首页 > 最新文献

Journal of molecular endocrinology最新文献

英文 中文
m6A readers, writers, erasers, and the m6A epitranscriptome in breast cancer. 乳腺癌中的 m6A 阅读器、写作器、擦除器和 m6A 表转录组。
IF 3.5 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2022-12-21 Print Date: 2023-02-01 DOI: 10.1530/JME-22-0110
Belinda J Petri, Carolyn M Klinge

Epitranscriptomic modification of RNA regulates human development, health, and disease. The true diversity of the transcriptome in breast cancer including chemical modification of transcribed RNA (epitranscriptomics) is not well understood due to limitations of technology and bioinformatic analysis. N-6-methyladenosine (m6A) is the most abundant epitranscriptomic modification of mRNA and regulates splicing, stability, translation, and intracellular localization of transcripts depending on m6A association with reader RNA-binding proteins. m6A methylation is catalyzed by the METTL3 complex and removed by specific m6A demethylase ALKBH5, with the role of FTO as an 'eraser' uncertain. In this review, we provide an overview of epitranscriptomics related to mRNA and focus on m6A in mRNA and its detection. We summarize current knowledge on altered levels of writers, readers, and erasers of m6A and their roles in breast cancer and their association with prognosis. We summarize studies identifying m6A peaks and sites in genes in breast cancer cells.

RNA 的表转录组修饰调节着人类的发育、健康和疾病。由于技术和生物信息分析的局限性,人们对乳腺癌转录组的真正多样性,包括转录 RNA 的化学修饰(表转录组学)还不甚了解。N-6-甲基腺苷(m6A)是 mRNA 上最丰富的表转录组学修饰,可调节剪接、稳定性、翻译和转录本的胞内定位,这取决于 m6A 与阅读器 RNA 结合蛋白的关联。m6A 甲基化由 METTL3 复合物催化,并由特异性 m6A 去甲基化酶 ALKBH5 去除,而 FTO 作为 "清除剂 "的作用尚不确定。在这篇综述中,我们概述了与 mRNA 有关的表观转录组学,并重点讨论了 mRNA 中的 m6A 及其检测。我们总结了目前关于 m6A 的书写者、阅读者和擦除者的水平变化及其在乳腺癌中的作用以及与预后的关系的知识。我们总结了确定乳腺癌细胞基因中 m6A 峰值和位点的研究。
{"title":"m6A readers, writers, erasers, and the m6A epitranscriptome in breast cancer.","authors":"Belinda J Petri, Carolyn M Klinge","doi":"10.1530/JME-22-0110","DOIUrl":"10.1530/JME-22-0110","url":null,"abstract":"<p><p>Epitranscriptomic modification of RNA regulates human development, health, and disease. The true diversity of the transcriptome in breast cancer including chemical modification of transcribed RNA (epitranscriptomics) is not well understood due to limitations of technology and bioinformatic analysis. N-6-methyladenosine (m6A) is the most abundant epitranscriptomic modification of mRNA and regulates splicing, stability, translation, and intracellular localization of transcripts depending on m6A association with reader RNA-binding proteins. m6A methylation is catalyzed by the METTL3 complex and removed by specific m6A demethylase ALKBH5, with the role of FTO as an 'eraser' uncertain. In this review, we provide an overview of epitranscriptomics related to mRNA and focus on m6A in mRNA and its detection. We summarize current knowledge on altered levels of writers, readers, and erasers of m6A and their roles in breast cancer and their association with prognosis. We summarize studies identifying m6A peaks and sites in genes in breast cancer cells.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 2","pages":""},"PeriodicalIF":3.5,"publicationDate":"2022-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9790079/pdf/nihms-1854432.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10597023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Adipocyte signaling affects thyroid-specific gene expression via down-regulation of TTF-2/FOXE1. 脂肪细胞信号通过下调TTF-2/FOXE1影响甲状腺特异性基因的表达。
IF 3.5 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2022-12-12 Print Date: 2023-01-01 DOI: 10.1530/JME-22-0129
Michela Zamboni, Georgios Strimpakos, Eleonora Poggiogalle, Lorenzo Maria Donini, Donato Civitareale

Obesity affects thyroid gland function. Hypothyroidism, thyroid nodules, goiter, and thyroid cancer are more frequent in patients with higher BMI values. Although these data are supported by many clinical and epidemiological studies, our knowledge is very scarce at the molecular level. In this study, we present the first experimental evidence that adipocyte signaling downregulates the expression of thyroid-specific transcription factor 2 (TTF-2/FoxE1). It plays a crucial role in thyroid development and thyroid homeostasis and it is strictly connected to thyroid cancer as well. We provide in vivo and in vitro evidence that inhibition of TTF-2/FoxE1 gene expression is mediated by adipocyte signaling.

肥胖会影响甲状腺功能。甲状腺功能减退、甲状腺结节、甲状腺肿和甲状腺癌症在BMI值较高的患者中更常见。尽管这些数据得到了许多临床和流行病学研究的支持,但我们在分子水平上的知识非常匮乏。在这项研究中,我们首次提出了脂肪细胞信号下调甲状腺特异性转录因子2(TTF-2/FoxE1)表达的实验证据。它在甲状腺发育和甲状腺稳态中起着至关重要的作用,也与甲状腺癌症密切相关。我们提供了体内和体外证据,证明TTF-2/FoxE1基因表达的抑制是由脂肪细胞信号介导的。
{"title":"Adipocyte signaling affects thyroid-specific gene expression via down-regulation of TTF-2/FOXE1.","authors":"Michela Zamboni,&nbsp;Georgios Strimpakos,&nbsp;Eleonora Poggiogalle,&nbsp;Lorenzo Maria Donini,&nbsp;Donato Civitareale","doi":"10.1530/JME-22-0129","DOIUrl":"10.1530/JME-22-0129","url":null,"abstract":"<p><p>Obesity affects thyroid gland function. Hypothyroidism, thyroid nodules, goiter, and thyroid cancer are more frequent in patients with higher BMI values. Although these data are supported by many clinical and epidemiological studies, our knowledge is very scarce at the molecular level. In this study, we present the first experimental evidence that adipocyte signaling downregulates the expression of thyroid-specific transcription factor 2 (TTF-2/FoxE1). It plays a crucial role in thyroid development and thyroid homeostasis and it is strictly connected to thyroid cancer as well. We provide in vivo and in vitro evidence that inhibition of TTF-2/FoxE1 gene expression is mediated by adipocyte signaling.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2022-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10718922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Structure of full-length TSH receptor in complex with antibody K1-70™. 全长TSH受体与抗体K1-70复合物的结构。
IF 3.5 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2022-12-07 Print Date: 2023-01-01 DOI: 10.1530/JME-22-0120
Ricardo Núñez Miguel, Paul Sanders, Lloyd Allen, Michele Evans, Matthew Holly, William Johnson, Andrew Sullivan, Jane Sanders, Jadwiga Furmaniak, Bernard Rees Smith

Determination of the full-length thyroid-stimulating hormone receptor (TSHR) structure by cryo-electron microscopy (cryo-EM) is described. The TSHR complexed with human monoclonal TSHR autoantibody K1-70™ (a powerful inhibitor of TSH action) was detergent solubilised, purified to homogeneity and analysed by cryo-EM. The structure (global resolution 3.3 Å) is a monomer with all three domains visible: leucine-rich domain (LRD), hinge region (HR) and transmembrane domain (TMD). The TSHR extracellular domain (ECD, composed of the LRD and HR) is positioned on top of the TMD extracellular surface. Extensive interactions between the TMD and ECD are observed in the structure, and their analysis provides an explanation of the effects of various TSHR mutations on TSHR constitutive activity and on ligand-induced activation. K1-70™ is seen to be well clear of the lipid bilayer. However, superimposition of M22™ (a human monoclonal TSHR autoantibody which is a powerful stimulator of the TSHR) on the cryo-EM structure shows that it would clash with the bilayer unless the TSHR HR rotates upwards as part of the M22™ binding process. This rotation could have an important role in TSHR stimulation by M22™ and as such provides an explanation as to why K1-70™ blocks the binding of TSH and M22™ without activating the receptor itself.

描述了用冷冻电镜(cryo-EM)测定全长促甲状腺激素受体(TSHR)结构。TSHR与人单克隆TSHR自身抗体K1-70复合物™ (TSH作用的强大抑制剂)被洗涤剂溶解,纯化至均匀,并通过冷冻电镜进行分析。该结构(全局分辨率3.3Å)是一种单体,所有三个结构域都可见:富含亮氨酸的结构域(LRD)、铰链区(HR)和跨膜结构域(TMD)。TSHR细胞外结构域(ECD,由LRD和HR组成)位于TMD细胞外表面的顶部。在结构中观察到TMD和ECD之间的广泛相互作用,它们的分析解释了各种TSHR突变对TSHR组成活性和配体诱导的激活的影响。K1-70™ 被认为非常清楚脂质双层。然而,M22的叠加™ (一种人类单克隆TSHR自身抗体,是TSHR的强大刺激物)表明,除非TSHR HR作为M22的一部分向上旋转,否则它将与双层发生冲突™ 绑定过程。这种旋转可能在M22刺激TSHR中发挥重要作用™ 并因此解释了为什么K1-70™ 阻断TSH和M22的结合™ 而不激活受体本身。
{"title":"Structure of full-length TSH receptor in complex with antibody K1-70™.","authors":"Ricardo Núñez Miguel,&nbsp;Paul Sanders,&nbsp;Lloyd Allen,&nbsp;Michele Evans,&nbsp;Matthew Holly,&nbsp;William Johnson,&nbsp;Andrew Sullivan,&nbsp;Jane Sanders,&nbsp;Jadwiga Furmaniak,&nbsp;Bernard Rees Smith","doi":"10.1530/JME-22-0120","DOIUrl":"10.1530/JME-22-0120","url":null,"abstract":"<p><p>Determination of the full-length thyroid-stimulating hormone receptor (TSHR) structure by cryo-electron microscopy (cryo-EM) is described. The TSHR complexed with human monoclonal TSHR autoantibody K1-70™ (a powerful inhibitor of TSH action) was detergent solubilised, purified to homogeneity and analysed by cryo-EM. The structure (global resolution 3.3 Å) is a monomer with all three domains visible: leucine-rich domain (LRD), hinge region (HR) and transmembrane domain (TMD). The TSHR extracellular domain (ECD, composed of the LRD and HR) is positioned on top of the TMD extracellular surface. Extensive interactions between the TMD and ECD are observed in the structure, and their analysis provides an explanation of the effects of various TSHR mutations on TSHR constitutive activity and on ligand-induced activation. K1-70™ is seen to be well clear of the lipid bilayer. However, superimposition of M22™ (a human monoclonal TSHR autoantibody which is a powerful stimulator of the TSHR) on the cryo-EM structure shows that it would clash with the bilayer unless the TSHR HR rotates upwards as part of the M22™ binding process. This rotation could have an important role in TSHR stimulation by M22™ and as such provides an explanation as to why K1-70™ blocks the binding of TSH and M22™ without activating the receptor itself.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2022-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9782461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9087634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
The epidermal growth factor receptor in healthy pregnancy and preeclampsia. 健康妊娠和子痫前期的表皮生长因子受体。
IF 3.5 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2022-12-07 Print Date: 2023-01-01 DOI: 10.1530/JME-22-0105
Luca Clemente, Ian M Bird

The epidermal growth factor receptor (EGFR) is expressed robustly in the placenta, and critical processes of pregnancy such as placental growth and trophoblast fusion are dependent on EGFR function. However, the role that aberrant EGFR signaling might play in the etiology and/or maintenance of preeclampsia (PE) remains largely unexplored. Recently, we have shown that overexpression of EGFR in cultured uterine artery endothelial cells (UAEC), which express little endogenous EGFR, remaps responsiveness away from vascular endothelial growth factor receptor (VEGFR) signaling and toward EGFR, suggesting that endothelial EGFR expression may be kept low to preserve VEGFR control of angiogenesis. Here we will consider the evidence for the possibility that the endothelial dysfunction observed in PE might in some cases result from elevation of endothelial EGFR. During pregnancy, trophoblasts are known to synthesize large amounts of EGFR protein, and the placenta regularly releases syncytiotrophoblast-derived exosomes and microparticles into the maternal circulation. Although there are no reports of elevated EGFR gene expression in preeclamptic endothelial cells, the ongoing shedding of placental vesicles into the vascular system raises the possibility that EGFR-rich vesicles might fuse with endothelium, thereby contributing to the symptoms of PE by interrupting angiogenesis and blocking pregnancy-adapted vasodilatory function.

表皮生长因子受体(EGFR)在胎盘中表达旺盛,胎盘生长和滋养细胞融合等妊娠关键过程都依赖于表皮生长因子受体的功能。然而,表皮生长因子受体信号异常在子痫前期(PE)的病因和/或维持过程中可能扮演的角色在很大程度上仍未得到探讨。最近,我们发现在培养的子宫动脉内皮细胞(UAEC)中过表达表皮生长因子受体(EGFR)会使血管内皮生长因子受体(VEGFR)信号转导的反应性从血管内皮生长因子受体转向表皮生长因子受体,这表明内皮表皮生长因子受体的表达可能保持在较低水平,以维持血管内皮生长因子受体对血管生成的控制。在此,我们将考虑 PE 中观察到的内皮功能障碍在某些情况下可能是由内皮表皮生长因子受体升高引起的证据。众所周知,妊娠期间滋养细胞会合成大量表皮生长因子受体蛋白,胎盘会定期向母体循环中释放滋养细胞合成的外泌体和微颗粒。虽然目前还没有关于子痫前期内皮细胞中表皮生长因子受体基因表达升高的报道,但胎盘囊泡不断脱落进入血管系统,这使富含表皮生长因子受体的囊泡有可能与内皮融合,从而通过干扰血管生成和阻断妊娠适应性血管舒张功能来导致子痫症状。
{"title":"The epidermal growth factor receptor in healthy pregnancy and preeclampsia.","authors":"Luca Clemente, Ian M Bird","doi":"10.1530/JME-22-0105","DOIUrl":"10.1530/JME-22-0105","url":null,"abstract":"<p><p>The epidermal growth factor receptor (EGFR) is expressed robustly in the placenta, and critical processes of pregnancy such as placental growth and trophoblast fusion are dependent on EGFR function. However, the role that aberrant EGFR signaling might play in the etiology and/or maintenance of preeclampsia (PE) remains largely unexplored. Recently, we have shown that overexpression of EGFR in cultured uterine artery endothelial cells (UAEC), which express little endogenous EGFR, remaps responsiveness away from vascular endothelial growth factor receptor (VEGFR) signaling and toward EGFR, suggesting that endothelial EGFR expression may be kept low to preserve VEGFR control of angiogenesis. Here we will consider the evidence for the possibility that the endothelial dysfunction observed in PE might in some cases result from elevation of endothelial EGFR. During pregnancy, trophoblasts are known to synthesize large amounts of EGFR protein, and the placenta regularly releases syncytiotrophoblast-derived exosomes and microparticles into the maternal circulation. Although there are no reports of elevated EGFR gene expression in preeclamptic endothelial cells, the ongoing shedding of placental vesicles into the vascular system raises the possibility that EGFR-rich vesicles might fuse with endothelium, thereby contributing to the symptoms of PE by interrupting angiogenesis and blocking pregnancy-adapted vasodilatory function.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2022-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9742168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9840994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
Embarking on an adventure of early career academic leadership. 开始职业生涯初期的学术领导探险。
IF 3.6 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2022-12-07 Print Date: 2023-01-01 DOI: 10.1530/JME-22-0049
Tijana Mitić

Leading a research group as an early career researcher (ECR) in academia presents many challenges. First, it imposes many additional pressures on individuals, causing fear of missing out on a great opportunity that could advance your career. Together, the unsettling nature of short-term or temporary contracts, lack of guidance and the imposter syndrome can trigger a crisis in future leadership. Most leadership positions at universities are held by senior colleagues. ECRs have modest input in decision-making, due to a requirement for specific leadership training and experience with oversight that precedes suitable decision-making. The turbulence of the unprecedented world COVID-19 crisis has been felt disproportionally by many researchers, intensely by those with caring responsibilities. In the current academic climate, navigating either between your postdoctoral or fellowship project, leading others, taking strategic project directions, mentoring or networking may feel like too much. This editorial expresses views on the current state of the matter in academia with suggestions for helpful strategies to employ to meet research endpoints. It also addresses some challenges that new principal investigators and academic leaders may face due to external or institutional change, and provides some tangible advice with action points.

作为学术界的一名早期职业研究人员(ECR),领导一个研究小组面临着许多挑战。首先,它给个人带来了许多额外的压力,让人担心会错过一个可以促进自己职业发展的绝佳机会。此外,短期或临时合同的不稳定性、缺乏指导以及冒名顶替综合症都可能引发未来领导力危机。大学的大多数领导职位都由资深同事担任。由于在做出适当决策之前,需要接受专门的领导培训并具有监督经验,因此 ECR 在决策中的参与度并不高。COVID-19 这场前所未有的世界性危机所带来的动荡对许多研究人员的影响尤为严重,对那些肩负着照顾他人责任的研究人员来说更是如此。在当前的学术环境下,在博士后或研究金项目、领导他人、把握项目战略方向、指导或网络之间游刃有余,可能会让人感觉力不从心。这篇社论就学术界的现状发表了看法,并提出了一些有用的策略建议,以达到研究终点。它还探讨了新任首席研究员和学术带头人因外部或机构变化而可能面临的一些挑战,并提供了一些切实可行的建议和行动要点。
{"title":"Embarking on an adventure of early career academic leadership.","authors":"Tijana Mitić","doi":"10.1530/JME-22-0049","DOIUrl":"10.1530/JME-22-0049","url":null,"abstract":"<p><p>Leading a research group as an early career researcher (ECR) in academia presents many challenges. First, it imposes many additional pressures on individuals, causing fear of missing out on a great opportunity that could advance your career. Together, the unsettling nature of short-term or temporary contracts, lack of guidance and the imposter syndrome can trigger a crisis in future leadership. Most leadership positions at universities are held by senior colleagues. ECRs have modest input in decision-making, due to a requirement for specific leadership training and experience with oversight that precedes suitable decision-making. The turbulence of the unprecedented world COVID-19 crisis has been felt disproportionally by many researchers, intensely by those with caring responsibilities. In the current academic climate, navigating either between your postdoctoral or fellowship project, leading others, taking strategic project directions, mentoring or networking may feel like too much. This editorial expresses views on the current state of the matter in academia with suggestions for helpful strategies to employ to meet research endpoints. It also addresses some challenges that new principal investigators and academic leaders may face due to external or institutional change, and provides some tangible advice with action points.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2022-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11376210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10853248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Retinoid metabolism: new insights. 视黄醇代谢:新见解。
IF 3.5 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2022-10-11 Print Date: 2022-11-01 DOI: 10.1530/JME-22-0082
Lorraine J Gudas

Vitamin A (retinol) is a critical micronutrient required for the control of stem cell functions, cell differentiation, and cell metabolism in many different cell types, both during embryogenesis and in the adult organism. However, we must obtain vitamin A from food sources. Thus, the uptake and metabolism of vitamin A by intestinal epithelial cells, the storage of vitamin A in the liver, and the metabolism of vitamin A in target cells to more biologically active metabolites, such as retinoic acid (RA) and 4-oxo-RA, must be precisely regulated. Here, I will discuss the enzymes that metabolize vitamin A to RA and the cytochrome P450 Cyp26 family of enzymes that further oxidize RA. Because much progress has been made in understanding the regulation of ALDH1a2 (RALDH2) actions in the intestine, one focus of this review is on the metabolism of vitamin A in intestinal epithelial cells and dendritic cells. Another focus is on recent data that 4-oxo-RA is a ligand required for the maintenance of hematopoietic stem cell dormancy and the important role of RARβ (RARB) in these stem cells. Despite this progress, many questions remain in this research area, which links vitamin A metabolism to nutrition, immune functions, developmental biology, and nuclear receptor pharmacology.

维生素A(视黄醇)是一种关键的微量营养素,在胚胎发生和成年生物体中,它是控制许多不同细胞类型的干细胞功能、细胞分化和细胞代谢所必需的。然而,我们必须从食物中获取维生素A。因此,必须精确调节肠上皮细胞对维生素A的摄取和代谢、维生素A在肝脏中的储存以及维生素A在靶细胞中代谢为更具生物活性的代谢产物,如视黄酸(RA)和4-氧代-RA。在这里,我将讨论将维生素A代谢为RA的酶和进一步氧化RA的细胞色素P450 Cyp26酶家族。由于在理解ALDH12a2(RALDH2)在肠道中的作用调节方面已经取得了很大进展,本综述的一个重点是维生素A在肠上皮细胞和树突状细胞中的代谢。另一个焦点是最近的数据,即4-氧代-RA是维持造血干细胞休眠所需的配体,以及RARβ(RARB)在这些干细胞中的重要作用。尽管取得了这一进展,但该研究领域仍存在许多问题,将维生素A代谢与营养、免疫功能、发育生物学和核受体药理学联系起来。
{"title":"Retinoid metabolism: new insights.","authors":"Lorraine J Gudas","doi":"10.1530/JME-22-0082","DOIUrl":"10.1530/JME-22-0082","url":null,"abstract":"<p><p>Vitamin A (retinol) is a critical micronutrient required for the control of stem cell functions, cell differentiation, and cell metabolism in many different cell types, both during embryogenesis and in the adult organism. However, we must obtain vitamin A from food sources. Thus, the uptake and metabolism of vitamin A by intestinal epithelial cells, the storage of vitamin A in the liver, and the metabolism of vitamin A in target cells to more biologically active metabolites, such as retinoic acid (RA) and 4-oxo-RA, must be precisely regulated. Here, I will discuss the enzymes that metabolize vitamin A to RA and the cytochrome P450 Cyp26 family of enzymes that further oxidize RA. Because much progress has been made in understanding the regulation of ALDH1a2 (RALDH2) actions in the intestine, one focus of this review is on the metabolism of vitamin A in intestinal epithelial cells and dendritic cells. Another focus is on recent data that 4-oxo-RA is a ligand required for the maintenance of hematopoietic stem cell dormancy and the important role of RARβ (RARB) in these stem cells. Despite this progress, many questions remain in this research area, which links vitamin A metabolism to nutrition, immune functions, developmental biology, and nuclear receptor pharmacology.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"69 4","pages":"T37-T49"},"PeriodicalIF":3.5,"publicationDate":"2022-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9561048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9286094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 9
Retinoic acid receptor structures: the journey from single domains to full-length complex. 视黄酸受体结构:从单一结构域到全长复合体的历程。
IF 3.6 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2022-10-11 Print Date: 2022-11-01 DOI: 10.1530/JME-22-0113
Fraydoon Rastinejad

The retinoic acid receptors (RARα, β, and γ) are multi-domain polypeptides that heterodimerize with retinoid X receptors (RXRα, β, and γ) to form functional transcription factors. Understanding the three-dimensional molecular organization of these nuclear receptors (NRs) began with RAR and RXR DNA-binding domains (DBDs), and were followed with studies on isolated ligand-binding domains (LBDs). The more complete picture emerged in 2017 with the multi-domain crystal structure of RXRα-RARβ on its response element with retinoic acid molecules and coactivator segments on both proteins. The analysis of that structure and its complementary studies have clarified the direct communication pathways within RXR-RAR polypeptides, through which DNA binding, protein-ligand, and protein-protein interactions are integrated for overall functional responses. Understanding the molecular connections in the RXR-RAR complex has benefited from direct observations of the multi-domain structures of RXRα-PPARγ, RXRα-LXRβ, HNF-4α homodimer, and androgen receptor homodimer, each bound to its response element. These comprehensive NR structures show unique quaternary architectures, yet all have DBD-DBD, LBD-LBD, and DBD-LBD domain-domain contacts within them. These convergence zones allow signals from discrete domains of their polypeptides to be propagated and integrated across their entire complex, shaping their overall responses in an allosteric fashion.

视黄酸受体(RARα、β和γ)是一种多结构域多肽,与类视黄醇X受体(RXRα、α和γ)异二聚形成功能性转录因子。了解这些核受体(NRs)的三维分子组织始于RAR和RXR DNA结合域(DBD),随后是对分离的配体结合域(LBD)的研究。2017年,RXRα-RARβ在其反应元件上的多结构域晶体结构与视黄酸分子和两种蛋白质上的共激活因子片段出现了更完整的画面。对该结构的分析及其互补研究已经阐明了RXR-RR多肽内的直接通讯途径,通过这些途径,DNA结合、蛋白质配体和蛋白质-蛋白质相互作用被整合以获得整体功能反应。了解RXR-RR复合物中的分子连接得益于对RXRα-PPARγ、RXRα-LXRβ、HNF-4α同源二聚体和雄激素受体同源二聚物的多结构域结构的直接观察,每个结构域都与其反应元件结合。这些全面的NR结构显示出独特的四元结构,但它们都具有DBD-DBD、LBD-LBD和DBD-LBD结构域接触。这些汇聚区允许来自其多肽的离散结构域的信号在其整个复合物中传播和整合,以变构方式形成其整体反应。
{"title":"Retinoic acid receptor structures: the journey from single domains to full-length complex.","authors":"Fraydoon Rastinejad","doi":"10.1530/JME-22-0113","DOIUrl":"10.1530/JME-22-0113","url":null,"abstract":"<p><p>The retinoic acid receptors (RARα, β, and γ) are multi-domain polypeptides that heterodimerize with retinoid X receptors (RXRα, β, and γ) to form functional transcription factors. Understanding the three-dimensional molecular organization of these nuclear receptors (NRs) began with RAR and RXR DNA-binding domains (DBDs), and were followed with studies on isolated ligand-binding domains (LBDs). The more complete picture emerged in 2017 with the multi-domain crystal structure of RXRα-RARβ on its response element with retinoic acid molecules and coactivator segments on both proteins. The analysis of that structure and its complementary studies have clarified the direct communication pathways within RXR-RAR polypeptides, through which DNA binding, protein-ligand, and protein-protein interactions are integrated for overall functional responses. Understanding the molecular connections in the RXR-RAR complex has benefited from direct observations of the multi-domain structures of RXRα-PPARγ, RXRα-LXRβ, HNF-4α homodimer, and androgen receptor homodimer, each bound to its response element. These comprehensive NR structures show unique quaternary architectures, yet all have DBD-DBD, LBD-LBD, and DBD-LBD domain-domain contacts within them. These convergence zones allow signals from discrete domains of their polypeptides to be propagated and integrated across their entire complex, shaping their overall responses in an allosteric fashion.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"69 4","pages":"T25-T36"},"PeriodicalIF":3.6,"publicationDate":"2022-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11376212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9109310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Retinoic acid, RARs and early development. 维甲酸、RARs和早期发育。
IF 3.5 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2022-10-11 Print Date: 2022-11-01 DOI: 10.1530/JME-22-0041
Marie Berenguer, Gregg Duester

Vitamin A (retinol) is an important nutrient for embryonic development and adult health. Early studies identified retinoic acid (RA) as a metabolite of retinol, however, its importance was not apparent. Later, it was observed that RA treatment of vertebrate embryos had teratogenic effects on limb development. Subsequently, the discovery of nuclear RA receptors (RARs) revealed that RA controls gene expression directly at the transcriptional level through a process referred to as RA signaling. This important discovery led to further studies demonstrating that RA and RARs are required for normal embryonic development. The determination of RA function during normal development has been challenging as RA gain-of-function studies often lead to conclusions about normal development that conflict with RAR or RA loss-of-function studies. However, genetic loss-of-function studies have identified direct target genes of endogenous RA/RAR that are required for normal development of specific tissues. Thus, genetic loss-of-function studies that eliminate RARs or RA-generating enzymes have been instrumental in revealing that RA signaling is required for normal early development of many organs and tissues, including the hindbrain, posterior body axis, somites, spinal cord, forelimbs, heart, and eye.

维生素A(视黄醇)是胚胎发育和成人健康的重要营养素。早期的研究发现视黄酸(RA)是视黄醇的代谢物,但其重要性并不明显。后来,观察到脊椎动物胚胎的RA治疗对肢体发育有致畸作用。随后,核RA受体(RARs)的发现表明,RA通过称为RA信号传导的过程直接在转录水平上控制基因表达。这一重要发现导致进一步的研究表明RA和RARs是正常胚胎发育所必需的。正常发育期间RA功能的确定一直具有挑战性,因为RA功能获得研究经常得出与RAR或RA功能丧失研究相冲突的正常发育结论。然而,基因功能缺失研究已经确定了内源性RA/RAR的直接靶基因,这些基因是特定组织正常发育所必需的。因此,消除RARs或RA生成酶的基因功能丧失研究有助于揭示RA信号是许多器官和组织正常早期发育所必需的,包括后脑、后体轴、体突、脊髓、前肢、心脏和眼睛。
{"title":"Retinoic acid, RARs and early development.","authors":"Marie Berenguer,&nbsp;Gregg Duester","doi":"10.1530/JME-22-0041","DOIUrl":"10.1530/JME-22-0041","url":null,"abstract":"<p><p>Vitamin A (retinol) is an important nutrient for embryonic development and adult health. Early studies identified retinoic acid (RA) as a metabolite of retinol, however, its importance was not apparent. Later, it was observed that RA treatment of vertebrate embryos had teratogenic effects on limb development. Subsequently, the discovery of nuclear RA receptors (RARs) revealed that RA controls gene expression directly at the transcriptional level through a process referred to as RA signaling. This important discovery led to further studies demonstrating that RA and RARs are required for normal embryonic development. The determination of RA function during normal development has been challenging as RA gain-of-function studies often lead to conclusions about normal development that conflict with RAR or RA loss-of-function studies. However, genetic loss-of-function studies have identified direct target genes of endogenous RA/RAR that are required for normal development of specific tissues. Thus, genetic loss-of-function studies that eliminate RARs or RA-generating enzymes have been instrumental in revealing that RA signaling is required for normal early development of many organs and tissues, including the hindbrain, posterior body axis, somites, spinal cord, forelimbs, heart, and eye.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"1 1","pages":"T59-T67"},"PeriodicalIF":3.5,"publicationDate":"2022-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9561040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41363455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 10
Female reproductive dysfunctions and the gut microbiota. 女性生殖功能障碍和肠道菌群。
IF 3.5 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2022-08-04 Print Date: 2022-10-01 DOI: 10.1530/JME-21-0238
Sangappa B Chadchan, Vertika Singh, Ramakrishna Kommagani

The gut microbiome is considered an endocrine organ that can influence distant organs and associated biological pathways. Recent advances suggest that gut microbial homeostasis is essential for reproductive health and that perturbations in the gut microbiota can lead to reproductive pathologies. This review provides an updated overview of the relationship between the gut microbiome and female reproductive diseases. Specifically, we highlight the most recent findings on the gut microbiome in gynecological pathologies including polycystic ovarian syndrome, endometriosis, and endometrial cancer. Most studies revealed associations between altered gut microbial compositions and these reproductive diseases, though few have suggested cause-effect relationships. Future studies should focus on determining the molecular mechanisms underlying associations between gut microbiota and reproductive diseases. Understanding this bidirectional relationship could lead to the development of novel and effective strategies to prevent, diagnose, and treat female reproductive organ-related diseases.

肠道微生物组被认为是一种内分泌器官,可以影响远处的器官和相关的生物途径。最近的进展表明,肠道微生物稳态对生殖健康至关重要,肠道微生物群的紊乱可能导致生殖病理。这篇综述提供了肠道微生物组与女性生殖疾病之间关系的最新综述。具体而言,我们强调了妇科病理中肠道微生物组的最新发现,包括多囊卵巢综合征、子宫内膜异位症和子宫内膜癌症。大多数研究揭示了肠道微生物组成的改变与这些生殖疾病之间的联系,尽管很少有研究表明因果关系。未来的研究应侧重于确定肠道微生物群与生殖疾病之间潜在联系的分子机制。了解这种双向关系可以开发新的有效策略来预防、诊断和治疗女性生殖器官相关疾病。
{"title":"Female reproductive dysfunctions and the gut microbiota.","authors":"Sangappa B Chadchan,&nbsp;Vertika Singh,&nbsp;Ramakrishna Kommagani","doi":"10.1530/JME-21-0238","DOIUrl":"10.1530/JME-21-0238","url":null,"abstract":"<p><p>The gut microbiome is considered an endocrine organ that can influence distant organs and associated biological pathways. Recent advances suggest that gut microbial homeostasis is essential for reproductive health and that perturbations in the gut microbiota can lead to reproductive pathologies. This review provides an updated overview of the relationship between the gut microbiome and female reproductive diseases. Specifically, we highlight the most recent findings on the gut microbiome in gynecological pathologies including polycystic ovarian syndrome, endometriosis, and endometrial cancer. Most studies revealed associations between altered gut microbial compositions and these reproductive diseases, though few have suggested cause-effect relationships. Future studies should focus on determining the molecular mechanisms underlying associations between gut microbiota and reproductive diseases. Understanding this bidirectional relationship could lead to the development of novel and effective strategies to prevent, diagnose, and treat female reproductive organ-related diseases.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"69 3","pages":"R81-R94"},"PeriodicalIF":3.5,"publicationDate":"2022-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10031513/pdf/nihms-1825897.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9170927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 14
Insulin signaling in the heart is impaired by growth hormone: a direct and early event. 心脏中的胰岛素信号受到生长激素的损害:这是一个直接和早期的事件。
IF 3.5 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2022-08-01 DOI: 10.1530/JME-21-0242
Marina C Muñoz, Verónica G Piazza, Valeria Burghi, Jorge F Giani, Carolina S Martinez, Nadia S Cicconi, Nadia V Muia, Yimin Fang, Sergio Lavandero, Ana I Sotelo, Andrzej Bartke, Patricia A Pennisi, Fernando P Dominici, Johanna G Miquet
Growth hormone (GH) exerts major actions in cardiac growth and metabolism. Considering the important role of insulin in the heart and the well-established anti-insulin effects of GH, cardiac insulin resistance may play a role in the cardiopathology observed in acromegalic patients. As conditions of prolonged exposure to GH are associated with a concomitant increase of circulating GH, IGF-1 and insulin levels, to dissect the direct effects of GH, in this study we evaluated the activation of insulin signaling in the heart using four different models: 1) transgenic mice overexpressing GH, with chronically elevated GH, IGF-1 and insulin circulating levels, 2) liver IGF-1-deficient mice, with chronically elevated GH and insulin but decreased IGF-1 circulating levels, 3) mice treated with GH for a short period of time, and 4) primary culture of rat cardiomyocytes incubated with GH. Despite the differences in the development of cardiomegaly and in the metabolic alterations among the three experimental mouse models analysed, exposure to GH was consistently associated with a decreased response to acute insulin stimulation in the heart at the receptor level and through the PI3K/Akt pathway. Moreover, a blunted response to insulin stimulation of this signaling pathway was also observed in cultured cardiomyocytes of neonatal rats incubated with GH. Therefore, the key novel finding of this work is that impairment of insulin signaling in the heart is a direct and early event observed as a consequence of exposure to GH, which may play a major role in the development of cardiac pathology.
生长激素(GH)在心脏生长和代谢中发挥重要作用。考虑到胰岛素在心脏中的重要作用以及生长激素的抗胰岛素作用,心脏胰岛素抵抗可能在肢端肥大症患者的心脏病理中起作用。由于长期暴露于生长激素的条件与伴随的循环生长激素、IGF1和胰岛素水平的增加有关,为了解剖生长激素的直接影响,在本研究中,我们使用四种不同的模型评估了心脏中胰岛素信号的激活:(i)转基因小鼠过度表达生长激素,长期升高生长激素、IGF1和胰岛素循环水平;(ii)肝脏IGF1缺陷小鼠,生长激素和胰岛素长期升高,但IGF1循环水平降低;(iii)短时间用生长激素治疗小鼠;(iv) GH孵育大鼠心肌细胞的原代培养。尽管所分析的三种实验小鼠模型在心脏肥大的发展和代谢改变方面存在差异,但生长激素暴露始终与心脏受体水平和PI3K/AKT通路对急性胰岛素刺激的反应降低有关。此外,在GH培养的新生大鼠心肌细胞中也观察到胰岛素刺激对该信号通路的迟钝反应。因此,这项工作的关键新发现是心脏中胰岛素信号的损伤是暴露于生长激素的直接和早期事件,这可能在心脏病理的发展中起主要作用。
{"title":"Insulin signaling in the heart is impaired by growth hormone: a direct and early event.","authors":"Marina C Muñoz,&nbsp;Verónica G Piazza,&nbsp;Valeria Burghi,&nbsp;Jorge F Giani,&nbsp;Carolina S Martinez,&nbsp;Nadia S Cicconi,&nbsp;Nadia V Muia,&nbsp;Yimin Fang,&nbsp;Sergio Lavandero,&nbsp;Ana I Sotelo,&nbsp;Andrzej Bartke,&nbsp;Patricia A Pennisi,&nbsp;Fernando P Dominici,&nbsp;Johanna G Miquet","doi":"10.1530/JME-21-0242","DOIUrl":"https://doi.org/10.1530/JME-21-0242","url":null,"abstract":"Growth hormone (GH) exerts major actions in cardiac growth and metabolism. Considering the important role of insulin in the heart and the well-established anti-insulin effects of GH, cardiac insulin resistance may play a role in the cardiopathology observed in acromegalic patients. As conditions of prolonged exposure to GH are associated with a concomitant increase of circulating GH, IGF-1 and insulin levels, to dissect the direct effects of GH, in this study we evaluated the activation of insulin signaling in the heart using four different models: 1) transgenic mice overexpressing GH, with chronically elevated GH, IGF-1 and insulin circulating levels, 2) liver IGF-1-deficient mice, with chronically elevated GH and insulin but decreased IGF-1 circulating levels, 3) mice treated with GH for a short period of time, and 4) primary culture of rat cardiomyocytes incubated with GH. Despite the differences in the development of cardiomegaly and in the metabolic alterations among the three experimental mouse models analysed, exposure to GH was consistently associated with a decreased response to acute insulin stimulation in the heart at the receptor level and through the PI3K/Akt pathway. Moreover, a blunted response to insulin stimulation of this signaling pathway was also observed in cultured cardiomyocytes of neonatal rats incubated with GH. Therefore, the key novel finding of this work is that impairment of insulin signaling in the heart is a direct and early event observed as a consequence of exposure to GH, which may play a major role in the development of cardiac pathology.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"69 2","pages":"357-376"},"PeriodicalIF":3.5,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9339477/pdf/nihms-1813926.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9968262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Journal of molecular endocrinology
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1