Objective:Glucose-6-phosphate isomerase(GPI)deficiency is a rare hereditary nonspherocytic hemolytic anemia caused by GPI gene variants.This disorder exhibits wide heterogeneity in its clinical manifestations and mole...Objective:Glucose-6-phosphate isomerase(GPI)deficiency is a rare hereditary nonspherocytic hemolytic anemia caused by GPI gene variants.This disorder exhibits wide heterogeneity in its clinical manifestations and molecular characteristics,often posing challenges for precise diagnoses using conventional methods.To this end,this study aimed to identify the novel variants responsible for GPI deficiency in a Chinese family.Methods:The clinical manifestations of the patient were summarized and analyzed for GPI deficiency phenotype diagnosis.Novel compound heterozygous variants of the GPI gene,c.174C>A(p.Asn58Lys)and c.1538G>T(p.Trp513Leu),were identified using whole-exome and Sanger sequencing.The AlphaFold program and Chimera software were used to analyze the effects of compound heterozygous variants on GPI structure.Results:By characterizing 53 GPI missense/nonsense variants from previous literature and two novel missense variants identified in this study,we found that most variants were located in exons 3,4,12,and 18,with a few localized in exons 8,9,and 14.This study identified novel compound heterozygous variants associated with GPI deficiency.These pathogenic variants disrupt hydrogen bonds formed by highly conserved GPI amino acids.Conclusion:Early family-based sequencing analyses,especially for patients with congenital anemia,can help increase diagnostic accuracy for GPI deficiency,improve child healthcare,and enable genetic counseling.展开更多
1958—1999年,在广东省佛山市南海区西樵镇一带发现了众多记录了史前人类活动的石器地点,石器中包括双肩石器和细石器。迄今为止,“西樵山遗址”被认定是4—7 ka B P的大型新石器时期采石场和加工场。2011—2022年,笔者经多次地质遗迹...1958—1999年,在广东省佛山市南海区西樵镇一带发现了众多记录了史前人类活动的石器地点,石器中包括双肩石器和细石器。迄今为止,“西樵山遗址”被认定是4—7 ka B P的大型新石器时期采石场和加工场。2011—2022年,笔者经多次地质遗迹和地质环境调查,在西樵山东南麓富贤村北面发现了良好的第四纪地层剖面。地质探槽剖面测量和地质年代学研究表明:富贤地点存在2套原始沉积地层:上部为第四纪全新世沼泽相地层,AMS14C校正年龄为5052—5409 a B P;下部为第四纪晚更新世冲积-洪积相地层,AMS14C校正年龄为38420—40502 a B P,OSL (光释光)年龄为41.977—43.796 ka B P;在晚更新世地层中发现2层含旧石器层,下部A1层主要石器类型有较大型刮削器、尖刃器、舌型刃器及小型石片工具,如各类刮削器、锯齿刃器、凹缺器、石刀、使用石片、石核等,包括带铤斧型小石刀;上部A2层明显出现更多石刀类型且常常附带修背和修铤工作,其中一件用于生产细小长石片的原始楔形石核引人关注。据平均沉积速率计算,下部A1石器层年龄为46.511—47.325 ka B P,上部A2石器层年龄为41.977—42.167 ka B P;距今大于5 ka的全新世沉积物中的石制品数量虽少,但器物类型仍具有明显继承性与发展性特点。本文的发现更新并延伸了西樵山国家地质公园和“西樵山文化”的内涵,首次突破了珠江三角洲地区有确切年代的晚更新世旧石器遗存的纪录,追踪到大约40—50 ka现代人在华南沿海的足迹,揭示了同期石器工业的面貌及其文化内涵的发展特征和演变。研究表明,在MIS3间冰段相对湿热时期以及MIS2相对干冷阶段,富贤地点的古人类面临环境变化的挑战而开启了新的生计模式,这对于揭示现代人对全球和区域环境变化的响应与适应的科学问题具有重要意义。展开更多
Inflammatory bowel disease(IBD)is chronic inflammation of the gastrointestinal tract that has a high epidemiological prevalence worldwide.The increasing disease burden worldwide,lack of response to current biologic th...Inflammatory bowel disease(IBD)is chronic inflammation of the gastrointestinal tract that has a high epidemiological prevalence worldwide.The increasing disease burden worldwide,lack of response to current biologic therapeutics,and treatment-related immunogenicity have led to major concerns regarding the clinical management of IBD patients and treatment efficacy.Understanding disease pathogenesis and disease-related molecular mechanisms is the most important goal in developing new and effective therapeutics.Sphingosine-1-phosphate(S1P)receptor(S1PR)modulators form a class of oral small molecule drugs currently in clinical development for IBD have shown promising effects on disease improvement.S1P is a sphingosine-derived phospholipid that acts by binding to its receptor S1PR and is involved in the regulation of several biological processes including cell survival,differentiation,migration,proliferation,immune response,and lymphocyte trafficking.T lymphocytes play an important role in regulating inflammatory responses.In inflamed IBD tissue,an imbalance between T helper(Th)and regulatory T lymphocytes and Th cytokine levels was found.The S1P/S1PR signaling axis and metabolism have been linked to inflammatory responses in IBD.S1P modulators targeting S1PRs and S1P metabolism have been developed and shown to regulate inflammatory responses by affecting lymphocyte trafficking,lymphocyte number,lymphocyte activity,cytokine production,and contributing to gut barrier function.展开更多
文摘Objective:Glucose-6-phosphate isomerase(GPI)deficiency is a rare hereditary nonspherocytic hemolytic anemia caused by GPI gene variants.This disorder exhibits wide heterogeneity in its clinical manifestations and molecular characteristics,often posing challenges for precise diagnoses using conventional methods.To this end,this study aimed to identify the novel variants responsible for GPI deficiency in a Chinese family.Methods:The clinical manifestations of the patient were summarized and analyzed for GPI deficiency phenotype diagnosis.Novel compound heterozygous variants of the GPI gene,c.174C>A(p.Asn58Lys)and c.1538G>T(p.Trp513Leu),were identified using whole-exome and Sanger sequencing.The AlphaFold program and Chimera software were used to analyze the effects of compound heterozygous variants on GPI structure.Results:By characterizing 53 GPI missense/nonsense variants from previous literature and two novel missense variants identified in this study,we found that most variants were located in exons 3,4,12,and 18,with a few localized in exons 8,9,and 14.This study identified novel compound heterozygous variants associated with GPI deficiency.These pathogenic variants disrupt hydrogen bonds formed by highly conserved GPI amino acids.Conclusion:Early family-based sequencing analyses,especially for patients with congenital anemia,can help increase diagnostic accuracy for GPI deficiency,improve child healthcare,and enable genetic counseling.
文摘1958—1999年,在广东省佛山市南海区西樵镇一带发现了众多记录了史前人类活动的石器地点,石器中包括双肩石器和细石器。迄今为止,“西樵山遗址”被认定是4—7 ka B P的大型新石器时期采石场和加工场。2011—2022年,笔者经多次地质遗迹和地质环境调查,在西樵山东南麓富贤村北面发现了良好的第四纪地层剖面。地质探槽剖面测量和地质年代学研究表明:富贤地点存在2套原始沉积地层:上部为第四纪全新世沼泽相地层,AMS14C校正年龄为5052—5409 a B P;下部为第四纪晚更新世冲积-洪积相地层,AMS14C校正年龄为38420—40502 a B P,OSL (光释光)年龄为41.977—43.796 ka B P;在晚更新世地层中发现2层含旧石器层,下部A1层主要石器类型有较大型刮削器、尖刃器、舌型刃器及小型石片工具,如各类刮削器、锯齿刃器、凹缺器、石刀、使用石片、石核等,包括带铤斧型小石刀;上部A2层明显出现更多石刀类型且常常附带修背和修铤工作,其中一件用于生产细小长石片的原始楔形石核引人关注。据平均沉积速率计算,下部A1石器层年龄为46.511—47.325 ka B P,上部A2石器层年龄为41.977—42.167 ka B P;距今大于5 ka的全新世沉积物中的石制品数量虽少,但器物类型仍具有明显继承性与发展性特点。本文的发现更新并延伸了西樵山国家地质公园和“西樵山文化”的内涵,首次突破了珠江三角洲地区有确切年代的晚更新世旧石器遗存的纪录,追踪到大约40—50 ka现代人在华南沿海的足迹,揭示了同期石器工业的面貌及其文化内涵的发展特征和演变。研究表明,在MIS3间冰段相对湿热时期以及MIS2相对干冷阶段,富贤地点的古人类面临环境变化的挑战而开启了新的生计模式,这对于揭示现代人对全球和区域环境变化的响应与适应的科学问题具有重要意义。
文摘Inflammatory bowel disease(IBD)is chronic inflammation of the gastrointestinal tract that has a high epidemiological prevalence worldwide.The increasing disease burden worldwide,lack of response to current biologic therapeutics,and treatment-related immunogenicity have led to major concerns regarding the clinical management of IBD patients and treatment efficacy.Understanding disease pathogenesis and disease-related molecular mechanisms is the most important goal in developing new and effective therapeutics.Sphingosine-1-phosphate(S1P)receptor(S1PR)modulators form a class of oral small molecule drugs currently in clinical development for IBD have shown promising effects on disease improvement.S1P is a sphingosine-derived phospholipid that acts by binding to its receptor S1PR and is involved in the regulation of several biological processes including cell survival,differentiation,migration,proliferation,immune response,and lymphocyte trafficking.T lymphocytes play an important role in regulating inflammatory responses.In inflamed IBD tissue,an imbalance between T helper(Th)and regulatory T lymphocytes and Th cytokine levels was found.The S1P/S1PR signaling axis and metabolism have been linked to inflammatory responses in IBD.S1P modulators targeting S1PRs and S1P metabolism have been developed and shown to regulate inflammatory responses by affecting lymphocyte trafficking,lymphocyte number,lymphocyte activity,cytokine production,and contributing to gut barrier function.
