This review addresses two puzzling findings related to mutations in galactocerebrosidase （GALC） that cause Krabbe disease （KD）, a severe lysosomal storage disorder characterized by extensive myelin damage in child...This review addresses two puzzling findings related to mutations in galactocerebrosidase （GALC） that cause Krabbe disease （KD）, a severe lysosomal storage disorder characterized by extensive myelin damage in children with mutations in both GALC alleles. First, heterozygous carriers of KD-causing mutations, which include the biological parents of children with KD, exhibit increased risk for developing other diseases. Second, variants in the GALC locus increase the risk of developing multiple sclerosis （MS）, another disease characterized by extensive myelin damage. What explains these correlations？ In studies on cuprizone-induced myelin damage in heterozygous （GALC＋/–） mice carrying one copy of a mutation that causes KD-like disease, the extent of damage was similar in GALC＋/– and wild-type （WT） mice. In contrast, GALC＋/- mice had striking defects in repair of cuprizone-induced damage. We further found unexpected microglial defects in myelin debris clearance and in the ability to up-regulate the Trem2 microglial protein critical for debris uptake. These defects were rescued by exposure to a lysosomal re-acidifying drug discovered in our studies on KD, and which provides multiple clinically relevant benefits in the twitcher （GALC＋/–） mouse model of KD. Thus, heterozygous GALC mutations cause effects on biological function that may help to understand the increased disease risk in heterozygous carriers of such mutations and to understand why GALC variations increase the risk of MS. Our findings indicate that while some genetic risk factors may contribute to complex diseases by increasing the risk of tissue damage, others may do so by compromising tissue repair.展开更多
A complete research of seismic risk assessment is presented herein focused on the existing build- ings of the extended urban region of Athens in Greece. The seismic risk assessment is fulfilled by discriminating the c...A complete research of seismic risk assessment is presented herein focused on the existing build- ings of the extended urban region of Athens in Greece. The seismic risk assessment is fulfilled by discriminating the current study in two approaches, probable and actual, conducting afterwards between them a comparison analysis. In the first part, a pilot methodology is developed for the seismic loss assessment in monetary terms regarding the buildings damages, consistent with the National Programme for Earthquake Management of Existing Buildings (NPEMEB). The building stock consists of typical building types of Southern Europe and refers to 750,085 buildings (18.80% of buildings in Greece) situated in the entire region of Athens according to the results of the 2000-1 statistical census. A wider research of seismic risk assessment could include direct losses of infrastructures and indirect economic losses. The evaluation of loss due to building damage in a certain region requires an assessment of both seismic hazard and vulnerability of the building stock in the study area. Four different existing damage scenarios are applied for the vulnerability assessment. The results of the seismic risk assessment for the four different aspects of the es- timated damage and the different soil conditions are presented in a map of the study region. The existing vulnerability curves corresponding to defined types of buildings have been derived from the National Technical Chamber of Greece and also from recently developed DPMs. The last DPMs were obtained in a previous research (Eleftheriadou, 2009) from the process of a created damage database after the 7th of September 1999 Parnitha’s earthquake and comprised 180,945 buildings which developed damage of varying degree, type and extent. In the second part of the research, the seismic risk is evaluated from the available data regarding the mean statistical repair/ strengthening or replacement cost for the total number of damaged structures (180,427 buildings) after the same (1999 Parnitha’s) seismic event. Data regarding the compatible (budget approved according to the ministry’s provisions) repair cost has been collected. The structural losses in monetary terms for the 180,427 buildings damaged structures are evaluated equal to 2450.0 Μ€, 1887.8 Μ€ and 2118.9 Μ€ based on the previously mentioned statistical seismic risk data. The statistically derived repair cost for Attica is compared with the results of the economic loss esti- mation for buildings using the aforementioned risk assessment methodology. From the analysis results, the seismic scenario based on the recently developed DPMs (Eleftheriadou, 2009) pre- sented the better correlation (2627.77 M€) with the total statistically evaluated repair cost (2450.02 M€). It is important to stress that the inclusion of the coefficient parameter S overes- timates significantly the seismic losses. The last result should be taken into consideration in future risk researches. The comparison of the estimated economic loss with the statistical repair cost calibrates the reliability of the commonly used risk assessment method and serves in the im- provement of seismic security prioritizing the criteria for seismic rehabilitation programmes of existing buildings.展开更多
互联网数据中心(Internet Data Center,IDC)网络系统在目前的各个行业领域中出现频率已经逐渐升高,业界对于该网络系统的安全特性关注度也相对较高。IDC网络安全问题繁多,对于整个行业的快速发展是一种阻碍。基于此,文章介绍IDC网络及...互联网数据中心(Internet Data Center,IDC)网络系统在目前的各个行业领域中出现频率已经逐渐升高,业界对于该网络系统的安全特性关注度也相对较高。IDC网络安全问题繁多,对于整个行业的快速发展是一种阻碍。基于此,文章介绍IDC网络及其安全特性表现,分析其所存在的安全问题,并研究相应处理技术,证明IDC网络系统安全问题处理与防护优化的重要价值。展开更多
基金supported by the following funding sources:National Institutes of Health,F31-NS078911,https://www.nih.gov(NSH)New York State Department of Health,NYS-DOH-C026877,http://www.stemcell.ny.gov(NSH)+4 种基金New York State Department of Health,NYS-DOH-C029557,http://www.stemcell.ny.gov(MN)New York State Department of Health,NYS-DOH-C026877,http://www.stemcell.ny.gov(CJF)Hunter’s Hope,http://www.huntershope.org/site/Page Server(MN)Children’s Neurobiological Solutions Foundation,http://pediatricbrainfoundation.org(MN)the Legacy of Angels,http://tloaf.org(MN)
文摘This review addresses two puzzling findings related to mutations in galactocerebrosidase （GALC） that cause Krabbe disease （KD）, a severe lysosomal storage disorder characterized by extensive myelin damage in children with mutations in both GALC alleles. First, heterozygous carriers of KD-causing mutations, which include the biological parents of children with KD, exhibit increased risk for developing other diseases. Second, variants in the GALC locus increase the risk of developing multiple sclerosis （MS）, another disease characterized by extensive myelin damage. What explains these correlations？ In studies on cuprizone-induced myelin damage in heterozygous （GALC＋/–） mice carrying one copy of a mutation that causes KD-like disease, the extent of damage was similar in GALC＋/– and wild-type （WT） mice. In contrast, GALC＋/- mice had striking defects in repair of cuprizone-induced damage. We further found unexpected microglial defects in myelin debris clearance and in the ability to up-regulate the Trem2 microglial protein critical for debris uptake. These defects were rescued by exposure to a lysosomal re-acidifying drug discovered in our studies on KD, and which provides multiple clinically relevant benefits in the twitcher （GALC＋/–） mouse model of KD. Thus, heterozygous GALC mutations cause effects on biological function that may help to understand the increased disease risk in heterozygous carriers of such mutations and to understand why GALC variations increase the risk of MS. Our findings indicate that while some genetic risk factors may contribute to complex diseases by increasing the risk of tissue damage, others may do so by compromising tissue repair.
文摘A complete research of seismic risk assessment is presented herein focused on the existing build- ings of the extended urban region of Athens in Greece. The seismic risk assessment is fulfilled by discriminating the current study in two approaches, probable and actual, conducting afterwards between them a comparison analysis. In the first part, a pilot methodology is developed for the seismic loss assessment in monetary terms regarding the buildings damages, consistent with the National Programme for Earthquake Management of Existing Buildings (NPEMEB). The building stock consists of typical building types of Southern Europe and refers to 750,085 buildings (18.80% of buildings in Greece) situated in the entire region of Athens according to the results of the 2000-1 statistical census. A wider research of seismic risk assessment could include direct losses of infrastructures and indirect economic losses. The evaluation of loss due to building damage in a certain region requires an assessment of both seismic hazard and vulnerability of the building stock in the study area. Four different existing damage scenarios are applied for the vulnerability assessment. The results of the seismic risk assessment for the four different aspects of the es- timated damage and the different soil conditions are presented in a map of the study region. The existing vulnerability curves corresponding to defined types of buildings have been derived from the National Technical Chamber of Greece and also from recently developed DPMs. The last DPMs were obtained in a previous research (Eleftheriadou, 2009) from the process of a created damage database after the 7th of September 1999 Parnitha’s earthquake and comprised 180,945 buildings which developed damage of varying degree, type and extent. In the second part of the research, the seismic risk is evaluated from the available data regarding the mean statistical repair/ strengthening or replacement cost for the total number of damaged structures (180,427 buildings) after the same (1999 Parnitha’s) seismic event. Data regarding the compatible (budget approved according to the ministry’s provisions) repair cost has been collected. The structural losses in monetary terms for the 180,427 buildings damaged structures are evaluated equal to 2450.0 Μ€, 1887.8 Μ€ and 2118.9 Μ€ based on the previously mentioned statistical seismic risk data. The statistically derived repair cost for Attica is compared with the results of the economic loss esti- mation for buildings using the aforementioned risk assessment methodology. From the analysis results, the seismic scenario based on the recently developed DPMs (Eleftheriadou, 2009) pre- sented the better correlation (2627.77 M€) with the total statistically evaluated repair cost (2450.02 M€). It is important to stress that the inclusion of the coefficient parameter S overes- timates significantly the seismic losses. The last result should be taken into consideration in future risk researches. The comparison of the estimated economic loss with the statistical repair cost calibrates the reliability of the commonly used risk assessment method and serves in the im- provement of seismic security prioritizing the criteria for seismic rehabilitation programmes of existing buildings.
文摘互联网数据中心(Internet Data Center,IDC)网络系统在目前的各个行业领域中出现频率已经逐渐升高,业界对于该网络系统的安全特性关注度也相对较高。IDC网络安全问题繁多,对于整个行业的快速发展是一种阻碍。基于此,文章介绍IDC网络及其安全特性表现,分析其所存在的安全问题,并研究相应处理技术,证明IDC网络系统安全问题处理与防护优化的重要价值。
