dependent phosphorylation of a set of proteins at motility activation. On the other hand, a sAC inhibitor does not affect on SAAF-induced transient increase of cAMP, motility activation or protein phosphorylation, but it reduced swimming velocity to half in theophylline-induced sperm. A sAC inhibitor KH-7 induced circular swimming trajectory with smaller diameter and significantly suppressed chemotaxis of sperm to SAAF. These results suggest that tmAC is involved in the basic mechanism for motility activation through cAMP-dependent protein phosphorylation, whereas sAC plays distinct roles in increase of flagellar beat frequency and in the Ca²⁺-dependent chemotactic movement of sperm.     

Decoding the Chemical Language of Motile Bacteria by Using High‐Throughput Microfluidic Assays

Motile bacteria navigate chemical environments by using chemoreceptors. The output of these protein sensors is linked to motility machinery and enables bacteria to follow chemical gradients. Understanding the chemical specificity of different families of chemoreceptors is essential for predicting and controlling bacterial behavior in ecological niches, including symbiotic and pathogenic interactions with plants and mammals. The identification of chemical(s) recognized by specific families of receptors is limited by the low throughput and complexity of chemotaxis assays. To address this challenge, we developed a microfluidic‐based chemotaxis assay that is quantitative, simple, and enables high‐throughput measurements of bacterial response to different chemicals. Using the model bacterium Escherichia coli, we demonstrated a strategy for identifying molecules that activate chemoreceptors from a diverse compound library and for determining how global behavioral strategies are tuned to chemical environments.     

基于改进粒子群算法的热工温度模型辨识

将细菌趋化、混沌搜索和模拟退火思想引入标准粒子群算法中,对比分析了细菌趋化粒子群算法、混沌模拟退火粒子群算法和模拟退火粒子群算法的辨识结果,探讨了改进算法的工程应用性问题,并将改进算法应用于单入单出的实验室锅炉温度和多入单出的超超临界锅炉主蒸汽温度模型的辨识中。辨识结果表明:细菌趋化粒子群算法可以很好地反映对象的动态特性,提高了辨识精度,缩短了辨识时间,改进了辨识效果。     

Bacterial communication systems: A mathematical formulation of negative chemotaxis

The emergence of molecular communication (MC) has provided a new paradigm for communication at nanoscale, besides the electromagnetic one. Numerous biological systems have been proposed that could be used for communication, using mostly bacteria as information carriers, ensuring biocompatibility and low complexity requirements. In this work, message dissemination dynamics in a bacterial communication system was under investigation by means of a simulation framework that was designed and developed based on a commercial tool. A mathematical formulation is proposed, in an effort to accurately predict the system's behavior under the presence of chemotactic‐like nodes. Simulation results are in strong agreement with the respective mathematical model, for a wide range of biological processes, including phenomena such as chemotaxis, bacterial growth cycle, and biological message transformation dynamics. In the case of a simple simulation scenario exhibiting chemotaxis, the mean accuracy improvement reaches values of up to 19% .     

基于细菌群体趋药性的有序盲信号分离算法

提出了一种基于细菌趋药性的细菌群优化算法。将探测判断策略和优势细菌随机扰动策略引入细菌群体的进化过程,解决了细菌个体在进化后期处于随机摄动状态而难以定位于全局最优位置的问题。通过使用测试函数对算法性能进行测试以及同其他算法的比较表明,所提出的算法在收敛速度和求解质量方面均有很好的性能。进一步将细菌群优化算法应用于解决盲信号分离问题,实现了对源信号的逐一有序盲分离。仿真实验表明,基于细菌群优化算法的盲信号分离算法具有很好的分离效果,可以将源信号按照其规范四阶累积量绝对值的降序进行有效分离。     

基于多阶段减排规划的发电厂碳捕集系统优化配置

根据二氧化碳减排规划的要求,并充分考虑目前二氧化碳捕集和封存（carbon capture and storage,CCS）技术发展的阶段性与不确定性,建立以阶段综合费用最小为目标函数的发电厂减排规划模型。引入技术成熟度因子,并考虑到发电厂运行参数未来的变化,将CCS技术的阶段性与不确定因素进行量化,依据技术进步率对碳捕集系统减排指标进行分解。采用离散细菌群体趋药性算法（discrete bacterial colony chemotaxis,DBCC）进行求解,通过对实际算例的方针分析,得到系统在不同减排场景下的碳捕集系统最优配置方案与碳捕集系统投资策略。最后通过灵敏度分析得到在不同减排场景下各因素对减排成本的影响。结果证明了所提模型以及优化算法的有效性和正确性。     

A mathematical model of adult subventricular neurogenesis

Neurogenesis has been the subject of active research in recent years and many authors have explored the phenomenology of the process, its regulation and its purported purpose. Recent developments in bioluminescent imaging (BLI) allow direct in vivo imaging of neurogenesis, and in order to interpret the experimental results, mathematical models are necessary. This study proposes such a mathematical model that describes adult mammalian neurogenesis occurring in the subventricular zone and the subsequent migration of cells through the rostral migratory stream to the olfactory bulb (OB). This model assumes that a single chemoattractant is responsible for cell migration, secreted both by the OB and in an endocrine fashion by the cells involved in neurogenesis. The solutions to the system of partial differential equations are compared with the physiological rodent process, as previously documented in the literature and quantified through the use of BLI, and a parameter space is described, the corresponding solution to which matches that of the rodent model. A sensitivity analysis shows that this parameter space is stable to perturbation and furthermore that the system as a whole is sloppy. A large number of parameter sets are stochastically generated, and it is found that parameter spaces corresponding to physiologically plausible solutions generally obey constraints similar to the conditions reported in vivo. This further corroborates the model and its underlying assumptions based on the current understanding of the investigated phenomenon. Concomitantly, this leaves room for further quantitative predictions pertinent to the design of future proposed experiments.     

Role of semiochemicals in mate location by parasitic sea louse,Lepeophtheirus salmonis

The role of olfaction and diffusible pheromones in mate location behavior of sea lice, Lepeophtheirus salmonis, was assessed with Y-tube behavioral bioassays. The pheromone emitting animals were located in a chamber in one arm of a Y-tube arena, with artificial seawater flowing through both arms. Adult male sea lice displayed both activation and directional responses to seawater conditioned with preadult II virgin females, but were only activated by mated adult female conditioned water. Further, when males were given the choice of preadult II virgin females or mated adult females, a significant number of males chose the arm with the preadult II virgin females. Adult males showed activation responses when presented with water conditioned with adult males but were not attracted to them. When presented with adult males, preadult II virgin females showed only directional responses, but not activation responses. Preadult II virgin female conditioned water was extracted using solid-phase extraction (SPE) protocols pioneered for semiochemical isolation. Adult male sea lice showed significant directional responses to the preadult II virgin female SPE extract. Distillation under vacuum was performed on the extract to give a distillate comprising components with a molecular weight range and physical properties comparable to those of compounds utilized as volatile semiochemicals by terrestrial organisms and a residue comprising components with higher molecular weight range comparable to those utilized as involatile semiochemicals. Adult males were found to be both significantly activated and attracted to the distillate, but not to the residue. This research provides evidence that small, lipophilic organic molecules are used by sea lice as sex pheromone signals to locate a member of the opposite sex.