As we enter the year of 2011, the 2009 H1N1 pandemic influenza virus is in the news again. At least 20 people have died of this virus in China since the beginning of 2011 and it is now the predominant flu strain in th...As we enter the year of 2011, the 2009 H1N1 pandemic influenza virus is in the news again. At least 20 people have died of this virus in China since the beginning of 2011 and it is now the predominant flu strain in the country. Although this novel virus was quite stable during its run in the flu season of 2009-2010, a genetic variant of this virus was found in Singapore in early 2010, and then in Australia and New Zealand during their 2010 winter influenza season. Several critical mutations in the HA protein of this variant were uncovered in the strains collected from January 2010 to April 2010. Moreover, a structural homology model of HA from the A/Brisbane/10/2010(H1N1) strain was made based on the structure of A/California/04/2009 (H1N1). The purpose of this study was to investigate mutations in the HA protein of 2009 H1N1 from sequence data collected worldwide from May 2010 to February 2011. A fundamental problem in bioinformatics and biology is to find the similar gene sequences for a given gene sequence of interest. Here we proposed the inverse problem, i.e., finding the exemplars from a group of related gene sequences. With a clustering algorithm affinity propagation, six exemplars of the HA sequences were identified to represent six clusters. One of the clusters contained strain A/Brisbane/12/2010(H1N1) that only differed from A/Brisbane/10/2010 in the HA sequence at position 449. Based on the sequence identity of the six exemplars, nine mutations in HA were located that could be used to distinguish these six clusters. Finally, we discovered the change of correlation patterns for the HA and NA of 2009 H1N1 as a result of the HA receptor binding specificity switch, revealing the balanced interplay between these two surface proteins of the virus.展开更多
N-methyI-D-aspartate receptors （NMDARs） containing different GluN2 subunits play distinct roles in synaptic plasticity. Such differences may not only be determined by the channel properties, but also by differential...N-methyI-D-aspartate receptors （NMDARs） containing different GluN2 subunits play distinct roles in synaptic plasticity. Such differences may not only be determined by the channel properties, but also by differential surface distribution and synaptic localization. In the present study, using a Cy3-conjugated Fab fragment of the GFP antibody to label surface-located GluN2 subunits tagged with GFP at the N-terminus, we observed the membrane distribution patterns of GluN2A- or GluN2B-containing NMDARs in cultured rat hippocampal neurons. We found that surface NMDARs containing GluN2A, but not those containing GluN2B, were inclined to cluster at DIV7. Swapping the carboxyl termini of the GluN2 subunits completely reversed these distribution patterns. In addition, surface NMDARs containing GluN2A were preferentially associated with PSD-95. Taken together, the results of our study suggest that the clustering distribution of GluN2A- containing NMDARs is determined by the GluN2A C-terminus, and its interaction with PSD-95 plays an important role in this process.展开更多
Previous studies have found that deficiency in nuclear receptor-related factor 1(Nurr1),which participates in the development,differentiation,survival,and degeneration of dopaminergic neurons,is associated with Parkin...Previous studies have found that deficiency in nuclear receptor-related factor 1(Nurr1),which participates in the development,differentiation,survival,and degeneration of dopaminergic neurons,is associated with Parkinson s disease,but the mechanism of action is perplexing.Here,we first asce rtained the repercussion of knocking down Nurr1 by pe rforming liquid chromatography coupled with tandem mass spectrometry.We found that 231 genes were highly expressed in dopaminergic neurons with Nurr1 deficiency,14 of which were linked to the Parkinson’s disease pathway based on Kyoto Encyclopedia of Genes and Genomes analysis.To better understand how Nurr1 deficiency autonomously invokes the decline of dopaminergic neurons and elicits Parkinson’s disease symptoms,we performed single-nuclei RNA sequencing in a Nurr1 LV-shRNA mouse model.The results revealed cellular heterogeneity in the substantia nigra and a number of activated genes,the preponderance of which encode components of the major histocompatibility Ⅱ complex.Cd74,H2-Ab1,H2-Aα,H2-Eb1,Lyz2,Mrc1,Slc6α3,Slc47α1,Ms4α4b,and Ptprc2 were the top 10 diffe rentially expressed genes.Immunofluorescence staining showed that,after Nurr1knockdown,the number of CD74-immunoreactive cells in mouse brain tissue was markedly increased.In addition,Cd74 expression was increased in a mouse model of Parkinson’s disease induced by treatment with 6-hydroxydopamine.Ta ken togethe r,our res ults suggest that Nurr1 deficiency results in an increase in Cd74 expression,thereby leading to the destruction of dopaminergic neuro ns.These findings provide a potential therapeutic target for the treatment of Parkinson’s disease.展开更多
It is known from experiments that in the presence of soluble antigen,B-cell receptors(BCRs)assemble into microclusters and then collect into a macrocluster known as a‘cap’.However,the mechanisms of BCR cluster forma...It is known from experiments that in the presence of soluble antigen,B-cell receptors(BCRs)assemble into microclusters and then collect into a macrocluster known as a‘cap’.However,the mechanisms of BCR cluster formation during recognition of soluble antigens remain unclear.In previous work,we demonstrated that effective intrinsic attractions among BCRs can lead to the formation of small microclusters of BCR molecules.The effective intrinsic attractions could be caused by multivalent antigen binding,association with lipid rafts,or other biochemical factors.In the present study,we have developed and studied a Monte Carlo model of BCR clustering mediated by explicit binding and crosslinking of soluble bivalent antigens.Antigen crosslinking is shown to microcluster BCRs in an affinity-dependent manner and also in a biologically relevant timescale;however,antigen crosslinking alone does not appear to be sufficient for the formation of a single macrocluster of receptor molecules.We show that directed transport of BCRs is needed to drive the formation of large macroclusters.We constructed a simple model of directed transport,where BCR molecules diffuse towards the largest cluster or towards a random BCR microcluster,which results in a single macrocluster of receptor molecules.The mechanisms for both types of directed transport are compared using network-based metrics.We also develop and use appropriate network measures to analyze the effect of BCR and antigen concentration on BCR clustering,the stability of the formed clusters over time and the size of BCR–antigen crosslinked chains.展开更多
目的:基于数据挖掘,探索中药治疗表皮生长因子受体抑制剂(EGFRIs)相关皮疹的用药规律。方法:检索外文数据库PubMed、Web of Science、Cochrane Library、EMBASE和中文数据库中国学术期刊全文数据库(CNKI)、中国生物医学文献数据库(CBMdi...目的:基于数据挖掘,探索中药治疗表皮生长因子受体抑制剂(EGFRIs)相关皮疹的用药规律。方法:检索外文数据库PubMed、Web of Science、Cochrane Library、EMBASE和中文数据库中国学术期刊全文数据库(CNKI)、中国生物医学文献数据库(CBMdisc)、万方数据知识服务平台(Wangfang)、维普中文科技期刊数据库(VIP)中关于中药治疗EGFRIs相关皮疹的随机对照试验,对随机对照试验中所用的中药进行频率统计,选取出现频率大于2%的药物,运用Spearman相关分析探索中药的配伍规律,并采用聚类分析挖掘相关聚类方剂组成。结果:最终纳入22项研究的中药方剂,其中频率大于2%的药物有15个,频率最高的是金银花;Spearman相关分析显示相关性较强的药对有9组,相关性极强的是荆芥和生地;聚类分析结果显示3组聚类方剂。结论:中药治疗EGFRIs相关皮疹有规律可循,辨证用药多以祛风、清热、除湿药为主,配伍严谨。聚类分析和Spearman相关分析是挖掘用药规律的可行性方法,但仍需要更多的临床随机对照研究。展开更多
文摘As we enter the year of 2011, the 2009 H1N1 pandemic influenza virus is in the news again. At least 20 people have died of this virus in China since the beginning of 2011 and it is now the predominant flu strain in the country. Although this novel virus was quite stable during its run in the flu season of 2009-2010, a genetic variant of this virus was found in Singapore in early 2010, and then in Australia and New Zealand during their 2010 winter influenza season. Several critical mutations in the HA protein of this variant were uncovered in the strains collected from January 2010 to April 2010. Moreover, a structural homology model of HA from the A/Brisbane/10/2010(H1N1) strain was made based on the structure of A/California/04/2009 (H1N1). The purpose of this study was to investigate mutations in the HA protein of 2009 H1N1 from sequence data collected worldwide from May 2010 to February 2011. A fundamental problem in bioinformatics and biology is to find the similar gene sequences for a given gene sequence of interest. Here we proposed the inverse problem, i.e., finding the exemplars from a group of related gene sequences. With a clustering algorithm affinity propagation, six exemplars of the HA sequences were identified to represent six clusters. One of the clusters contained strain A/Brisbane/12/2010(H1N1) that only differed from A/Brisbane/10/2010 in the HA sequence at position 449. Based on the sequence identity of the six exemplars, nine mutations in HA were located that could be used to distinguish these six clusters. Finally, we discovered the change of correlation patterns for the HA and NA of 2009 H1N1 as a result of the HA receptor binding specificity switch, revealing the balanced interplay between these two surface proteins of the virus.
基金supported by grants from the National Basic Research Program of China (2010CB912002)the National Natural Science Foundation of China (81221003 and 81271453)Fundamental Research Funds for the Central Universities of China
文摘N-methyI-D-aspartate receptors （NMDARs） containing different GluN2 subunits play distinct roles in synaptic plasticity. Such differences may not only be determined by the channel properties, but also by differential surface distribution and synaptic localization. In the present study, using a Cy3-conjugated Fab fragment of the GFP antibody to label surface-located GluN2 subunits tagged with GFP at the N-terminus, we observed the membrane distribution patterns of GluN2A- or GluN2B-containing NMDARs in cultured rat hippocampal neurons. We found that surface NMDARs containing GluN2A, but not those containing GluN2B, were inclined to cluster at DIV7. Swapping the carboxyl termini of the GluN2 subunits completely reversed these distribution patterns. In addition, surface NMDARs containing GluN2A were preferentially associated with PSD-95. Taken together, the results of our study suggest that the clustering distribution of GluN2A- containing NMDARs is determined by the GluN2A C-terminus, and its interaction with PSD-95 plays an important role in this process.
基金supported by the National Natural Science Foundation of China,No. 81971006 (to DSG)。
文摘Previous studies have found that deficiency in nuclear receptor-related factor 1(Nurr1),which participates in the development,differentiation,survival,and degeneration of dopaminergic neurons,is associated with Parkinson s disease,but the mechanism of action is perplexing.Here,we first asce rtained the repercussion of knocking down Nurr1 by pe rforming liquid chromatography coupled with tandem mass spectrometry.We found that 231 genes were highly expressed in dopaminergic neurons with Nurr1 deficiency,14 of which were linked to the Parkinson’s disease pathway based on Kyoto Encyclopedia of Genes and Genomes analysis.To better understand how Nurr1 deficiency autonomously invokes the decline of dopaminergic neurons and elicits Parkinson’s disease symptoms,we performed single-nuclei RNA sequencing in a Nurr1 LV-shRNA mouse model.The results revealed cellular heterogeneity in the substantia nigra and a number of activated genes,the preponderance of which encode components of the major histocompatibility Ⅱ complex.Cd74,H2-Ab1,H2-Aα,H2-Eb1,Lyz2,Mrc1,Slc6α3,Slc47α1,Ms4α4b,and Ptprc2 were the top 10 diffe rentially expressed genes.Immunofluorescence staining showed that,after Nurr1knockdown,the number of CD74-immunoreactive cells in mouse brain tissue was markedly increased.In addition,Cd74 expression was increased in a mouse model of Parkinson’s disease induced by treatment with 6-hydroxydopamine.Ta ken togethe r,our res ults suggest that Nurr1 deficiency results in an increase in Cd74 expression,thereby leading to the destruction of dopaminergic neuro ns.These findings provide a potential therapeutic target for the treatment of Parkinson’s disease.
基金ASR,PKT and SR are supported from National Institutes of Health grant AI074022.
文摘It is known from experiments that in the presence of soluble antigen,B-cell receptors(BCRs)assemble into microclusters and then collect into a macrocluster known as a‘cap’.However,the mechanisms of BCR cluster formation during recognition of soluble antigens remain unclear.In previous work,we demonstrated that effective intrinsic attractions among BCRs can lead to the formation of small microclusters of BCR molecules.The effective intrinsic attractions could be caused by multivalent antigen binding,association with lipid rafts,or other biochemical factors.In the present study,we have developed and studied a Monte Carlo model of BCR clustering mediated by explicit binding and crosslinking of soluble bivalent antigens.Antigen crosslinking is shown to microcluster BCRs in an affinity-dependent manner and also in a biologically relevant timescale;however,antigen crosslinking alone does not appear to be sufficient for the formation of a single macrocluster of receptor molecules.We show that directed transport of BCRs is needed to drive the formation of large macroclusters.We constructed a simple model of directed transport,where BCR molecules diffuse towards the largest cluster or towards a random BCR microcluster,which results in a single macrocluster of receptor molecules.The mechanisms for both types of directed transport are compared using network-based metrics.We also develop and use appropriate network measures to analyze the effect of BCR and antigen concentration on BCR clustering,the stability of the formed clusters over time and the size of BCR–antigen crosslinked chains.
文摘目的:基于数据挖掘,探索中药治疗表皮生长因子受体抑制剂(EGFRIs)相关皮疹的用药规律。方法:检索外文数据库PubMed、Web of Science、Cochrane Library、EMBASE和中文数据库中国学术期刊全文数据库(CNKI)、中国生物医学文献数据库(CBMdisc)、万方数据知识服务平台(Wangfang)、维普中文科技期刊数据库(VIP)中关于中药治疗EGFRIs相关皮疹的随机对照试验,对随机对照试验中所用的中药进行频率统计,选取出现频率大于2%的药物,运用Spearman相关分析探索中药的配伍规律,并采用聚类分析挖掘相关聚类方剂组成。结果:最终纳入22项研究的中药方剂,其中频率大于2%的药物有15个,频率最高的是金银花;Spearman相关分析显示相关性较强的药对有9组,相关性极强的是荆芥和生地;聚类分析结果显示3组聚类方剂。结论:中药治疗EGFRIs相关皮疹有规律可循,辨证用药多以祛风、清热、除湿药为主,配伍严谨。聚类分析和Spearman相关分析是挖掘用药规律的可行性方法,但仍需要更多的临床随机对照研究。
