Hierarchical Echo State Network With Sparse Learning: A Method for Multidimensional Chaotic Time Series Prediction.

Echo state network (ESN), a type of special recurrent neural network with a large-scale randomly fixed hidden layer (called a reservoir) and an adaptable linear output layer, has been widely employed in the field of time series analysis and modeling. However, when tackling the problem of multidimensional chaotic time series prediction, due to the randomly generated rules for input and reservoir weights, not only the representation of valuable variables is enriched but also redundant and irrelevant information is accumulated inevitably. To remove the redundant components, reduce the approximate collinearity among echo-state information, and improve the generalization and stability, a new method called hierarchical ESN with sparse learning (HESN-SL) is proposed. The HESN-SL mines and captures the latent evolution patterns hidden from the dynamic system by means of layer-by-layer processing in stacked reservoirs, and leverage monotone accelerated proximal gradient algorithm to train a sparse output layer with variable selection capability. Meanwhile, we further prove that the HESN-SL satisfies the echo state property, which guarantees the stability and convergence of the proposed model when applied to time series prediction. Experimental results on two synthetic chaotic systems and a real-world meteorological dataset illustrate the proposed HESN-SL outperforms both original ESN and existing hierarchical ESN-based models for multidimensional chaotic time series prediction.

Modified BBO-Based Multivariate Time-Series Prediction System With Feature Subset Selection and Model Parameter Optimization.

Multivariate time-series prediction is a challenging research topic in the field of time-series analysis and modeling, and is continually under research. The echo state network (ESN), a type of efficient recurrent neural network, has been widely used in time-series prediction, but when using ESN, two crucial problems have to be confronted: 1) how to select the optimal subset of input features and 2) how to set the suitable parameters of the model. To solve this problem, the modified biogeography-based optimization ESN (MBBO-ESN) system is proposed for system modeling and multivariate time-series prediction, which can simultaneously achieve feature subset selection and model parameter optimization. The proposed MBBO algorithm is an improved evolutionary algorithm based on biogeography-based optimization (BBO), which utilizes an S -type population migration rate model, a covariance matrix migration strategy, and a Lévy distribution mutation strategy to enhance the rotation invariance and exploration ability. Furthermore, the MBBO algorithm cannot only optimize the key parameters of the ESN model but also uses a hybrid-metric feature selection method to remove the redundancies and distinguish the importance of the input features. Compared with the traditional methods, the proposed MBBO-ESN system can discover the relationship between the input features and the model parameters automatically and make the prediction more accurate. The experimental results on the benchmark and real-world datasets demonstrate that MBBO outperforms the other traditional evolutionary algorithms, and the MBBO-ESN system is more competitive in multivariate time-series prediction than other classic machine-learning models.

Early CALP2 expression and microglial activation are potential inducers of spinal IL-6 up-regulation and bilateral pain following motor nerve injury.

Previous work from our laboratory showed that motor nerve injury by lumbar 5 ventral root transection (L5-VRT) led to interleukin-6 (IL-6) over-expression in bilateral spinal cord, and that intrathecal administration of IL-6 neutralizing antibody delayed the induction of mechanical allodynia in bilateral hind paws. However, early events and upstream mechanisms underlying spinal IL-6 expression following L5-VRT require elucidation. The model of L5-VRT was used to induce neuropathic pain, which was assessed with von Frey hairs and the plantar tester in adult male Sprague-Dawley rats. Calpain-2 (CALP2, a calcium-dependent protease) knockdown or over-expression and microglia depletion were conducted intrathecally. Western blots and immunohistochemistry were performed to explore the possible mechanisms. Here, we provide the first evidence that both IL-6 and CALP2 levels are increased in lumbar spinal cord within 30 min following L5-VRT. IL-6 and CALP2 co-localized in both spinal dorsal horn (SDH) and spinal ventral horn. Post-operative (PO) increase in CALP2 in ipsilateral SDH was evident at 10 min PO, preceding increased IL-6 at 20 min PO. Knockdown of spinal CALP2 by intrathecal CALP2-shRNA administration prevented VRT-induced IL-6 overproduction in ipsilateral spinal cord and alleviated bilateral mechanical allodynia. Spinal microglia activation also played a role in early IL-6 up-regulation. Macrophage/microglia markers ED1/Iba1 were increased at 30 min PO, while glial fibrillary acidic protein (astrocyte) and CNPase (oligodendrocyte) markers were not. Increased Iba1 was detected as early as 20 min PO and peaked at 3 days. Morphology changed from a small soma with fine processes in resting cells to an activated ameboid shape. Depletion of microglia using Mac-1-saporin partially prevented IL-6 up-regulation and attenuated VRT-induced bilateral mechanical allodynia. Taken together, our findings provide evidence that increased spinal cord CALP2 and microglia cell activation may have early causative roles in IL-6 over-expression following motor nerve injury. Agents that inhibit CALP2 and/or microglia activation may therefore prove valuable for treating neuropathic pain.

The indirect pathway of the nucleus accumbens shell amplifies neuropathic pain.

We examined adaptations in nucleus accumbens (NAc) neurons in mouse and rat peripheral nerve injury models of neuropathic pain. Injury selectively increased excitability of NAc shell indirect pathway spiny projection neurons (iSPNs) and altered their synaptic connectivity. Moreover, injury-induced tactile allodynia was reversed by inhibiting and exacerbated by exciting iSPNs, indicating that they not only participated in the central representation of pain, but gated activity in ascending nociceptive pathways.

Calpain-2 contributes to neuropathic pain following motor nerve injury via up-regulating interleukin-6 in DRG neurons.

Motor nerve injury by L5 ventral root transection (L5-VRT) initiates interleukin-6 (IL-6) up-regulation in primary afferent system contributing to neuropathic pain. However, the early upstream regulatory mechanisms of IL-6 after L5-VRT are still unknown. Here, we monitored both the activity of calpain, a calcium-dependent protease suggested as one of the earliest mediators for cytokine regulation, and the expression of IL-6 in bilateral L4-L6 dorsal root ganglias (DRGs) soon after L5-VRT. We found that the protein level of calpain-2 in DRGs, but not calpain-1 was increased transiently in the first 10 min(-1)h ipsilaterally and 20 min(-1)h contralaterally after L5-VRT, long before mechanical allodynia was initiated (5-15 h ipsilaterally and 15 h(-1)d contralaterally). The early activation of calpain evaluated by the generation of spectrin breakdown products (SBDP) correlated well with IL-6 up-regulation in bilateral DRGs. Double immunofluorescence staining revealed that almost all the calpain-2 positive neurons expressed IL-6, indicating an association between calpain-2 and IL-6. Inhibition of calpain by pre-treatment with MDL28170 (25mg/kg, i.p.) attenuated the rat mechanical allodynia and prevented the early up-regulation of IL-6 following L5-VRT. Addition of exogenous calpain-2 onto the surface of left L5 DRG triggered a temporal allodynia and increased IL-6 in bilateral DRGs simultaneously. Taken together, the early increase of calpain-2 in L5-VRT rats might be responsible for the induction of allodynia via up-regulating IL-6 in DRG neurons.

Upregulation of tumor necrosis factor-alpha in nucleus accumbens attenuates morphine-induced rewarding in a neuropathic pain model.

Treatment of neuropathic pain with opioid analgesics remains controversial and a major concern is the risk of addiction. Here, we investigated this issue with spared nerve injury (SNI) model of neuropathic pain in rats and mice. SNI prevented conditioned place preference (CPP) induced by low dose (3.5mg/kg) of morphine (MOR), which was effective for anti-allodynia, but not by high dose (⩾5.0 mg/kg) of MOR. Tumor necrosis factor-alpha (TNF-α) was upregulated in nucleus accumbens (NAcc) following SNI. The inhibitory effect of SNI on MOR-induced CPP was blocked by either genetic deletion of TNF receptor 1 (TNFR1) or microinjection of anti-TNF-α into the NAcc and was mimicked by intra-NAcc injection of TNF-α in sham rats. Furthermore, SNI reduced dopamine (DA) level and upregulated dopamine transporter (DAT) in the NAcc, but did not affect total tyrosine hydroxylase (TH) or phospho-TH (p-TH), a rate-limiting enzyme of catecholamine biosynthesis, in ventral tegmental area (VTA). Accordingly, the increase in DA reuptake but not decrease in its synthesis may lead to the reduction of DA level. Finally, the upregulation of DAT in the NAcc of SNI animals was again blocked by either genetic deletion of TNFR1 or NAcc injection of anti-TNF-α, and was mimicked by NAcc injection of TNF-α in sham animals. Thus, our data provided novel evidence that upregulation of TNF-α in NAcc may attenuate MOR-induced rewarding by upregulation of DAT in NAcc under neuropathic pain condition.

The up-regulation of IL-6 in DRG and spinal dorsal horn contributes to neuropathic pain following L5 ventral root transection.

Our previous works have shown that pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) plays an important role in neuropathic pain produced by lumber 5 ventral root transection (L5-VRT). In the present work we evaluate the role of interleukin-6 (IL-6), another key inflammatory cytokine, in the L5-VRT model. We found that IL-6 was up-regulated in the ipsilateral L4 and L5 dorsal root ganglian (DRG) neurons and in bilateral lumbar spinal cord following L5-VRT. Double immunofluorescence stainings revealed that in DRGs the increased immunoreactivity (IR) of IL-6 was almost restricted in neuronal cells, while in the spinal dorsal horn IL-6-IR up-regulated in both glial cells (astrocyte and microglia) and neurons. Intrathecal administration of IL-6 neutralizing antibody significantly delayed the induction of mechanical allodynia in bilateral hindpaws after L5-VRT. Furthermore, inhibition of TNF-α synthesis by intraperitoneal thalidomide prevented both mechanical allodynia and the up-regulation of IL-6 in DRGs following L5-VRT. These data suggested that the increased IL-6 in afferent neurons and spinal cord contribute to the development of neuropathic pain following motor fiber injury, and that TNF-α is responsible for the up-regulation of IL-6.

Activation of p38 signaling in the microglia in the nucleus accumbens contributes to the acquisition and maintenance of morphine-induced conditioned place preference.

Several lines of evidence have suggested that activated glia contributes to morphine-induced reward (conditioned place preference, CPP). Compared to well-defined roles of astrocyte in morphine CPP, the role of microglia in the nucleus accumbens (NAc) remains poorly characterized. The aim of the present study was to investigate the distinct role of microglia in morphine-induced CPP. Systemic administration of morphine (7.5 mg/kg for 5 days) induced significant preference for the morphine-paired compartment in rats, which lasted for at least 6 days after cessation of morphine treatment. Immunohistochemistry results showed that activation of p38 in the NAc microglia induced by chronic morphine treatment maintained on day 11. Bilateral intra-NAc injection of minocycline, a putative microglia inhibitor, or SB203580, an inhibitor of p38, prior to morphine administration not only inhibited p38 activation in the microglia but impaired the acquisition of CPP. On the day following the acquisition of morphine CPP, a single injection of minocycline or SB203580 failed to block the expression of CPP. Notably, pretreatment with minocycline or SB203580 for 5 days following the acquisition of morphine CPP significantly suppressed the activation of p38 and attenuated the maintenance of morphine CPP. Collectively, our present study indicates that the p38 signaling in the NAc microglia may play an important role in the acquisition and maintenance but not the expression of morphine CPP, and provides new evidence that microglia might be a potential target for the therapy of morphine addiction.

Impact of urbanization on natural ecosystem service values: a comparative study.

With rapid population growth and rural to-urban migration in many Chinese cities, a large amount of natural lands have been converted to urban and agricultural lands recently. During this process of land conversion, economic development and quality of life improvement are considered as major goals, and their influences on ecological systems have often been neglected. The degradation of natural ecological systems due to land use change, however, has become severe,and may require immediate attentions from urban planners and local governments. Taking HaDaQi industrial corridor, Heilongjiang Province, China,as a case study area, this paper examined the trend of land use changes during 1990­2005, and quantified their influences on natural eco system service values. In particular, this study applied two major valuation methods, and examined whether different valuation methods generate significantly different results. Analysis of results suggests that human dominated land uses (e.g., urban and agriculture)have expanded rapidly at the cost of natural lands (e.g., wetlands and forest). Due to these land use changes, the total ecosystem service value decreased 29% (2.26% annually) from 1990 to 2005 when the first method was applied, and this rate is estimated to be 15.7% (1.13% annually)with the second approach. Moreover, the annual rate of ecosystem service value decline during 2000­2005 is about four times higher than that in 1990­2000 with both methods, suggesting much more severe ecosystem degradation during 2000­2005.

[Role of bone marrow-derived mesenchymal stem cells in reduction of graft-versus-host disease by effecting CD4+CD25+ regulatory T cells in rats].

The study was purposed to investigate the effects and mechanism of bone marrow-derived mesenchymal stem cells (MSCs) on graft-versus-host desease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The model of GVHD in rat had been established by allo-HSCT with donor derived T cells. The occurence of GVHD in recipients was observed in condition with or without donor derived MSC co-transplantation. Effects of MSCs on GVHD were analyzed by model rat survival rate and pathology. Proportions of CD4+CD25+ regulatory T cells were determined by using label spleen lymphocytes and thymocytes with double fluorescent-labeled antibodies and flow cytometry. The results showed that MSCs inhibited the lethal GVHD after HSC co-transplantation and increased the survival rate. The ratio of CD4/CD8 deceased in GVHD group in different levels, as compared with that in the experimental group. The proportion of CD4+CD25+ regulatory T cells of spleen lymphocytes was 31.55 +/- 7.58% and 20.90 +/- 1.90% in experimental and GVHD groups, respectively. Similarly, the proportion of CD4+CD25+ regulatory T cells of thymocytes was 93.20 +/- 2.69% and 57.17 +/- 6.79% in experimental and the GVHD groups, respectively. Meanwhile the proportion of CD4+CD25+ regulatory T cells was higher in experimental group than that in GVHD group. It is concluded that MSCs may prevent the lethal GVHD after allo-HSC co-transplantation and raise the survival rate of model rats by acting on the CD4+CD25+ regulatory T cells in vivo.

[Analysis of the different effects of murine bone marrow endothelial cell conditioned medium on the growth of embryonic and adult hematopoietic stem/progenitor cells in vitro].

In the present study, the effects of murine bone marrow endothelial cell conditioned medium (mBMEC-CM) on the growth of yolk sac and bone marrow hematopoietic stem/progenitor cells (HSPC) were investigated. Nonadherent cells of yolk sac and bone marrow were collected for semisolid culture assay of CFU-GM and HPP-CFC after being cultured in DMEM with 10% FBS, 10% mBMEC-CM and/or FL (5 ng/ml), TPO (2 ng/ml) for 24 hours. The number of CFU-GM and HPP-CFC was counted by day 7 and 14 respectively. Atlas cDNA Expression Array was used for analysis of cytokine receptor expression of yolk sac and bone marrow HSPC. The results showed that mBMEC-CM could support the expansion of CFU-GM and HPP-CFC in liquid culture system. The expansion effects of mBMEC-CM were enhanced by combination with FL and TPO. mBMEC-CM was more effective on expansion of bone marrow CFU-GM and HPP-CFC than that of yolk sac CFU-GM and HPP-CFC. The differential expression of cytokine receptors were detected between yolk sac and bone marrow HSPC. PDGF-Rbeta, PDGF-Ralpha and corticotropin releasing factor receptor (CRFR) were only expressed in yolk sac hematopoietic cells while IFN-gammaR, GM-CSFR, Dopamine D2R and follicle-stimulating hormone receptor were only expressed in bone marrow hematopoietic cells. In conclusion, mBMEC-CM could support the growth and proliferation of yolk sac and bone marrow HSPC, and this effect was further enhanced by addition of FL and TPO. mBMEC-CM was more effective on expansion of bone marrow HSPC than on expansion of yolk sac HSPC. The comparative study indicated that the different expressions of cytokine receptors existed between yolk sac and bone marrow hematopoietic cells, which might lead to the difference in expansion in vitro between embryonic and adult HSPC.

[Effects of murine bone marrow endothelial cell conditioned medium on the growth of yolk sac hematopoietic stem cells and progenitors].

OBJECTIVE: To investigate the effects of murine bone marrow endothelial cell conditioned medium (mBMEC-CM) on the growth of yolk sac hematopoietic progenitors. METHODS: The serum-free mBMEC-CM was obtained from subcultures of murine endothelial cell line derived from bone marrow which was established in our laboratory. The murine yolk sacs were harvested on day 8.5 postcoitus (pc) and incubated with 0.1% collagenase in 10% fetal calf serum at 37 degrees C for 40 minutes. Yolk sac cells were incubated in tissue culture dishes at 37 degrees C for 1 hour. Nonadherent cells were collected for semisolid culture assay of granulocyte-macrophage colony forming unit (CFU-GM) and high proliferative potential-colony forming cell (HPP-CFC) after being cultured in DMEM with 10% mBMEC-CM and 10% FBS for 24 hours. The number of CFU-GM and HPP-CFC was counted at day 7 and day 14 respectively. RESULTS: The growth of CFU-GM and HPP-CFC was supported by mBMEC-CM with GM-CSF. mBMEC-CM could induce the proliferation and differentiation of yolk sac hematopoietic stem cells and progenitors in liquid culture system. The percentages of CFU-GM and HPP-CFC compared with the 0 hour control were (119.5 +/- 5.7)% and (130.8 +/- 9.8)% respectively after 24 hours liquid culture (P < 0.05). The expansion effects of mBMEC-CM on CFU-GM and HPP-CFC were enhanced by compounded with flt3 ligand (FL) and thrombopoietin (TPO). The percentages of CFU-GM and HPP-CFC compared with the 0 hour control were (132.0 +/- 6.2)% and (176.9 +/- 12.8)% respectively after 24 hours liquid culture (P < 0.01). CONCLUSION: Murine bone marrow endothelial cell conditioned medium could support the growth and proliferation of yolk sac hematopoitic stem cells and progenitors, and this promoting effect was further enhanced by addition of FL and TPO.

[Osteogenic differentiation of murine yolk sac mesenchymal stem cells in vitro].

OBJECTIVE: To investigate the potential of yolk sac mesenchymal stem cells in osteogenic differentiation. METHODS: Murine yolk sacs were harvested on day 8.5 postcoitus, yolk sac cells were obtained after the yolk sacs were digested by 0.1% type I collagenase for 1 hour, the non-adherent cells were removed after being cultured for 1 hour. The adherent cells were cultured in DMEM containing of 5 ng/ml bFGF and 15% FBS, and passaged when they became subconfluent. The morphologic characteristics, and AKP, BMP-2, as well as type I, III collagen of the yolk sac adherent cells were observed and tested. The attached cells were treated with 10(-8) mol/L dexamethasone, 10 mmol/L beta-glycerophosphate, and 50 micrograms/ml vitamin C at passage 4. Alternations of morphological characteristic, AKP activity, collagen of type I, III and mineralization were detected. RESULTS: Pure mesenchymal stem cells which were of spindle shape, uniform in size, positive in type I, III collagen staining and weak positive in AKP activity could be induced to pleomorphism osteoblast-like cells in vitro. The cells were transformed from spindle shape to polygonal cells which were positive in type I collagen, negative in type III collagen, strong positive in BMP-2, and positive in Von Kossa's stain at week 8. The polygonal cells could form nodular structure and their AKP activity was increased. All these were coincidence with the characters of osteoblast. CONCLUSION: Yolk sac mesenchymal stem cell can be purified and induced to osteoblast in vitro.