Inflammation and Stem Cell Therapy for Stroke

Ischemic stroke is a leading cause of death and disability worldwide. Currently, there is no treatment that can promote recovery in the chronic phase. It has been shown that neurogenesis occurs in ischemic striatum in rodents and probably also in humans. Moreover, blood-borne macrophages have been found to enhance spontaneous post- stroke recovery in mice. These findings have suggested potential new targets to improve functional restoration after stroke. In this thesis, we first showed that inflammation without neuronal loss is sufficient to trigger striatal neurogenesis comparable to that after stroke, indicating that inflammation might be the main inducer of post-stroke striatal neurogenesis. Using microarray on sorted microglia from subventricular zone (SVZ) and striatum, several factors were identified that potentially could regulate different steps of striatal neurogenesis after stroke. Some of the identified factors have previously been reported to regulate neural stem/progenitor cells (NSPC) proliferation or differentiation. We examined in some detail one factor, Cxcl13, and found that it promotes neuroblasts migration in vitro. Next, we provided evidence that monocyte-derived macrophages (MDM) can take the choroid plexus (CP)-cerebrospinal fluid (CSF) route for infiltration into the brain after cortical stroke. We found that in vitro-derived anti-inflammatory (M2-like) MDM delivered into CSF migrate into ischemic cortex, maintain their M2-like phenotype, and most importantly, improve recovery of motor and cognitive function in stroke-subjected mice without influencing infarct volume. These findings highlight the crucial role of inflammatory cells, such as microglia and macrophages, in post-stroke cellular plasticity and functional recovery. We also explored another approach for cell delivery into the brain using human induced pluripotent stem cells (iPSC)-derived long-term neuroepithelial-like stem (lt-NES) cells. Following our previous findings that transplantation of these cells and their derivatives promotes post-stroke motor function recovery, we showed that strokeinfluences the migration and axonal projection pattern of iPSC-derived lt-NES cells implanted adjacent to the neurogenic SVZ. These data indicate that the occurrence of ischemic injury strongly affects crucial parameters in the behavior of transplanted neural progenitors, which will be important to consider in a potential, future clinical translation. Finally, by combining immunoelectron microscopy, rabies virus-based trans-synaptic tracing, in vivo electrophysiological recordings and optogenetic techniques, we for the first time showed that neurons derived from transplanted iPSC-derived lt-NES cells receive functional synaptic inputs from host neurons located in the appropriate brain areas, e.g. ventral thalamus, after stroke. We demonstrated that tactile stimulation of nose and paws can activate or inhibit spontaneous activity in grafted neurons, providing evidence that they can become incorporated into injured cortical circuitry. Since we have found that transplanted M2-like MDM promote post-stroke recovery, possibly by modulating neuronal circuit plasticity, it seems highly warranted to examine whether delivery of M2-like MDM would further enhance the integration of neurons generated from grafted iPSC-derived lt-NES cells in the stroke model. Taken together, our findings raise the possibility that modulation of inflammatory mechanisms, delivery of M2-like MDM and transplantation of neurons generated from iPSC-derived lt-NES cells might become of value in future therapeutic approaches for improved functional recovery in stroke patients

Classification of four-class motor imagery employing single-channel electroencephalography.

With advances in brain-computer interface (BCI) research, a portable few- or single-channel BCI system has become necessary. Most recent BCI studies have demonstrated that the common spatial pattern (CSP) algorithm is a powerful tool in extracting features for multiple-class motor imagery. However, since the CSP algorithm requires multi-channel information, it is not suitable for a few- or single-channel system. In this study, we applied a short-time Fourier transform to decompose a single-channel electroencephalography signal into the time-frequency domain and construct multi-channel information. Using the reconstructed data, the CSP was combined with a support vector machine to obtain high classification accuracies from channels of both the sensorimotor and forehead areas. These results suggest that motor imagery can be detected with a single channel not only from the traditional sensorimotor area but also from the forehead area

Forecasting Real-Time Tourist Arrivals using Hierarchical Cluster and Gaussian Fitting Algorithm: A Case Study of Jiuzhai Valley

In the process of studying the number of tourist arrivals of each moment on every day, one of the key findings is a very good statistical regularity about tourist total arrivals. There exists high similarity among different scales of tourist arrivals, including the nearly same change trend. And on this basis this paper puts forward a new method of modeling and forecasting real-time tourist arrivals of each moment on every day. The forecasting process of the new proposed model is innovative. We consider the scales of tourist arrivals mainly, and model using hierarchical cluster and Gaussian fitting algorithm according to the different scales of tourist arrivals, thus predict real-time arrivals of the future a scale (the overall size of the known) through the existing scales. Finally take Jiuzhai Valley as an example to analysis, and experimental results show that the forecast method is effective

Best accuracy for different feature-extraction and classification methods.

<p>Since there are four classes of imagery movements, the chance level is 25.</p><p>AAR: adaptive autoregressive; MDA: minimum distance analysis; CAR: common average reference; CSP: common spatial pattern; NN: neural network; SVM: support vector machine; WPD: wavelet packet decomposition; ME: mixture of experts; PLV: phase-locking value; PCA: principal component analysis; STFT: short-time Fourier transform.</p

Position of EEG electrodes.

<p>Position of EEG electrodes.</p

Accuracy values at different m values for participants K3, K6 and L1. The mean accuracy value peaked at m = 7 for all three participants.

<p>Accuracy values at different m values for participants K3, K6 and L1. The mean accuracy value peaked at m = 7 for all three participants.</p

Accuracy values for different time ranges and electrodes for participants K3, K6 and L1.

<p>Accuracy values for different time ranges and electrodes for participants K3, K6 and L1.</p

Forecasting Real-Time Tourist Arrivals using Hierarchical Cluster and Gaussian Fitting Algorithm: A

one of the key findings is a very good statistical regularity about tourist total arrivals. There exists high similarity among different scales of tourist arrivals, including the nearly same change trend. And on this basis this paper puts forward a new method of modeling and forecasting real-time tourist arrivals of each moment on every day. The forecasting process of the new proposed model is innovative. We consider the scales of tourist arrivals mainly, and model using hierarchical cluster and Gaussian fitting algorithm according to the different scales of tourist arrivals, thus predict real-time arrivals of the future a scale (the overall size of the known) through the existing scales. Finally take Jiuzhai Valley as an example to analysis, and experimental results show that the forecast method is effective

Choroid plexus-cerebrospinal fluid route for monocyte-derived macrophages after stroke

Abstract Background Choroid plexus (CP) supports the entry of monocyte-derived macrophages (MDMs) to the central nervous system in animal models of traumatic brain injury, spinal cord injury, and Alzheimer’s disease. Whether the CP is involved in the recruitment of MDMs to the injured brain after ischemic stroke is unknown. Methods Adult male C57BL/6 mice were subjected to focal cortical ischemia by permanent occlusion of the distal branch of the right middle cerebral artery. Choroid plexus tissues were collected and analyzed for Vcam1, Madcam1, Cx3cl1, Ccl2, Nt5e, and Ifnγ expression at different timepoints after stroke using qPCR. Changes of MDMs in CP and cerebrospinal fluid (CSF) at 1 day and 3 days after stroke were analyzed using flow cytometry. Infiltration of MDMs into CP and CSF were validated using β-actin-GFP chimeric mice and Fgd5-CreERT2 x Lox-stop-lox-Tomato mice. CD115+ monocytes were isolated using a magnetic cell separation system from bone marrow of Cx3cr1-GFP or wild-type C57BL/6 donor mice. The freshly isolated monocytes or M2-like MDMs primed in vitro with IL4 and IL13 were stereotaxically injected into the lateral ventricle of stroke-affected mice to trace for their migration into ischemic hemisphere or to assess their effect on post-stroke recovery using open field, corridor, and active avoidance behavioral tests. Results We found that CP responded to cortical stroke by upregulation of gene expression for several possible mediators of MDM trafficking and, concomitantly, MDMs increased in CP and cerebrospinal fluid (CSF). We then confirmed that MDMs infiltrated from blood into CP and CSF after the insult using β-actin-GFP chimeric mice and Fgd5-CreERT2 x Lox-stop-lox-Tomato mice. When MDMs were directly administered into CSF following stroke, they homed to the ischemic hemisphere. If they had been primed in vitro prior to their administration to become M2-like macrophages, they promoted post-stroke recovery of motor and cognitive function without influencing infarct volume. Conclusions Our findings suggest the possibility that autologous transplantation of M2-like MDMs into CSF might be developed into a new strategy for promoting recovery also in patients with stroke