Niching particle swarm optimization based euclidean distance and hierarchical clustering for multimodal optimization

Abstract : Multimodal optimization is still one of the most challenging tasks in the evolutionary computation field, when multiple global and local optima need to be effectively and efficiently located. In this paper, a niching Particle Swarm Optimization (PSO) based Euclidean Distance and Hierarchical Clustering (EDHC) for multimodal optimization is proposed. This technique first uses the Euclidean distance based PSO algorithm to perform preliminarily search. In this phase, the particles are rapidly clustered around peaks. Secondly, hierarchical clustering is applied to identify and concentrate the particles distributed around each peak to finely search as a whole. Finally, a small world network topology is adopted in each niche to improve the exploitation ability of the algorithm. At the end of this paper, the proposed EDHC-PSO algorithm is applied to the Traveling Salesman Problems (TSP) after being discretized. The experiments demonstrate that the proposed method outperforms existing niching techniques on benchmark problems, and is effective for TSP

Dynamic small world network topology for particle swarm optimization

Abstract: A new particle optimization algorithm with dynamic topology is proposed based on a small world network. The technique imitates the dissemination of information in a small world network by dynamically updating the neighborhood topology of the particle swarm optimization(PSO). In comparison with other four classic topologies and two PSO algorithms based on small world network, the proposed dynamic neighborhood strategy is more eÆective in coordinating the exploration and exploitation ability of PSO. Simulations demonstrated that the convergence of the swarms is faster than its competitors. Meanwhile, the proposed method maintains population diversity and enhances the global search ability for a series of benchmark problems

Osteocyte-Driven Downregulation of Snail Restrains Effects of Drd2 Inhibitors on Mammary Tumor Cells

While bone is a frequent target of breast cancer-associated metastasis, little is known about the effects of tumor-bone interactions on the efficacy of tumor-suppressing agents. Here we examined the effect of two FDA-approved dopamine modulators, fluphenazine and trifluoperazine, on mammary tumor cells, osteoclasts, osteoblasts, and osteocytes. These agents suppressed proliferation and migration of mammary tumor cells chiefly by antagonizing dopamine receptor D2 and reduced bone resorption by downregulating nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1). Three-dimensional spheroid formation assays revealed that tumor cells have high affinity to osteocytes and type I collagen, and interactions with osteocytes as well as administration of fluphenazine and trifluoperazine downregulated Snail and suppressed migratory behaviors. Unlike the inhibitory action of fluphenazine and trifluoperazine on tumor growth, tumor-osteocyte interactions stimulated tumor proliferation by upregulating NFκB and Akt. In the bone microenvironment, osteocytes downregulated Snail and acted as an attractant as well as a stimulant to mammary tumor cells. These results demonstrate that tumor-osteocyte interactions strengthen dopamine receptor-mediated suppression of tumor migration but weaken its inhibition of tumor proliferation in the osteocyte-rich bone microenvironment.Significance: These findings provide novel insight into the cellular cross-talk in the bone microevironment and the effects of dopamine modulators on mammary tumor cells and osteocytes. Cancer Res; 78(14); 3865-76. ©2018 AACR

Salubrinal improves mechanical properties of the femur in osteogenesis imperfecta mic

Salubrinal is an agent that reduces the stress to the endoplasmic reticulum by inhibiting de-phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). We and others have previously shown that the elevated phosphorylation of eIF2α stimulates bone formation and attenuates bone resorption. In this study, we applied salubrinal to a mouse model of osteogenesis imperfecta (Oim), and examined whether it would improve Oim's mechanical property. We conducted in vitro experiments using RAW264.7 pre-osteoclasts and bone marrow derived cells (BMDCs), and performed in vivo administration of salubrinal to Oim (+/−) mice. The animal study included two control groups (wildtype and Oim placebo). The result revealed that salubrinal decreased expression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1) and suppressed osteoclast maturation, and it stimulated mineralization of mesenchymal stem cells from BMDCs. Furthermore, daily injection of salubrinal at 2 mg/kg for 2 months made stiffness (N/mm) and elastic module (GPa) of the femur undistinguishable to those of the wildtype control. Collectively, this study supported salubrinal's beneficial role to Oim's femora. Unlike bisphosphonates, salubrinal stimulates bone formation. For juvenile OI patients who may favor strengthening bone without inactivating bone remodeling, salubrinal may present a novel therapeutic option

Finite Element Analysis of the Mouse Distal Femur with Tumor Burden in Response to Knee Loading

Breast cancer-associated bone metastasis induces bone loss, followed by an increased risk of bone fracture. To develop a strategy for preventing tumor growth and protecting bone, an understanding of the mechanical properties of bone under tumor burden is indispensable. Using a mouse model of mammary tumor, we conducted finite element analysis (FEA) of two bone samples from the distal femur. One sample was from a placebo-treated mouse, and the other was from a mouse treated with the investigational drug candidate, PD407824, an inhibitor of checkpoint kinases. Mechanical testing and microCT images revealed that bone strength is improved by administration of PD407824. In response to loading to the knee, FEA predicted that the peaks of von Mises stress, an indicator of fracture yielding, as well as the third principal compressive stress, were higher in the placebo-treated femur than the drug-treated femur. Higher peak stresses in trabecular segments were observed in the lateral condyle, a critical region for integrity of the knee joint. Collectively, this FE study supports the notion that mechanical weakening of the femur was observed in the tumor-invaded trabecular bone, and chemical agents such as PD407824 may potentially assist in preventing bone loss and bone fracture

Guanabenz Downregulates Inflammatory Responses via eIF2α Dependent and Independent Signaling

Integrated stress responses (ISR) may lead to cell death and tissue degeneration via eukaryotic translation initiation factor 2 α (eIF2α)-mediated signaling. Alleviating ISR by modulating eIF2α phosphorylation can reduce the symptoms associated with various diseases. Guanabenz is known to elevate the phosphorylation level of eIF2α and reduce pro-inflammatory responses. However, the mechanism of its action is not well understood. In this study, we investigated the signaling pathway through which guanabenz induces anti-inflammatory effects in immune cells, in particular macrophages. Genome-wide mRNA profiling followed by principal component analysis predicted that colony stimulating factor 2 (Csf2, or GM-CSF as granulocyte macrophage colony stimulating factor) is involved in the responses to guanabenz. A partial silencing of Csf2 or eIF2α by RNA interference revealed that Interleukin-6 (IL6), Csf2, and Cyclooxygenase-2 (Cox2) are downregulated by guanabenz-driven phosphorylation of eIF2α. Although expression of IL1β and Tumor Necrosis Factor-α (TNFα) was suppressed by guanabenz, their downregulation was not directly mediated by eIF2α signaling. Collectively, the result herein indicates that anti-inflammatory effects by guanabenz are mediated by not only eIF2α-dependent but also eIF2α-independent signaling

Analysis of Vegetation Vulnerability Dynamics and Driving Forces to Multiple Drought Stresses in a Changing Environment

Quantifying changes in the vulnerability of vegetation to various drought stresses in different seasons is important for rational and effective ecological conservation and restoration. However, the vulnerability of vegetation and its dynamics in a changing environment are still unknown, and quantitative attribution analysis of vulnerability changes has been rarely studied. To this end, this study explored the changes of vegetation vulnerability characteristics under various drought stresses in Xinjiang and conducted quantitative attribution analysis using the random forest method. In addition, the effects of ecological water transport and increased irrigation areas on vegetation vulnerability dynamics were examined. The standardized precipitation index (SPI), standardized precipitation-evapotranspiration index (SPEI), and standardized soil moisture index (SSMI) represent atmospheric water supply stress, water and heat supply stress, and soil water supply stress, respectively. The results showed that: (1) different vegetation types responded differently to water stress, with grasslands being more sensitive than forests and croplands in summer; (2) increased vegetation vulnerability under drought stresses dominated in Xinjiang after 2003, with vegetation growth and near-surface temperature being the main drivers, while increased soil moisture in the root zone was the main driver of decreased vegetation vulnerability; (3) vulnerability of cropland to SPI/SPEI/SSMI-related water stress increased due to the rapid expansion of irrigation areas, which led to increasing water demand in autumn that was difficult to meet; and (4) after ecological water transport of the Tarim River Basin, the vulnerability of its downstream vegetation to drought was reduced

Effects of a checkpoint kinase inhibitor, AZD7762, on tumor suppression and bone remodeling

Chemotherapy for suppressing tumor growth and metastasis tends to induce various effects on other organs. Using AZD7762, an inhibitor of checkpoint kinase (Chk) 1 and 2, the present study examined its effect on mammary tumor cells in addition to bone cells (osteoclasts, osteoblasts and osteocytes), using monolayer cell cultures and three-dimensional (3D) cell spheroids. The results revealed that AZD7762 blocked the proliferation of 4T1.2 mammary tumor cells and suppressed the development of RAW264.7 pre-osteoclast cells by downregulating nuclear factor of activated T cells cytoplasmic 1. AZD7762 also promoted the mineralization of MC3T3 osteoblast-like cells and 3D bio-printed bone constructs of MLO-A5 osteocyte spheroids. While a Chk1 inhibitor, PD407824, suppressed the proliferation of tumor cells and the differentiation of pre-osteoclasts, its effect on gene expression in osteoblasts was markedly different compared with AZD7762. Western blotting indicated that the stimulating effect of AZD7762 on osteoblast development was associated with the inhibition of Chk2 and the downregulation of cellular tumor antigen p53. The results of the present study indicated that in addition to acting as a tumor suppressor, AZD7762 may prevent bone loss by inhibiting osteoclastogenesis and stimulating osteoblast mineralization