Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)...Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)have shown potential for brain injury repair in central nervous system diseases.In this study,we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism.Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits,enhanced blood-brain barrier integrity,and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage.Additionally,hiPSC-NSC-Exos decreased immune cell infiltration,activated astrocytes,and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1,macrophage inflammatory protein-1α,and tumor necrosis factor-αpost-intracerebral hemorrhage,thereby improving the inflammatory microenvironment.RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion,thereby improving blood-brain barrier integrity.Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects.In summary,our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity,in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.展开更多
Some studies have confirmed the neuroprotective effect of remote ischemic conditioning against stroke. Although numerous animal researches have shown that the neuroprotective effect of remote ischemic conditioning may...Some studies have confirmed the neuroprotective effect of remote ischemic conditioning against stroke. Although numerous animal researches have shown that the neuroprotective effect of remote ischemic conditioning may be related to neuroinflammation, cellular immunity, apoptosis, and autophagy, the exact underlying molecular mechanisms are unclear. This review summarizes the current status of different types of remote ischemic conditioning methods in animal and clinical studies and analyzes their commonalities and differences in neuroprotective mechanisms and signaling pathways. Remote ischemic conditioning has emerged as a potential therapeutic approach for improving stroke-induced brain injury owing to its simplicity, non-invasiveness, safety, and patient tolerability. Different forms of remote ischemic conditioning exhibit distinct intervention patterns, timing, and application range. Mechanistically, remote ischemic conditioning can exert neuroprotective effects by activating the Notch1/phosphatidylinositol 3-kinase/Akt signaling pathway, improving cerebral perfusion, suppressing neuroinflammation, inhibiting cell apoptosis, activating autophagy, and promoting neural regeneration. While remote ischemic conditioning has shown potential in improving stroke outcomes, its full clinical translation has not yet been achieved.展开更多
Human neural stem cell-derived extracellular vesicles exhibit analogous functions to their parental cells,and can thus be used as substitutes for stem cells in stem cell therapy,thereby mitigating the risks of stem ce...Human neural stem cell-derived extracellular vesicles exhibit analogous functions to their parental cells,and can thus be used as substitutes for stem cells in stem cell therapy,thereby mitigating the risks of stem cell therapy and advancing the frontiers of stem cell-derived treatments.This lays a foundation for the development of potentially potent new treatment modalities for ischemic stroke.However,the precise mechanisms underlying the efficacy and safety of human neural stem cell-derived extracellular vesicles remain unclear,presenting challenges for clinical translation.To promote the translation of therapy based on human neural stem cell-derived extracellular vesicles from the bench to the bedside,we conducted a comprehensive preclinical study to evaluate the efficacy and safety of human neural stem cell-derived extracellular vesicles in the treatment of ischemic stroke.We found that administration of human neural stem cell-derived extracellular vesicles to an ischemic stroke rat model reduced the volume of cerebral infarction and promoted functional recovery by alleviating neuronal apoptosis.The human neural stem cell-derived extracellular vesicles reduced neuronal apoptosis by enhancing phosphorylation of phosphoinositide 3-kinase,mammalian target of rapamycin,and protein kinase B,and these effects were reversed by treatment with a phosphoinositide 3-kinase inhibitor.These findings suggest that human neural stem cell-derived extracellular vesicles play a neuroprotective role in ischemic stroke through activation of phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway.Finally,we showed that human neural stem cell-derived extracellular vesicles have a good in vivo safety profile.Therefore,human neural stem cell-derived extracellular vesicles are a promising potential agent for the treatment of ischemic stroke.展开更多
离群点检测任务是指检测与正常数据在特征属性上存在显著差异的异常数据。大多数基于聚类的离群点检测方法主要从全局角度对数据集中的离群点进行检测,而对局部离群点的检测性能较弱。基于此,本文通过引入快速搜索和发现密度峰值方法改...离群点检测任务是指检测与正常数据在特征属性上存在显著差异的异常数据。大多数基于聚类的离群点检测方法主要从全局角度对数据集中的离群点进行检测,而对局部离群点的检测性能较弱。基于此,本文通过引入快速搜索和发现密度峰值方法改进K-means聚类算法,提出了一种名为KLOD(local outlier detection based on improved K-means and least-squares methods)的局部离群点检测方法,以实现对局部离群点的精确检测。首先,利用快速搜索和发现密度峰值方法计算数据点的局部密度和相对距离,并将二者相乘得到γ值。其次,将γ值降序排序,利用肘部法则选择γ值最大的k个数据点作为K-means聚类算法的初始聚类中心。然后,通过K-means聚类算法将数据集聚类成k个簇,计算数据点在每个维度上的目标函数值并进行升序排列。接着,确定数据点的每个维度的离散程度并选择适当的拟合函数和拟合点,通过最小二乘法对升序排列的每个簇的每1维目标函数值进行函数拟合并求导,以获取变化率。最后,结合信息熵,将每个数据点的每个维度目标函数值乘以相应的变化率进行加权,得到最终的异常得分,并将异常值得分较高的top-n个数据点视为离群点。通过人工数据集和UCI数据集,对KLOD、LOF和KNN方法在准确度上进行仿真实验对比。结果表明KLOD方法相较于KNN和LOF方法具有更高的准确度。本文提出的KLOD方法能够有效改善K-means聚类算法的聚类效果,并且在局部离群点检测方面具有较好的精度和性能。展开更多
为了充分利用实际高速公路路段交通拥堵信息,更合理地聚类交通拥堵的内在规律和特征变化,提出自适应确定聚类中心C和类别K值(adaptive center and K-means value,ACK-Means)的聚类算法,进行高速公路拥堵路段聚类。ACK-Means算法借助簇...为了充分利用实际高速公路路段交通拥堵信息,更合理地聚类交通拥堵的内在规律和特征变化,提出自适应确定聚类中心C和类别K值(adaptive center and K-means value,ACK-Means)的聚类算法,进行高速公路拥堵路段聚类。ACK-Means算法借助簇类密度、簇类间距以及簇类强度,同时又考虑到数据样本的偶然性,对离群点进行合理分配,ACK-Means算法可实现自适应确定聚类中心C和类别K值。基于实际交通拥堵信息构建数据集,Python编程实现高速公路拥堵路段ACK-Means聚类,巧妙解决了高速公路拥堵路段聚类数目K和聚类中心C设定问题。聚类结果表明,ACK-Means算法实现高速公路拥堵路段无监督聚类,聚类结果完全基于实际的高速公路交通拥堵信息,具有更高的实用性。展开更多
基金supported by the National Natural Science Foundation of China,No.8227050826(to PL)Tianjin Science and Technology Bureau Foundation,No.20201194(to PL)Tianjin Graduate Research and Innovation Project,No.2022BKY174(to CW).
文摘Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)have shown potential for brain injury repair in central nervous system diseases.In this study,we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism.Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits,enhanced blood-brain barrier integrity,and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage.Additionally,hiPSC-NSC-Exos decreased immune cell infiltration,activated astrocytes,and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1,macrophage inflammatory protein-1α,and tumor necrosis factor-αpost-intracerebral hemorrhage,thereby improving the inflammatory microenvironment.RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion,thereby improving blood-brain barrier integrity.Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects.In summary,our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity,in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.
基金supported partly by the National Natural Science Foundation of China,No.82071332the Chongqing Natural Science Foundation Joint Fund for Innovation and Development,No.CSTB2023NSCQ-LZX0041 (both to ZG)。
文摘Some studies have confirmed the neuroprotective effect of remote ischemic conditioning against stroke. Although numerous animal researches have shown that the neuroprotective effect of remote ischemic conditioning may be related to neuroinflammation, cellular immunity, apoptosis, and autophagy, the exact underlying molecular mechanisms are unclear. This review summarizes the current status of different types of remote ischemic conditioning methods in animal and clinical studies and analyzes their commonalities and differences in neuroprotective mechanisms and signaling pathways. Remote ischemic conditioning has emerged as a potential therapeutic approach for improving stroke-induced brain injury owing to its simplicity, non-invasiveness, safety, and patient tolerability. Different forms of remote ischemic conditioning exhibit distinct intervention patterns, timing, and application range. Mechanistically, remote ischemic conditioning can exert neuroprotective effects by activating the Notch1/phosphatidylinositol 3-kinase/Akt signaling pathway, improving cerebral perfusion, suppressing neuroinflammation, inhibiting cell apoptosis, activating autophagy, and promoting neural regeneration. While remote ischemic conditioning has shown potential in improving stroke outcomes, its full clinical translation has not yet been achieved.
基金supported by the National Nature Science Foundation of China,No.81471308(to JL)the Innovative Leading Talents of Liaoning Province,No.XLYC1902031(to JL)+2 种基金Science and Technology Projects in Liaoning Province,No.2022-BS-238(to CH)Young Top Talents of Liaoning Province,No.XLYC1907009(to LW)Dalian Science and Technology Innovation Fund,No.2018J11CY025(to JL)。
文摘Human neural stem cell-derived extracellular vesicles exhibit analogous functions to their parental cells,and can thus be used as substitutes for stem cells in stem cell therapy,thereby mitigating the risks of stem cell therapy and advancing the frontiers of stem cell-derived treatments.This lays a foundation for the development of potentially potent new treatment modalities for ischemic stroke.However,the precise mechanisms underlying the efficacy and safety of human neural stem cell-derived extracellular vesicles remain unclear,presenting challenges for clinical translation.To promote the translation of therapy based on human neural stem cell-derived extracellular vesicles from the bench to the bedside,we conducted a comprehensive preclinical study to evaluate the efficacy and safety of human neural stem cell-derived extracellular vesicles in the treatment of ischemic stroke.We found that administration of human neural stem cell-derived extracellular vesicles to an ischemic stroke rat model reduced the volume of cerebral infarction and promoted functional recovery by alleviating neuronal apoptosis.The human neural stem cell-derived extracellular vesicles reduced neuronal apoptosis by enhancing phosphorylation of phosphoinositide 3-kinase,mammalian target of rapamycin,and protein kinase B,and these effects were reversed by treatment with a phosphoinositide 3-kinase inhibitor.These findings suggest that human neural stem cell-derived extracellular vesicles play a neuroprotective role in ischemic stroke through activation of phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway.Finally,we showed that human neural stem cell-derived extracellular vesicles have a good in vivo safety profile.Therefore,human neural stem cell-derived extracellular vesicles are a promising potential agent for the treatment of ischemic stroke.
文摘离群点检测任务是指检测与正常数据在特征属性上存在显著差异的异常数据。大多数基于聚类的离群点检测方法主要从全局角度对数据集中的离群点进行检测,而对局部离群点的检测性能较弱。基于此,本文通过引入快速搜索和发现密度峰值方法改进K-means聚类算法,提出了一种名为KLOD(local outlier detection based on improved K-means and least-squares methods)的局部离群点检测方法,以实现对局部离群点的精确检测。首先,利用快速搜索和发现密度峰值方法计算数据点的局部密度和相对距离,并将二者相乘得到γ值。其次,将γ值降序排序,利用肘部法则选择γ值最大的k个数据点作为K-means聚类算法的初始聚类中心。然后,通过K-means聚类算法将数据集聚类成k个簇,计算数据点在每个维度上的目标函数值并进行升序排列。接着,确定数据点的每个维度的离散程度并选择适当的拟合函数和拟合点,通过最小二乘法对升序排列的每个簇的每1维目标函数值进行函数拟合并求导,以获取变化率。最后,结合信息熵,将每个数据点的每个维度目标函数值乘以相应的变化率进行加权,得到最终的异常得分,并将异常值得分较高的top-n个数据点视为离群点。通过人工数据集和UCI数据集,对KLOD、LOF和KNN方法在准确度上进行仿真实验对比。结果表明KLOD方法相较于KNN和LOF方法具有更高的准确度。本文提出的KLOD方法能够有效改善K-means聚类算法的聚类效果,并且在局部离群点检测方面具有较好的精度和性能。
文摘为了充分利用实际高速公路路段交通拥堵信息,更合理地聚类交通拥堵的内在规律和特征变化,提出自适应确定聚类中心C和类别K值(adaptive center and K-means value,ACK-Means)的聚类算法,进行高速公路拥堵路段聚类。ACK-Means算法借助簇类密度、簇类间距以及簇类强度,同时又考虑到数据样本的偶然性,对离群点进行合理分配,ACK-Means算法可实现自适应确定聚类中心C和类别K值。基于实际交通拥堵信息构建数据集,Python编程实现高速公路拥堵路段ACK-Means聚类,巧妙解决了高速公路拥堵路段聚类数目K和聚类中心C设定问题。聚类结果表明,ACK-Means算法实现高速公路拥堵路段无监督聚类,聚类结果完全基于实际的高速公路交通拥堵信息,具有更高的实用性。
