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20 Years Anniversary for SORLA/SORL1 (1996-2016) SORLA/SORL1 20周年纪念(1996-2016)
Pub Date : 2019-05-07 DOI: 10.14800/rci.1611
G. Monti, O. Andersen
SORLA is a sorting receptor known to control the intracellular trafficking of the amyloid precursor protein, which impaired pathway has a central role in the development of Alzheimer’s disease (AD). Recently, genetic analyses confirmed the casual role for SORLA in AD, as coding variants and single nucleotide polymorphisms of SORL1 (gene encoding SORLA) were identified in individuals affected by early-onset AD and late-onset AD, respectively. However, many other different types of ligands were found to target the receptor, thus strongly indicating that SORLA can exert multifunctional activities. In the current review, we provide an overview of the multi-ligand properties of SORLA, showing how this complex receptor is involved in a variety of biological functions.
SORLA是一种已知的分选受体,可控制淀粉样蛋白前体蛋白的细胞内运输,其受损通路在阿尔茨海默病(AD)的发展中起核心作用。最近,遗传分析证实了SORLA在AD中的偶然作用,因为在早发性AD和晚发性AD患者中分别发现了SORL1(编码SORLA的基因)的编码变异和单核苷酸多态性。然而,许多其他不同类型的配体被发现靶向受体,从而强烈表明SORLA可以发挥多功能活性。在当前的综述中,我们提供了SORLA的多配体特性的概述,展示了这种复杂受体是如何参与各种生物学功能的。
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引用次数: 3
The role of leptin in the central nervous system remyelination 瘦素在中枢神经系统髓鞘再生中的作用
Pub Date : 2019-05-07 DOI: 10.14800/RCI.1583
K. Matoba, R. Muramatsu, T. Yamashita
Leptin is identified as a mouse obesity gene, which is also preserved in humans. Leptin receptor is highly expressed in the hypothalamus relative to other tissues; therefore, the function of leptin is mainly attributed to hypothalamic control of food intake and body weight. Although the expression of leptin receptors is not limited to the hypothalamus but is also present in other regions of the central nervous system (CNS), such as the spinal cord, the functions of leptin and leptin receptor in the CNS have not been fully clarified. In this research highlight, we focus on the novel function of leptin in CNS remyelination in pathologic conditions, such as the demyelination mouse model. Because remyelination is a crucial process for repair of neuronal networks after injury and wound healing, knowledge of the underlying molecular mechanism of remyelination is useful to establish a therapeutic strategy against demyelinating diseases. We only revealed the role of leptin in remyelination at a histological level; however, a behavioral analysis and evidence of the beneficial effect of leptin for humans may add to knowledge of the effect of leptin on remyelination function.
瘦素是一种小鼠肥胖基因,在人类中也存在。相对于其他组织,瘦素受体在下丘脑高度表达;因此,瘦素的功能主要归因于下丘脑对食物摄入和体重的控制。虽然瘦素受体的表达并不局限于下丘脑,也存在于中枢神经系统(CNS)的其他区域,如脊髓,但瘦素和瘦素受体在中枢神经系统(CNS)中的功能尚未完全阐明。在本研究重点中,我们重点关注瘦素在病理条件下,如脱髓鞘小鼠模型中,在中枢神经系统脱髓鞘中的新功能。由于髓鞘再生是损伤和伤口愈合后神经网络修复的关键过程,因此了解髓鞘再生的潜在分子机制有助于建立针对脱髓鞘疾病的治疗策略。我们只在组织学水平上揭示了瘦素在髓鞘再生中的作用;然而,对瘦素对人类有益作用的行为分析和证据可能会增加对瘦素对髓鞘再生功能影响的认识。
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引用次数: 0
Targeting sympathetic glia for treating cardiovascular diseases 靶向交感神经胶质治疗心血管疾病
Pub Date : 2019-04-27 DOI: 10.14800/RCI.1572
A. Xie, Angelo Chaia, K. McCarthy
Gq G protein-coupled receptor (Gq-GPCR) signaling in glial fibrillary acidic protein-expressing (GFAP + ) glia is essential for neuron-glia interaction in the Central Nervous System (CNS). However, the exploration of the roles of Gq-GPCR signaling in peripheral GFAP + glia has just begun. Our recent study showed that GFAP + glia in the sympathetic ganglia, namely satellite glial cells (SGCs), positively modulate sympathetic-regulated cardiac functions following their Gq-GPCR activation. In this research highlight, we discuss the significance of satellite glial modulation of sympathetic nerve activity (SNA) in both physiology and in diseases. We also present a new experimental strategy for manipulating satellite glial signaling in the sympathetic ganglia using adeno-associated virus (AAV). The success of targeted viral transduction in ganglionic SGCs suggest a strong therapeutic potential of targeting sympathetic glia for the treatment of cardiovascular diseases (CVDs).
Gq蛋白偶联受体(Gq- gpcr)信号在中枢神经系统(CNS)中对神经元-胶质相互作用至关重要。然而,关于Gq-GPCR信号在外周GFAP +胶质细胞中的作用的探索才刚刚开始。我们最近的研究表明,交感神经节中的GFAP +胶质细胞,即卫星胶质细胞(SGCs),在其Gq-GPCR激活后,正调节交感调节的心功能。在本研究重点中,我们讨论了卫星胶质调节交感神经活动(SNA)在生理和疾病中的意义。我们还提出了一种利用腺相关病毒(AAV)操纵交感神经节卫星胶质信号的新实验策略。在神经节细胞SGCs中靶向病毒转导的成功表明,靶向交感神经胶质治疗心血管疾病(cvd)具有很强的治疗潜力。
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引用次数: 2
Computational analysis in Influenza virus 流感病毒的计算分析
Pub Date : 2017-07-31 DOI: 10.14800/RCI.1574
R. Chavan, S. Bapat, V. Patil, A. Chowdhary, A. Kale
Influenza viruses are major human pathogens accountable for respiratory diseases affecting millions of people worldwide and characterized by high morbidity and significant mortality. Influenza infections can be controlled by vaccination and antiviral drugs. However, vaccines need yearly updating and give limited protection. In addition, the currently available drugs suffer from the rapid and extensive emergence of drug resistance. All this highlights the urgent need for developing new antiviral strategies with novel mechanisms of action and with reduced drug resistance potential. Recent advances in the understanding of Influenza virus replication have discovered a number of cellular drug targets that counteract viral drug resistance. With expanded bioinformatics’ knowledge on computational modeling and molecular dynamic stimulations, novel small molecule inhibitors of herbal/ayurvedic origin are being explored due to their non-toxicity and affordability. Using in-silico techniques the structural details and information of influenza protein have been studied to identify the potential drugs for inhibition. Further, we have discussed the various computational studies carried out on major protein/targets of Influenza which could provide new clues for a newer class of antiviral (ayurvedic) drugs. In the years to come ahead, the influenza treatment will go through major changes, with advancing our knowledge of pathogenesis as new methods becoming clinically validated.
流感病毒是造成影响全世界数百万人的呼吸道疾病的主要人类病原体,其特点是高发病率和高死亡率。流感感染可通过接种疫苗和使用抗病毒药物加以控制。然而,疫苗需要每年更新,并且提供有限的保护。此外,目前可用的药物受到迅速和广泛出现的耐药性的影响。所有这些都突出表明迫切需要开发具有新的作用机制和降低耐药潜力的新的抗病毒策略。最近在了解流感病毒复制方面的进展已经发现了一些细胞药物靶点,这些靶点可以抵消病毒的耐药性。随着生物信息学在计算建模和分子动力学刺激方面的知识的扩展,源于草药/阿育吠陀的新型小分子抑制剂由于其无毒和可负担性正在被探索。利用计算机技术研究了流感蛋白的结构细节和信息,以确定潜在的抑制药物。此外,我们还讨论了针对流感主要蛋白/靶点进行的各种计算研究,这些研究可能为开发一类新的抗病毒(阿育吠陀)药物提供新的线索。在未来的几年里,流感治疗将经历重大变化,随着新方法的临床验证,我们对发病机理的认识将不断提高。
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引用次数: 0
HIF-1α promotes NSCs migration by modulating Slit2-Robo1 signaling after cerebral ischemia 脑缺血后HIF-1α通过调节Slit2-Robo1信号通路促进NSCs迁移
Pub Date : 2017-06-26 DOI: 10.14800/RCI.1549
Hua Ye, Minrong Chen, Wan-fu Wu
Our previous studies have shown that transplantation of Hypoxia-inducible factor-1α (HIF-1α) gene modified neural stem cells (NSCs) reduced brain injury by improving the survival of NSCs and protecting the vascular system. HIF-1α plays pivotal roles during hypoxia, and its downstream pathways might be the primary mechanisms for the growth of NSCs. However, there are very few studies reported whether HIF-1α regulates NSCs migration. In this study, to test the hypothesis that HIF-1α modulates migration of NSCs after cerebral ischemia, we compared the injection of HIF-1α gene recombinant adenovirus, and control adenovirus in ischemia penumbra at 24 h after transient middle cerebral artery occlusion (tMCAO). BrdU labeled NSCs were transplanted in the lateral ventricle at the same time in both groups. The modified neurological severity score (NSS) was used to evaluate neurological deficits. Immunohistochemistry for HIF-1α, BrdU, Slit2 and Robo1 were performed. Comparing with vehicle group HIF-1α group showed better behavioral recovery on day 21 and 28. Expression of HIF-1α in HIF-1α group is higher than that in vehicle group. In HIF-1α group, more BrdU-positive cells were found than that in vehicle group. There are increased Slit2 in HIF-1α group. However, robo1, a receptor of Slits is decreased than that in vehicle group. Thus, we concluded that in cerebral ischemia rat model HIF-1α increased NSCs migration by inhibiting Slit2-Robo1 pathway, and improved the neurological behavior. In conclusion, our results indicate that HIF-1α may be a potential therapeutic target for ischemic stroke through promoting neuroregeneration.
我们之前的研究表明,缺氧诱导因子-1α (HIF-1α)基因修饰的神经干细胞(NSCs)移植通过提高NSCs的存活率和保护血管系统来减少脑损伤。HIF-1α在缺氧过程中起关键作用,其下游通路可能是NSCs生长的主要机制。然而,HIF-1α是否调节NSCs迁移的研究很少。为了验证HIF-1α调节脑缺血后NSCs迁移的假说,我们比较了短暂性大脑中动脉闭塞(tMCAO)后24 h在缺血半暗区注射HIF-1α基因重组腺病毒和对照腺病毒。两组同时将BrdU标记的NSCs移植至侧脑室。改良神经严重程度评分(NSS)用于评估神经功能缺损。对HIF-1α、BrdU、Slit2和Robo1进行免疫组化。与对照组相比,HIF-1α组在第21、28天表现出较好的行为恢复。HIF-1α组中HIF-1α的表达高于载药组。HIF-1α组brdu阳性细胞明显多于对照组。HIF-1α组Slit2升高。而Slits受体robo1较载药组减少。因此,我们认为在脑缺血大鼠模型中,HIF-1α通过抑制Slit2-Robo1通路增加NSCs的迁移,改善神经行为。总之,我们的研究结果表明HIF-1α可能通过促进神经再生成为缺血性卒中的潜在治疗靶点。
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引用次数: 0
Zero to one: normal derived human ER+ cells in culture-proliferating 0到1:正常来源的人ER+细胞在培养中增殖
Pub Date : 2016-12-27 DOI: 10.14800/RCI.1449
B. M. Hopkinson
Cell culture technology is used to model structural and functional properties of human organs under normal and pathological conditions “in a dish”. The most obvious reason to culture human breast-derived cells is our fundamental desire to understand and ultimately treat breast cancer. Highly reproducible serum-free formulations for long-term propagation of normal human breast epithelial cells have existed for more than three decades and have served to complement the insight gained from a vast number of established breast cancer cell lines. The unspoken dichotomy in the experimental approach, however, has lied in the puzzling fact that normal-derived cells show a more myoepithelial expression profile, while breast cancer cells show more of a luminal profile making these difficult to compare experimentally. Moreover, normal estrogen receptor positive (ER+) luminal cells, thought to be equivalents to the most frequent form of human breast cancer, the ER+ subtype, completely fail to grow under standard culture conditions. One might choose to ignore this fact since breast homeostasis relies on a stem cell hierarchy and stem cells reside in the myoepithelial compartment which, if given the right conditions, can differentiate into ER+ luminal cells. The problem with this is that myoepithelial cells in culture, for unknown reasons, fail to behave like myoepithelial cells in vivo. This review summarizes some of the progress that has been made in the field with regard to the ER+ luminal breast epithelial lineage, especially within a human context, and its relevance to human breast cancer.
细胞培养技术用于在“培养皿”中模拟正常和病理条件下人体器官的结构和功能特性。培养人类乳腺细胞最明显的原因是我们了解并最终治疗乳腺癌的基本愿望。用于正常人类乳腺上皮细胞长期增殖的高可重复性无血清制剂已经存在了30多年,并为从大量已建立的乳腺癌细胞系中获得的见解提供了补充。然而,实验方法中不言而喻的二分法在于一个令人困惑的事实,即正常来源的细胞表现出更多的肌上皮表达谱,而乳腺癌细胞则表现出更多的管腔表达谱,这使得它们难以在实验中进行比较。此外,正常的雌激素受体阳性(ER+)腔细胞,被认为相当于最常见的人类乳腺癌形式,ER+亚型,在标准培养条件下完全不能生长。人们可能会选择忽略这一事实,因为乳腺内稳态依赖于干细胞层次结构,而干细胞位于肌上皮室中,如果给予适当的条件,可以分化为ER+腔细胞。问题是,由于未知的原因,培养的肌上皮细胞不能像体内的肌上皮细胞那样表现。本文综述了在ER+腔内乳腺上皮谱系方面取得的一些进展,特别是在人类背景下,以及它与人类乳腺癌的相关性。
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引用次数: 0
Activation of necroptosis to overcome drug resistance in leukemia 活化坏死下垂克服白血病耐药
Pub Date : 2016-10-24 DOI: 10.14800/RCI.1440
B. Bornhauser, J. Aguadé-Gorgorió
The understanding of cell death mechanisms is crucial for the development and application of novel anti-cancer therapies to avoid or circumvent drug-resistance in refractory malignancies. Impairment of apoptotic cell death plays a major role in therapy resistance and relapse of acute lymphoblastic leukemia (ALL) patients. Therefore, efforts are being directed at new agents reactivating apoptosis or inducing alternative cell death pathways such as necroptosis, a regulated form of necrosis. In a recent study published in Science Translational Medicine we show that the IAP (inhibitor of apoptosis proteins) inhibitor birinapant potently induces cell death in patient-derived ALL cells in vitro and in vivo through a receptor-interacting protein kinase 1- (RIP1) dependent mechanism. To define the cell death modality induced downstream of RIP1, we used a multicolor lentiCRISPR approach that allows simultaneous knockout of multiple genes. We observed that apoptosis and necroptosis are induced simultaneously as the inhibition of both pathways is required to restore cell viability upon birinapant treatment.  This induction of dual cell death makes birinapant and other IAP inhibitors interesting agents for the treatment of refractory or drug resistant malignancies.
了解细胞死亡机制对于开发和应用新的抗癌疗法以避免或规避难治性恶性肿瘤的耐药性至关重要。凋亡细胞死亡损伤在急性淋巴细胞白血病(ALL)患者的治疗耐药和复发中起重要作用。因此,人们正在努力寻找新的药物来重新激活细胞凋亡或诱导其他细胞死亡途径,如坏死下垂(一种受调节的坏死形式)。最近发表在《科学转化医学》杂志上的一项研究表明,IAP(凋亡蛋白抑制剂)抑制剂birinapant通过受体相互作用蛋白激酶1- (RIP1)依赖机制,在体外和体内诱导患者源性ALL细胞的细胞死亡。为了确定RIP1下游诱导的细胞死亡模式,我们使用了一种允许同时敲除多个基因的多色透镜crispr方法。我们观察到细胞凋亡和坏死下垂是同时诱导的,因为抑制这两种途径是在双抗治疗后恢复细胞活力所必需的。双细胞死亡的诱导使biinapant和其他IAP抑制剂成为治疗难治性或耐药恶性肿瘤的有趣药物。
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引用次数: 0
The ephrin-B2/EphB4 system is required in musculoskeletal development and protects the articulation during osteoarthritis: a research highlight ephrin-B2/EphB4系统是肌肉骨骼发育所必需的,并保护骨关节炎期间的关节:一个研究热点
Pub Date : 2016-09-26 DOI: 10.14800/RCI.1426
J. Martel-Pelletier, G. Valverde-Franco, J. Pelletier
Ephrin ligands and their Eph receptors have been implicated in the control of extracellular matrix of some tissues. Although ephrin-B2 and its specific receptor EphB4 were found to be involved in postembryonic control of bone homeostasis, their roles were unclear in musculoskeletal growth and development as well as in osteoarthritis pathology. The role of this ephrin system in musculoskeletal growth and development was delineated in vivo using a cartilage-specific ephrin-B2 knockout mouse model. Its role in osteoarthritis in vivo was explored in mice using a bone-specific overexpression of EphB4 in which osteoarthritis was induced, and in vitro in human osteoarthritic subchondral bone osteoblasts and chondrocytes. In vivo , ephrin-B2 demonstrated to be essential for normal long bone growth and development and its absence in cartilage led to knee and hip osteoarthritis features in aged mice. In vitro data showed that the ephrin-B2-induced EphB4 receptor positively impacted the abnormal metabolism of both osteoarthritic subchondral bone osteoblasts and chondrocytes. The bone‑specific EphB4 overexpression in mice validated the in vitro data in that it had beneficial effects not only on the osteoarthritic subchondral bone but also on the cartilage and synovial membrane, and further substantiated the hypothesis that by prophylactically protecting the subchondral bone, the genesis of osteoarthritis could be, at least in part, inhibited. In the context of identifying new candidates targeting osteoarthritis progression, this ephrin system is extremely attractive as a potential novel therapeutic avenue, as therapies having a more global articular approach may prove to be the most successful to arrest or slow the progression of this disease.
Ephrin配体及其Eph受体与一些组织的细胞外基质调控有关。虽然发现ephrin-B2及其特异性受体EphB4参与胚胎后骨稳态的控制,但它们在肌肉骨骼生长发育以及骨关节炎病理中的作用尚不清楚。利用软骨特异性ephrin- b2敲除小鼠模型,在体内描述了这种ephrin系统在肌肉骨骼生长和发育中的作用。在小鼠体内通过诱导骨关节炎的骨特异性过表达EphB4来探索其在骨关节炎中的作用,并在体外在人骨关节炎软骨下成骨细胞和软骨细胞中进行了研究。在体内,ephrin-B2被证明是正常长骨生长和发育所必需的,在软骨中缺乏ephrin-B2导致老年小鼠膝关节和髋关节骨关节炎的特征。体外实验结果显示,ephrin- b2诱导的EphB4受体对骨关节炎软骨下成骨细胞和软骨细胞代谢异常均有正向影响。骨特异性EphB4在小鼠体内的过表达证实了体外数据,它不仅对骨关节炎软骨下骨,而且对软骨和滑膜都有有益的影响,并进一步证实了通过预防性保护软骨下骨,至少在一定程度上可以抑制骨关节炎的发生的假设。在确定针对骨关节炎进展的新候选药物的背景下,这种ephrin系统作为一种潜在的新治疗途径非常有吸引力,因为具有更全面的关节方法的治疗可能被证明是最成功的阻止或减缓这种疾病的进展。
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引用次数: 0
Structural and functional insights into a quorum-sensing signal peptide receptor, the ComD histidine protein kinase of streptococcus mutans 变异链球菌群体感应信号肽受体ComD组氨酸蛋白激酶的结构和功能研究
Pub Date : 2016-09-19 DOI: 10.14800/RCI.1424
Xiaolin Tian, Yung-Hua Li
Quorum sensing activation by signal peptide pheromones (SP) in Gram-positive bacteria depends on a membrane-associated histidine kinase receptor, which senses the signal and triggers the signaling cascade for various cell density-dependent activities. However, relatively little is known of peptide pheromone-receptor interactions in these bacteria, largely because of technical challenges in working with membrane-associated proteins in these bacteria. Recently, we have described a genetic approach and several analysis methods to studying membrane topology and structure-function interaction of a quorum sensing pheromone receptor ComD in a Gram-positive bacterium Streptococcus mutans . Using these methods, we confirm that the membrane-spanning domain of the ComD protein forms six transmembrane segments and three extracellular loops, loopA, loopB and loopC. By mutational analyses of these three extracellular loops, we demonstrate that both loopC and loopB are required for signal recognition and quorum sensing activation, while loopA plays little role in signal detection. In particular, a deletion or substitution mutation of four residues NVIP within loopC abolishes signal recognition for quorum sensing activation. Consistent with these findings, the loopC and loopB mutants are completely or partially defective in bacteriocin production. We conclude that both loopC and loopB are required to form the signal peptide receptor and the residues NVIP of loopC are essential for signal recognition and quorum sensing activation in S. mutans .
在革兰氏阳性细菌中,信号肽信息素(SP)的群体感应激活依赖于膜相关的组氨酸激酶受体,该受体感知信号并触发各种细胞密度依赖性活动的信号级联。然而,对这些细菌中肽信息素受体相互作用的了解相对较少,主要是因为在这些细菌中处理膜相关蛋白的技术挑战。最近,我们描述了一种遗传方法和几种分析方法来研究革兰氏阳性细菌变形链球菌群体感应信息素受体ComD的膜拓扑结构和结构-功能相互作用。通过这些方法,我们证实了ComD蛋白的跨膜结构域形成6个跨膜片段和3个细胞外环,环a,环b和环c。通过对这三个细胞外环的突变分析,我们发现loopC和loopB都是信号识别和群体感应激活所必需的,而loopA在信号检测中起不到什么作用。特别是,环c中四个残基NVIP的缺失或替换突变取消了群体感应激活的信号识别。与这些发现一致,loopC和loopB突变体在细菌素的产生中完全或部分有缺陷。我们得出结论,loopC和loopB都是形成信号肽受体所必需的,并且loopC的残基NVIP对于突变链球菌的信号识别和群体感应激活至关重要。
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引用次数: 0
HOIL1 cleavage by MALT1, the knives are out HOIL1切割由MALT1,刀是出来的
Pub Date : 2016-09-14 DOI: 10.14800/RCI.1410
Tiphaine Douanne, N. Bidère
The paracaspase MALT1 functions as a bifunctional regulator of lymphocyte activation following the engagement of antigen receptors. First, MALT1 scaffolds the CARMA1-BCL10-MALT1 (CBM) signaling complex in charge of activating the NF-κB transcription factor. Second, MALT1 proteolytic activity governs NF-κB fine-tuning and the homeostasis of the immune system. MALT1 is also constitutively activated in the activated B-cell like (ABC) subset of diffuse large B-cell lymphoma (DLBCL), and the discovery that its chemical inhibition is toxic has opened new perspectives of treatment. Yet, the nature of MALT1 substrates continues to be elucidated. Herein, we review the recent identification of the linear ubiquitin assembly chain complex (LUBAC) element HOIL1 as a new substrate for MALT1 in lymphocytes and lymphoma. We discuss how this processing may affect NF-κB signaling and impact on lymphocyte homeostasis.
副半胱天蛋白酶MALT1在抗原受体参与后作为淋巴细胞活化的双功能调节剂。首先,MALT1是CARMA1-BCL10-MALT1 (CBM)信号复合物的支架,负责激活NF-κB转录因子。其次,MALT1蛋白水解活性控制着NF-κB的微调和免疫系统的稳态。MALT1也在弥漫性大b细胞淋巴瘤(DLBCL)的活化b细胞样(ABC)亚群中被组成性激活,其化学抑制是毒性的发现为治疗开辟了新的视角。然而,MALT1底物的性质仍在继续阐明。在此,我们回顾了最近发现的线性泛素组装链复合物(LUBAC)元件HOIL1作为淋巴细胞和淋巴瘤中MALT1的新底物。我们讨论了这个过程如何影响NF-κB信号传导和对淋巴细胞稳态的影响。
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引用次数: 0
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Receptors and clinical investigation
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