Two important questions are addressed in this paper using the Global Ensemble Forecast System （GEFS） from the National Centers for Environmental Prediction （NCEP）： （1） How many ensemble members are needed to be...Two important questions are addressed in this paper using the Global Ensemble Forecast System （GEFS） from the National Centers for Environmental Prediction （NCEP）： （1） How many ensemble members are needed to better represent forecast uncertainties with limited computational resources？ （2） What is tile relative impact on forecast skill of increasing model resolution and ensemble size？ Two-month experiments at T126L28 resolution were used to test the impact of varying the ensemble size from 5 to 80 members at the 500- hPa geopotential height. Results indicate that increasing the ensemble size leads to significant improvements in the performance for all forecast ranges when measured by probabilistic metrics, but these improvements are not significant beyond 20 members for long forecast ranges when measured by deterministic metrics. An ensemble of 20 to 30 members is the most effective configuration of ensemble sizes by quantifying the tradeoff between ensemble performance and the cost of computational resources. Two representative configurations of the GEFS the T126L28 model with 70 members and the T190L28 model with 20 members, which have equivalent computing costs--were compared. Results confirm that, for the NCEP GEFS, increasing the model resolution is more （less） beneficial than increasing the ensemble size for a short （long） forecast range.展开更多
Primary liver cancers constitute the fourth leading cause of cancer mortality worldwide,due to their high morbidity,late diagnosis and lack of effective treatments.Hepatocellular carcinoma(HCC)represents 80%and cholan...Primary liver cancers constitute the fourth leading cause of cancer mortality worldwide,due to their high morbidity,late diagnosis and lack of effective treatments.Hepatocellular carcinoma(HCC)represents 80%and cholangiocarcinoma(CCA)15%of liver cancers.Several genetic and epigenetic gene alterations(e.g.,TERT,TP53 or CTNNB1)are HCC drivers,although many additional gene alterations contribute to HCC initiation and/or progression.Rho and Ras GTPases have been widely implicated in tumorigenesis and their activators(GEFs)have recently emerged as putative key players in liver cancer.The Ras GEF,C3G(RAPGEF1),a GEF mainly for Rap proteins,has recently been uncovered as a relevant gene in HCC.Its upregulation promotes tumor growth,although a decrease in C3G levels favors migration/invasion and lung metastasis.Rap1A/1B/2A/2B are overexpressed in HCC tumors,but their effects are controversial and not equivalent to those of C3G.The C3G partner,CRKL,is also overexpressed in HCC,promoting proliferation,migration and invasion.Various Rho GEFs are also deregulated in liver cancer.Tiam1 and Tiam2 expression is upregulated in HCC,promoting proliferation,migration and metastasis.In addition,ARHGEF-10L/9/19/39 are overexpressed in HCC tumors,facilitating migration,invasion,metastasis and proliferation.Another Rho GEF,Vav2,is also involved in metastasis.Little is known about the participation of these GEFs and GTPases in CCA.However,analysis of cancer databases uncovered deregulations or genetic alterations in several of these genes,in both CCA and HCC.Hence,GEFs function appear essential for liver homeostasis,although future studies are needed to define their precise function in liver cancer.展开更多
Dbl家族鸟苷交换因子(GEFs)是Rho家族蛋白发生恶性转化的主要调控单位,它通过使Rho蛋白从无活性的GDP形式转换为GTP形式的Rho蛋白而发挥作用,参与细胞骨架重排,细胞的生长和活力。P92GEF是一GEFs家族分子。本研究通过Real time PCR对P92...Dbl家族鸟苷交换因子(GEFs)是Rho家族蛋白发生恶性转化的主要调控单位,它通过使Rho蛋白从无活性的GDP形式转换为GTP形式的Rho蛋白而发挥作用,参与细胞骨架重排,细胞的生长和活力。P92GEF是一GEFs家族分子。本研究通过Real time PCR对P92GEF在人体48种正常组织中的表达情况进行了测定;GST-pulldown技术对P92GEF的体内GEF活性进行了检测;双荧光素酶报告基因检测技术对下游小分子进行转录因子活性检测;应用免疫荧光双染标记法完成了高表达P92GEF对正常细胞骨架形态的影响;在细胞表型实验中分别使用CCK8法、Transwell法及软琼脂克隆形成实验检测了高表达P92GEF对细胞增殖侵袭迁移及体外成瘤能力的影响。研究结果显示P92GEF有841个氨基酸,具有典型的Dbl家族分子结构域,在肺组织中表达量最高,能够促使正常成纤维细胞中的应力纤维(stress fiber)增多,P92GEF转染的NIH3T3细胞可以独立生长和形成继发性病灶,同时促使细胞增殖,侵袭及克隆形成能力增强,体外转录因子活性检测发现该基因可能与JAK/STAT通路有关。因此,P92GEF是一个典型的鸟苷交换因子家族分子,能激活Rho家族分子Rho A,具有明显的癌基因特征。展开更多
文摘Two important questions are addressed in this paper using the Global Ensemble Forecast System （GEFS） from the National Centers for Environmental Prediction （NCEP）： （1） How many ensemble members are needed to better represent forecast uncertainties with limited computational resources？ （2） What is tile relative impact on forecast skill of increasing model resolution and ensemble size？ Two-month experiments at T126L28 resolution were used to test the impact of varying the ensemble size from 5 to 80 members at the 500- hPa geopotential height. Results indicate that increasing the ensemble size leads to significant improvements in the performance for all forecast ranges when measured by probabilistic metrics, but these improvements are not significant beyond 20 members for long forecast ranges when measured by deterministic metrics. An ensemble of 20 to 30 members is the most effective configuration of ensemble sizes by quantifying the tradeoff between ensemble performance and the cost of computational resources. Two representative configurations of the GEFS the T126L28 model with 70 members and the T190L28 model with 20 members, which have equivalent computing costs--were compared. Results confirm that, for the NCEP GEFS, increasing the model resolution is more （less） beneficial than increasing the ensemble size for a short （long） forecast range.
基金supported by grants from the Spanish Ministry of Economy and Competitiveness(SAF2016-76588-C2-1-R and PID2019-104143RB-C22 to Porras A,SAF2016-76588-C2-2-R and PID2019-104143RB-C21 to Guerrero G and PID2019-104991RB-I00 to Bragado P)by two grants from the Council of Education of Junta de Castilla y León,Spain(SA017U16 and SA078P20 to Guerrero C)+2 种基金cosponsored by the European FEDER ProgramSequera C was supported by a fellowship from Complutense University from Madrid.Gutierrez-Uzquiza A is supported by Madrid Community Program for Talent Attraction(MRF 2017-T1/BMD-5468)Bragado P received support from BBVA(Becas Leonardo 2018,BBM-TRA-0041).
文摘Primary liver cancers constitute the fourth leading cause of cancer mortality worldwide,due to their high morbidity,late diagnosis and lack of effective treatments.Hepatocellular carcinoma(HCC)represents 80%and cholangiocarcinoma(CCA)15%of liver cancers.Several genetic and epigenetic gene alterations(e.g.,TERT,TP53 or CTNNB1)are HCC drivers,although many additional gene alterations contribute to HCC initiation and/or progression.Rho and Ras GTPases have been widely implicated in tumorigenesis and their activators(GEFs)have recently emerged as putative key players in liver cancer.The Ras GEF,C3G(RAPGEF1),a GEF mainly for Rap proteins,has recently been uncovered as a relevant gene in HCC.Its upregulation promotes tumor growth,although a decrease in C3G levels favors migration/invasion and lung metastasis.Rap1A/1B/2A/2B are overexpressed in HCC tumors,but their effects are controversial and not equivalent to those of C3G.The C3G partner,CRKL,is also overexpressed in HCC,promoting proliferation,migration and invasion.Various Rho GEFs are also deregulated in liver cancer.Tiam1 and Tiam2 expression is upregulated in HCC,promoting proliferation,migration and metastasis.In addition,ARHGEF-10L/9/19/39 are overexpressed in HCC tumors,facilitating migration,invasion,metastasis and proliferation.Another Rho GEF,Vav2,is also involved in metastasis.Little is known about the participation of these GEFs and GTPases in CCA.However,analysis of cancer databases uncovered deregulations or genetic alterations in several of these genes,in both CCA and HCC.Hence,GEFs function appear essential for liver homeostasis,although future studies are needed to define their precise function in liver cancer.
基金Natural Science Foundation of China(30701719 30701519)~~
文摘Dbl家族鸟苷交换因子(GEFs)是Rho家族蛋白发生恶性转化的主要调控单位,它通过使Rho蛋白从无活性的GDP形式转换为GTP形式的Rho蛋白而发挥作用,参与细胞骨架重排,细胞的生长和活力。P92GEF是一GEFs家族分子。本研究通过Real time PCR对P92GEF在人体48种正常组织中的表达情况进行了测定;GST-pulldown技术对P92GEF的体内GEF活性进行了检测;双荧光素酶报告基因检测技术对下游小分子进行转录因子活性检测;应用免疫荧光双染标记法完成了高表达P92GEF对正常细胞骨架形态的影响;在细胞表型实验中分别使用CCK8法、Transwell法及软琼脂克隆形成实验检测了高表达P92GEF对细胞增殖侵袭迁移及体外成瘤能力的影响。研究结果显示P92GEF有841个氨基酸,具有典型的Dbl家族分子结构域,在肺组织中表达量最高,能够促使正常成纤维细胞中的应力纤维(stress fiber)增多,P92GEF转染的NIH3T3细胞可以独立生长和形成继发性病灶,同时促使细胞增殖,侵袭及克隆形成能力增强,体外转录因子活性检测发现该基因可能与JAK/STAT通路有关。因此,P92GEF是一个典型的鸟苷交换因子家族分子,能激活Rho家族分子Rho A,具有明显的癌基因特征。
