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Targeting microglial autophagic degradation of the NLRP3 inflammasome for identification of thonningianin A in Alzheimer's disease. 靶向NLRP3炎性体的小胶质细胞自噬降解在阿尔茨海默病中的鉴定
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2022-08-03 DOI: 10.1186/s41232-022-00209-7
Xiao-Gang Zhou, Wen-Qiao Qiu, Lu Yu, Rong Pan, Jin-Feng Teng, Zhi-Pei Sang, Betty Yuen-Kwan Law, Ya Zhao, Li Zhang, Lu Yan, Yong Tang, Xiao-Lei Sun, Vincent Kam Wai Wong, Chong-Lin Yu, Jian-Ming Wu, Da-Lian Qin, An-Guo Wu

Background: NLRP3 inflammasome-mediated neuroinflammation plays a critical role in the pathogenesis and development of Alzheimer's disease (AD). Microglial autophagic degradation not only decreases the deposits of extracellular Aβ fibrils but also inhibits the activation of NRLP3 inflammasome. Here, we aimed to identify the potent autophagy enhancers from Penthorum chinense Pursh (PCP) that alleviate the pathology of AD via inhibiting the NLRP3 inflammasome.

Methods: At first, autophagic activity-guided isolation was performed to identify the autophagy enhancers in PCP. Secondly, the autophagy effect was monitored by detecting LC3 protein expression using Western blotting and the average number of GFP-LC3 puncta per microglial cell using confocal microscopy. Then, the activation of NLRP3 inflammasome was measured by detecting the protein expression and transfected fluorescence intensity of NLRP3, ASC, and caspase-1, as well as the secretion of proinflammatory cytokines. Finally, the behavioral performance was evaluated by measuring the paralysis in C. elegans, and the cognitive function was tested by Morris water maze (MWM) in APP/PS1 mice.

Results: Four ellagitannin flavonoids, including pinocembrin-7-O-[4″,6″-hexahydroxydiphenoyl]-glucoside (PHG), pinocembrin-7-O-[3″-O-galloyl-4″,6″-hexahydroxydiphenoyl]-glucoside (PGHG), thonningianin A (TA), and thonningianin B (TB), were identified to be autophagy enhancers in PCP. Among these, TA exhibited the strongest autophagy induction effect, and the mechanistic study demonstrated that TA activated autophagy via the AMPK/ULK1 and Raf/MEK/ERK signaling pathways. In addition, TA effectively promoted the autophagic degradation of NLRP3 inflammasome in Aβ(1-42)-induced microglial cells and ameliorated neuronal damage via autophagy induction. In vivo, TA activated autophagy and improved behavioral symptoms in C. elegans. Furthermore, TA might penetrate the blood-brain barrier and could improve cognitive function and ameliorate the Aβ pathology and the NLRP3 inflammasome-mediated neuroinflammation via the AMPK/ULK1 and Raf/MEK/ERK signaling pathways in APP/PS1 mice.

Conclusion: We identified TA as a potent microglial autophagy enhancer in PCP that promotes the autophagic degradation of the NLRP3 inflammasome to alleviate the pathology of AD via the AMPK/ULK1 and Raf/MEK/ERK signaling pathways, which provides novel insights for TA in the treatment of AD.

背景:NLRP3炎症小体介导的神经炎症在阿尔茨海默病(AD)的发病和发展中起着关键作用。小胶质细胞的自噬降解不仅减少了细胞外Aβ原纤维的沉积,而且抑制了NRLP3炎性小体的激活。在这里,我们的目的是鉴定来自Penthorum chinense Pursh (PCP)的有效自噬增强剂,通过抑制NLRP3炎性体来减轻AD的病理。方法:首先采用自噬活性引导分离方法鉴定PCP中自噬促进因子。其次,通过Western blotting检测LC3蛋白表达,共聚焦显微镜检测每个小胶质细胞GFP-LC3点的平均数量,监测自噬效应。然后,通过检测NLRP3、ASC、caspase-1的蛋白表达、转染荧光强度以及促炎细胞因子的分泌,检测NLRP3炎性小体的活化情况。最后,通过测量秀丽隐杆线虫的麻痹程度来评估其行为表现,并通过Morris水迷宫(MWM)测试APP/PS1小鼠的认知功能。结果:鉴定出4种鞣花单宁类黄酮类化合物,分别为:松皮素-7- o -[4″,6″-六羟基二酚]-葡萄糖苷(PHG)、松皮素-7- o -[3″- o -没食子酰基-4″,6″-六羟基二酚]-葡萄糖苷(PGHG)、松皮素A (TA)和松皮素B (TB),可促进PCP的自噬。其中,TA诱导自噬作用最强,机制研究表明TA通过AMPK/ULK1和Raf/MEK/ERK信号通路激活自噬。此外,TA有效促进了Aβ(1-42)诱导的小胶质细胞NLRP3炎性体的自噬降解,并通过自噬诱导改善神经元损伤。在体内,TA激活了秀丽隐杆线虫的自噬并改善了行为症状。此外,TA可能穿过血脑屏障,通过AMPK/ULK1和Raf/MEK/ERK信号通路改善APP/PS1小鼠的认知功能,改善Aβ病理和NLRP3炎症小体介导的神经炎症。结论:我们发现TA在PCP中是一种有效的小胶质细胞自噬增强剂,通过AMPK/ULK1和Raf/MEK/ERK信号通路促进NLRP3炎性体的自噬降解,从而减轻AD的病理,这为TA治疗AD提供了新的见解。
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引用次数: 12
Diet-induced obesity impairs spermatogenesis: the critical role of NLRP3 in Sertoli cells. 饮食诱导的肥胖损害精子发生:NLRP3在支持细胞中的关键作用。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2022-08-02 DOI: 10.1186/s41232-022-00203-z
Yang Mu, Tai-Lang Yin, Yan Zhang, Jing Yang, Yan-Ting Wu

Background: Accumulating evidence indicates a key role of Sertoli cell (SC) malfunction in spermatogenesis impairment induced by obesity. Nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) is expressed in SCs, but the role of NLRP3 in the pathological process of obesity-induced male infertility remains unclear.

Methods: NLRP3-deficient mice were fed a high-fat diet for 24 weeks to establish obesity-related spermatogenesis impairment. In another set of experiments, a lentiviral vector containing a microRNA (miR)-451 inhibitor was injected into AMP-activated protein kinase α (AMPKα)-deficient mouse seminiferous tubules. Human testis samples were obtained by testicular puncture from men with obstructive azoospermia whose samples exhibited histologically normal spermatogenesis. Isolated human SCs were treated with palmitic acid (PA) to mimic obesity model in vitro.

Results: Increased NLRP3 expression was observed in the testes of obese rodents. NLRP3 was also upregulated in PA-treated human SCs. NLRP3 deficiency attenuated obesity-related male infertility. SC-derived NLRP3 promoted interleukin-1β (IL-1β) secretion to impair testosterone synthesis and sperm performance and increased matrix metalloproteinase-8 (MMP-8) expression to degrade occludin via activation of nuclear factor-kappa B (NF-κB). Increased miR-451 caused by obesity, decreased AMPKα expression and sequentially increased NADPH oxidase activity were responsible for the activation of NLRP3. miR-451 inhibition protected against obesity-related male infertility, and these protective effects were abolished by AMPKα deficiency in mice.

Conclusions: NLRP3 promoted obesity-related spermatogenesis impairment. Increased miR-451 expression, impaired AMPKα pathway and the subsequent ROS production were responsible for NLRP3 activation. Our study provides new insight into the mechanisms underlying obesity-associated male infertility.

背景:越来越多的证据表明,支持细胞(SC)功能障碍在肥胖引起的精子发生障碍中起着关键作用。具有pyrin结构域3的核苷酸结合寡聚化结构域样受体(NLRP3)在SCs中表达,但NLRP3在肥胖诱导的男性不育病理过程中的作用尚不清楚。方法:用高脂饮食喂养nlrp3缺陷小鼠24周,建立肥胖相关的精子发生障碍。在另一组实验中,将含有microRNA (miR)-451抑制剂的慢病毒载体注射到amp活化蛋白激酶α (AMPKα)缺陷的小鼠精管中。人类睾丸样本是通过睾丸穿刺从梗阻性无精子症的男性获得的,其样本在组织学上表现为正常的精子发生。用棕榈酸(PA)处理离体人SCs,模拟肥胖模型。结果:肥胖鼠睾丸NLRP3表达升高。在pa处理的人SCs中,NLRP3也上调。NLRP3缺乏可减轻肥胖相关男性不育。sc来源的NLRP3促进白细胞介素-1β (IL-1β)分泌,从而影响睾酮合成和精子性能,并通过激活核因子κB (NF-κB)增加基质金属蛋白酶-8 (MMP-8)表达,从而降解occludin。肥胖导致miR-451升高,AMPKα表达降低,NADPH氧化酶活性随之升高是NLRP3激活的原因。miR-451抑制对肥胖相关的男性不育具有保护作用,而这些保护作用被小鼠AMPKα缺乏所消除。结论:NLRP3促进肥胖相关的精子发生障碍。miR-451表达增加、AMPKα通路受损以及随后的ROS产生是NLRP3激活的原因。我们的研究为肥胖相关男性不育的潜在机制提供了新的见解。
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引用次数: 7
Extracellular vesicles in idiopathic pulmonary fibrosis: pathogenesis and therapeutics. 特发性肺纤维化的细胞外囊泡:发病机制和治疗方法。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2022-08-01 DOI: 10.1186/s41232-022-00210-0
Yu Fujita

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease that occurs due to increased fibrosis of lung tissue in response to chronic injury of the epithelium. Therapeutic options for IPF remain limited as current therapies only function to decrease disease progression. Recently, extracellular vesicles (EVs), including exosomes and microvesicles, have been recognized as paracrine communicators through the component cargo. The population of cell-specific microRNAs and proteins present in EVs can regulate gene expressions of recipient cells, resulting in modulation of biological activities. EV cargoes reflect cell types and their physiological and pathological status of donor cells. Many current researches have highlighted the functions of EVs on the epithelial phenotype and fibroproliferative response in the pathogenesis of IPF. Furthermore, some native EVs could be used as a cell-free therapeutic approach for IPF as vehicles for drug delivery, given their intrinsic biocompatibility and specific target activity. EV-based therapies have been proposed as a new potential alternative to cell-based approaches. The advantage is that EVs, depending on their source, may be less immunogenic than their parental cells, likely due to a lower abundance of transmembrane proteins such as major histocompatibility complex (MHC) proteins on the surface. In the last decade, mesenchymal stem cell (MSC)-derived EVs have been rapidly developed as therapeutic products ready for clinical trials against various diseases. Considering EV functional complexity and heterogeneity, there is an urgent need to establish refined systemic standards for manufacturing processes and regulatory requirements of these medicines. This review highlights the EV-mediated cellular crosstalk involved in IPF pathogenesis and discusses the potential for EV-based therapeutics as a novel treatment modality for IPF.

特发性肺纤维化(Idiopathic pulmonary fibrosis, IPF)是一种进行性肺部疾病,是由于慢性上皮损伤导致肺组织纤维化增加而发生的。IPF的治疗选择仍然有限,因为目前的治疗方法只起到减少疾病进展的作用。最近,细胞外囊泡(EVs),包括外泌体和微囊泡,已被认为是通过成分货物的旁分泌通讯员。ev中存在的细胞特异性microrna和蛋白质群体可以调节受体细胞的基因表达,从而调节生物活性。EV载物反映供体细胞的细胞类型及其生理病理状态。目前许多研究都强调了EVs在IPF发病机制中对上皮表型和纤维增殖反应的作用。此外,由于其固有的生物相容性和特异性靶标活性,一些天然ev可以作为IPF的无细胞治疗方法作为药物递送的载体。基于ev的治疗方法被认为是一种新的潜在的替代细胞治疗方法。其优势在于,取决于其来源,ev的免疫原性可能低于其亲本细胞,这可能是由于表面上的跨膜蛋白(如主要组织相容性复合体(MHC)蛋白)丰度较低。在过去的十年中,间充质干细胞(MSC)衍生的ev已经迅速发展成为治疗各种疾病的治疗产品。考虑到EV功能的复杂性和异质性,迫切需要为这些药物的生产工艺和监管要求建立完善的系统标准。这篇综述强调了ev介导的细胞串扰在IPF发病机制中的作用,并讨论了ev为基础的治疗方法作为一种新的IPF治疗方式的潜力。
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引用次数: 9
Inflammation-associated premetastatic niche formation. 炎症相关的转移前龛位形成。
IF 5 3区 医学 Q2 IMMUNOLOGY Pub Date : 2022-07-03 DOI: 10.1186/s41232-022-00208-8
Atsuko Deguchi, Yoshiro Maru

Metastasis remains the leading cause of cancer-related death. In 1889, Stephen Paget originally proposed the theory "seed-and-soil." Both cancer cell-intrinsic properties ("seed") and fertile microenvironment ("soil") are essential for metastasis formation. To date, accumulating evidences supported the theory using mouse models. The formation of a premetastatic niche has been widely accepted as an accel for metastasis. Similar to tumor microenvironment, various types of cells, such as immune cells, endothelial cells, and fibroblasts are involved in premetastatic niche formation. We have discovered that primary tumors hijack Toll-like receptor 4 (TLR4) signaling to establish a premetastatic niche in the lung by utilizing the endogenous ligands. In this review, we discuss the mechanisms that underlie inflammation-associated premetastatic niche formation upon metastasis, focusing especially on myeloid cells and macrophages as the cells executing and mediating complicated processes.

转移仍然是癌症相关死亡的主要原因。1889 年,斯蒂芬-帕吉特最初提出了 "种子与土壤 "理论。癌细胞的内在特性("种子")和肥沃的微环境("土壤")都是转移形成的必要条件。迄今为止,越来越多的小鼠模型证据支持这一理论。转移前生态位的形成已被广泛认为是转移的加速因素。与肿瘤微环境类似,免疫细胞、内皮细胞和成纤维细胞等各类细胞也参与了转移前生态位的形成。我们发现,原发性肿瘤会劫持Toll样受体4(TLR4)信号,利用内源性配体在肺部建立转移前生态位。在这篇综述中,我们讨论了转移时与炎症相关的转移前生态位形成的机制,尤其侧重于作为执行和介导复杂过程的细胞的骨髓细胞和巨噬细胞。
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引用次数: 0
Clinical perspectives and therapeutic strategies: pediatric autoinflammatory disease-a multi-faceted approach to fever of unknown origin of childhood. 临床观点和治疗策略:儿童自身炎症疾病-一个多方面的途径不明起源的儿童发烧。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2022-07-02 DOI: 10.1186/s41232-022-00204-y
Akihiro Yachie

Among the different etiologies for fever of unknown origin in children, infectious diseases are the most frequent final diagnosis, followed by autoimmune diseases and malignancies. Autoinflammatory diseases are relatively rare among children and are frequently overlooked as differential diagnoses for fever of unknown origin. Once the possibility of a particular autoimmune disease is considered by physicians, the diagnosis might be easily made by a genetic approach because many of autoinflammatory diseases are of monogenic origin. To reach the diagnosis, detailed history-taking, precise physical examinations, and cytokine profiling as well as extensive mutation analysis of candidate genes should be undertaken for febrile children. Such the approach will protect the patients, and their family to undergo "diagnostic odyssey" in which unnecessary and sometimes risky diagnostic and therapeutic interventions are taken.This short review discusses the clinical and laboratory features of familial Mediterranean fever and systemic juvenile idiopathic arthritis, as representative illnesses of monogenic and polygenic autoinflammatory diseases, respectively. Cytokine profiling and mutation analyses both help to understand and decipher the heterogeneous pathologies in both disease categories.

在各种病因不明的儿童发热中,感染性疾病是最常见的最终诊断,其次是自身免疫性疾病和恶性肿瘤。自身炎症性疾病在儿童中相对罕见,但作为不明原因发热的鉴别诊断常常被忽视。一旦医生考虑到某种自身免疫性疾病的可能性,通过遗传学方法就很容易做出诊断,因为许多自身炎症性疾病都是单基因起源的。为达到诊断,应对发热儿童进行详细的病史记录、精确的体格检查、细胞因子谱分析以及广泛的候选基因突变分析。这种方法将保护患者及其家属免受“诊断奥德赛”的困扰,在这一过程中,采取了不必要的、有时是危险的诊断和治疗干预措施。这篇简短的综述讨论了家族性地中海热和系统性青少年特发性关节炎的临床和实验室特征,分别作为单基因和多基因自身炎症疾病的代表疾病。细胞因子谱分析和突变分析都有助于理解和破译这两种疾病类别的异质性病理。
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引用次数: 0
Single transcription factor efficiently leads human induced pluripotent stem cells to functional microglia. 单转录因子有效诱导人多能干细胞向功能性小胶质细胞转变。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2022-07-01 DOI: 10.1186/s41232-022-00201-1
Iki Sonn, Fumiko Honda-Ozaki, Sho Yoshimatsu, Satoru Morimoto, Hirotaka Watanabe, Hideyuki Okano

Background: Microglia are innate immune cells that are the only residential macrophages in the central nervous system. They play vital physiological roles in the adult brain and during development. Microglia are particularly in the spotlight because many genetic risk factors recently identified for neurodegenerative diseases are largely expressed in microglia. Rare polymorphisms in these risk alleles lead to abnormal activity of microglia under traumatic or disease conditions.

Methods: In the present study, to investigate the multifaceted functions of human microglia, we established a novel robust protocol to generate microglia from human induced pluripotent stem cells (hiPSCs) using a combination of cytokines and small chemicals essential for microglia ontogeny. Moreover, we highly enhanced the microglial differentiation efficiency by forcing the expression of PU.1, a crucial transcription factor for microglial development, during posterior mesoderm differentiation.

Results: By our novel method, we demonstrated the generation of a greater number of hiPSC-derived microglia (hiMGLs, approximately 120-folds) than the prior methods (at most 40-folds). Over 90% of the hiMGLs expressed microglia-specific markers, such as CX3CR1 and IBA-1. Whole-transcriptome analysis revealed that these hiMGLs are similar to human primary microglia but differ from monocytes/macrophages. Furthermore, the specific physiological functions of microglia were confirmed through indices of lipopolysaccharide responsiveness, phagocytotic ability, and inflammasome formation. By co-culturing these hiMGLs with mouse primary neurons, we demonstrated that hiMGLs can regulate the activity and maturation of neurons.

Conclusions: In this study, our new simple, rapid, and highly efficient method for generating microglia from hiPSCs will prove useful for future investigations on microglia in both physiological and disease conditions, as well as for drug discovery.

背景:小胶质细胞是一种天然免疫细胞,是中枢神经系统中唯一的巨噬细胞。它们在成人大脑和发育过程中起着至关重要的生理作用。小胶质细胞尤其受到关注,因为最近发现的许多神经退行性疾病的遗传风险因素主要在小胶质细胞中表达。这些风险等位基因的罕见多态性导致小胶质细胞在创伤或疾病条件下的异常活动。方法:在本研究中,为了研究人类小胶质细胞的多方面功能,我们建立了一种新的强大的方案,利用细胞因子和小胶质细胞个体发育所必需的小化学物质的组合,从人诱导多能干细胞(hiPSCs)生成小胶质细胞。此外,我们通过在后中胚层分化过程中强制表达PU.1(小胶质细胞发育的关键转录因子),大大提高了小胶质细胞的分化效率。结果:通过我们的新方法,我们证明了产生更多的hipsc衍生的小胶质细胞(hiMGLs,大约120倍)比以前的方法(最多40倍)。超过90%的hiMGLs表达小胶质细胞特异性标志物,如CX3CR1和IBA-1。全转录组分析显示,这些hiMGLs与人类初级小胶质细胞相似,但与单核细胞/巨噬细胞不同。此外,通过脂多糖反应性、吞噬能力和炎性体形成等指标证实了小胶质细胞的特定生理功能。通过将这些hiMGLs与小鼠原代神经元共培养,我们发现hiMGLs可以调节神经元的活性和成熟。结论:在这项研究中,我们新的简单、快速、高效的从hipsc中生成小胶质细胞的方法将为未来小胶质细胞在生理和疾病条件下的研究以及药物发现提供有用的方法。
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引用次数: 8
Marine-derived microbes and molecules for drug discovery 用于药物发现的海洋微生物和分子
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2022-06-03 DOI: 10.1186/s41232-022-00207-9
Yoshimasa Tanaka, M. Nishikawa, Kaho Kamisaki, Saki Hachiya, Moeka Nakamura, Takahiro Kuwazuru, S. Tanimura, K. Soyano, K. Takeda
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引用次数: 2
Duration of SARS-CoV-2 RNA positivity from various specimens and clinical characteristics in patients with COVID-19: a systematic review and meta-analysis. 不同标本中SARS-CoV-2 RNA阳性持续时间与COVID-19患者临床特征:系统综述和荟萃分析
IF 5 3区 医学 Q2 IMMUNOLOGY Pub Date : 2022-06-01 DOI: 10.1186/s41232-022-00205-x
Yasutaka Okita, Takayoshi Morita, Atsushi Kumanogoh

Background: The duration of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA positivity will be important to prevent the spread of coronavirus disease 2019 (COVID-19). A systematic review and meta-analysis were conducted following PRISMA to determine the duration from several parts of the body and clinical characteristics affecting it.

Main text: PubMed, Web of Science, Scopus, and CENTRAL were searched for original studies reporting the duration from COVID-19 onset to the disappearance of viral RNA. Of the 1682 studies identified, 100 met the selection criteria and 13,431 patients were included in this study. The duration of SARS-CoV-2 RNA positivity was 18.29 [95% confidence interval: 17.00-19.89] days in the upper respiratory tract samples, 23.79 [20.43-27.16] days in the sputum, 14.60 [12.16-17.05] days in the blood, and 22.38 [18.40-26.35] days in the stool. Sensitivity analysis revealed that the duration was positively correlated with age, comorbidities, severity, and usage of glucocorticoid. Subgroup analysis indicated that the presence or absence of complications had the greatest impact on the difference in DSRP.

Conclusions: The duration of SARS-CoV-2 RNA positivity was 18.29 days in the upper respiratory tract samples. The duration in the sputum and the stool was longer, while that in the blood was shorter. The duration in the upper respiratory tract samples was longer in older, with any comorbidities, severer, and treated with glucocorticoid. These results provide the basic data for the duration of SARS-CoV-2 RNA positivity, and in the future, the effect of vaccination against SARS-CoV-2 and the SARS-CoV-2 variants on the duration of RNA positivity should be assessed.

背景:严重急性呼吸系统综合征冠状病毒2(SARS-CoV-2)RNA阳性持续时间对于预防2019年冠状病毒病(COVID-19)的传播非常重要。按照PRISMA进行了系统综述和荟萃分析,以确定来自身体多个部位的持续时间和影响其的临床特征:PubMed、Web of Science、Scopus和CENTRAL检索了报告COVID-19发病至病毒RNA消失持续时间的原始研究。在找到的 1682 项研究中,有 100 项符合选择标准,13431 名患者被纳入本研究。在上呼吸道样本中,SARS-CoV-2 RNA 阳性持续时间为 18.29 天[95% 置信区间:17.00-19.89];在痰液中,持续时间为 23.79 天[20.43-27.16];在血液中,持续时间为 14.60 天[12.16-17.05];在粪便中,持续时间为 22.38 天[18.40-26.35]。敏感性分析表明,病程与年龄、合并症、严重程度和使用糖皮质激素呈正相关。亚组分析表明,有无并发症对DSRP的差异影响最大:结论:在上呼吸道样本中,SARS-CoV-2 RNA 阳性持续时间为 18.29 天。痰和粪便中的持续时间较长,而血液中的持续时间较短。年龄较大、有任何合并症、病情较重和接受过糖皮质激素治疗的患者上呼吸道样本中的持续时间较长。这些结果为 SARS-CoV-2 RNA 阳性持续时间提供了基本数据,今后应评估接种 SARS-CoV-2 疫苗和 SARS-CoV-2 变种对 RNA 阳性持续时间的影响。
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引用次数: 0
Neuroplasticity related to chronic pain and its modulation by microglia 与慢性疼痛相关的神经可塑性及其小胶质细胞的调节
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2022-05-03 DOI: 10.1186/s41232-022-00199-6
Shin-ichiro Hiraga, T. Itokazu, Mariko Nishibe, T. Yamashita
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引用次数: 18
The superficial zone of articular cartilage 关节软骨的浅层
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2022-05-02 DOI: 10.1186/s41232-022-00202-0
Taku Saito
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引用次数: 12
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Inflammation and Regeneration
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