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991.
Qinghong Wang Jijun Zhou Bei Zhang Zhiqiang Tian Jun Tang Yanhua Zheng Zemin Huang Yi Tian Zhengcai Jia Yan Tang Jennifer C. van Velkinburgh Qing Mao Xiuwu Bian Yifang Ping Bing Ni Yuzhang Wu 《PLoS pathogens》2013,9(6)
IL-23 regulates myriad processes in the innate and adaptive immune systems, and is a critical mediator of the proinflammatory effects exerted by Th17 cells in many diseases. In this study, we investigated whether and how hepatitis B virus (HBV) causes liver damage directly through the IL-23 signaling pathway. In biopsied liver tissues from HBV-infected patients, expression of both IL-23 and IL-23R was remarkably elevated. In vivo observations also indicated that the main sources of IL-23 were myeloid dendritic cells (mDCs) and macrophages. Analysis of in vitro differentiated immature DCs and macrophages isolated from healthy donors revealed that the HBV surface antigen (HBsAg) efficiently induces IL-23 secretion in a mannose receptor (MR)-dependent manner. Culture with an endosomal acidification inhibitor and the dynamin inhibitor showed that, upon binding to the MR, the HBsAg is taken up by mDCs and macrophages through an endocytosis mechanism. In contrast, although the HBV core antigen (HBcAg) can also stimulate IL-23 secretion from mDCs, the process was MR- and endocytosis-independent. In addition, IL-23 was shown to be indispensible for HBsAg-stimulated differentiation of naïve CD4+ T cells into Th17 cells, which were determined to be the primary source of IL-17 in HBV-infected livers. The cognate receptor, IL-17R, was found to exist on the hepatic stellate cells and mDCs, both of which might represent the potential target cells of IL-17 in hepatitis B disease. These data provide novel insights into a yet unrecognized mechanism of HBV-induced hepatitis, by which increases in IL-23 expression, through an MR/endocytosis-dependent or -independent manner, produce liver damage through the IL-23/IL-17 axis. 相似文献
992.
Kristen M. Varney Alexandre M. J. J. Bonvin Marzena Pazgier Jakob Malin Wenbo Yu Eugene Ateh Taiji Oashi Wuyuan Lu Jing Huang Marlies Diepeveen-de Buin Joseph Bryant Eefjan Breukink Alexander D. MacKerell Jr Erik P. H. de Leeuw 《PLoS pathogens》2013,9(11)
We have previously reported on the functional interaction of Lipid II with human alpha-defensins, a class of antimicrobial peptides. Lipid II is an essential precursor for bacterial cell wall biosynthesis and an ideal and validated target for natural antibiotic compounds. Using a combination of structural, functional and in silico analyses, we present here the molecular basis for defensin-Lipid II binding. Based on the complex of Lipid II with Human Neutrophil peptide-1, we could identify and characterize chemically diverse low-molecular weight compounds that mimic the interactions between HNP-1 and Lipid II. Lead compound BAS00127538 was further characterized structurally and functionally; it specifically interacts with the N-acetyl muramic acid moiety and isoprenyl tail of Lipid II, targets cell wall synthesis and was protective in an in vivo model for sepsis. For the first time, we have identified and characterized low molecular weight synthetic compounds that target Lipid II with high specificity and affinity. Optimization of these compounds may allow for their development as novel, next generation therapeutic agents for the treatment of Gram-positive pathogenic infections. 相似文献
993.
Xiao Na Wang Ze Song Li Yu Ren Tao Jiang Ya Qing Wang Min Chen Jun Zhang Jian Xiu Hao Yan Bo Wang Ri Na Sha Yi Huang Xiao Liu Jing Chu Hu Guang Qing Sun Hong Gang Li Cheng Liang Xiong Jun Xie Zhi Mao Jiang Zhi Ming Cai Jun Wang Jian Wang Vicki Huff Yao Ting Gui Fei Gao 《PLoS genetics》2013,9(8)
Azoospermia is one of the major reproductive disorders which cause male infertility in humans; however, the etiology of this disease is largely unknown. In the present study, six missense mutations of WT1 gene were detected in 529 human patients with non-obstructive azoospermia (NOA), indicating a strong association between WT1 mutation and NOA. The Wilms tumor gene, Wt1, is specifically expressed in Sertoli cells (SCs) which support spermatogenesis. To examine the functions of this gene in spermatogenesis, Wt1 was deleted in adult testis using Wt1flox and Cre-ERTM mice strains. We found that inactivation of Wt1 resulted in massive germ cell death and only SCs were present in most of the seminiferous tubules which was very similar to NOA in humans. In investigating the potential mechanism for this, histological studies revealed that the blood–testis barrier (BTB) was disrupted in Wt1 deficient testes. In vitro studies demonstrated that Wt1 was essential for cell polarity maintenance in SCs. Further studies found that the expression of cell polarity associated genes (Par6b and E-cadherin) and Wnt signaling genes (Wnt4, Wnt11) were downregulated in Wt1 deficient SCs, and that the expression of Par6b and E-cadherin was regulated by Wnt4. Our findings suggest that Wt1 is important in spermatogenesis by regulating the polarity of SCs via Wnt signaling pathway and that WT1 mutation is one of the genetic causes of NOA in humans. 相似文献
994.
In eukaryotic cells short-lived proteins are degraded in a specific process by the ubiquitin-proteasome system (UPS), whereas long-lived proteins and damaged organelles are degraded by macroautophagy (hereafter referred to as autophagy). A growing body of evidence now suggests that autophagy is important for clearance of protein aggregates that form in cells as a consequence of ageing, oxidative stress, alterations that elevate the amounts of certain aggregation-prone proteins or expression of aggregating mutant variants of specific proteins. Autophagy is generally considered to be a non-specific, bulk degradation process. However, a recent study suggests that p62/SQSTM1 may link the recognition of polyubiquitinated protein aggregates to the autophagy machinery.1 This protein is able to polymerize via its N-terminal PB1 domain and to recognize polyubiquitin via its C-terminal UBA domain. It can also recruit the autophagosomal protein LC3 and co-localizes with many types of polyubiquitinated protein aggregates.1 Here we discuss possible implications of these findings and raise some questions for further investigation. 相似文献
995.
Juanjuan Zhang Fuxin Zhao Qun Fu Min Liang Yi Tong Xiaoling Liu Bei Lin Hui Mi Minglian Zhang Qi-Ping Wei Ling Xue Pingping Jiang Xiangtian Zhou Jun Qin Mo Taosheng Huang Jia Qu Min-Xin Guan 《Mitochondrion》2013,13(6):772-781
Mitochondrial m.14484T>C (MT-ND6) mutation has been associated with Leber's hereditary optic neuropathy. Previous investigations revealed that the m.14484T>C mutation is a primary factor underlying the development of optic neuropathy but is not sufficient to produce a clinical phenotype. However, mitochondrial haplogroups have been proposed to modulate the phenotypic manifestation of the m.14484T>C mutation. Here, we performed the clinical, genetic evaluation and complete mitochondrial genome sequence analysis of 41 Han Chinese pedigrees carrying the m.14484T>C mutation. These families exhibited a wide range of penetrances and expressivities of optic neuropathy. The average ratio between affected male/female matrilineal relatives from 41 families was 2:1. The penetrance of optic neuropathy in these Chinese pedigrees ranged from 5.6% to 100%, with the average of 23.8%. Furthermore, the age-of-onset for optic neuropathy varied from 4 to 44 years, with the average of 19.3 years. Sequence analysis of their mitochondrial genomes identified distinct sets of polymorphisms belonging to ten Eastern Asian haplogroups, indicating that the m.14484T>C mutation occurred through recurrent origins and founder events. We showed that mitochondrial haplogroups M9, M10 and N9 increased the penetrance of optic neuropathy in these Chinese families. In particular, these mitochondrial haplogroup specific variants: m.3394T>C (MT-ND1), m.14502T>C (MT-ND4) and m.14693A>G (MT-TE) enhanced the penetrance of visual loss in these Chinese families. These data provided the direct evidence that mitochondrial modifiers modulate the variable penetrance and expressivity of optic neuropathy among Chinese pedigrees carrying the m.14484T>C mutation. 相似文献
996.
997.
目的:探讨地佐辛用于神经外科患者术后镇痛的效果和安全性。方法:将64例ASAⅠ~Ⅱ级行神经外科手术患者随机分为两组,术后均以静脉自控镇痛(PCIA),其中A组(34例)用地佐辛,B组(30例)用舒芬太尼,观察两组镇痛、镇静效果及不良反应。结果:术后4 h、8 h、12 h、24 h视觉模拟评分(VAS)和不良反应发生率A组明显低于B组(P〈0.05),Ramsay评分明显高于B组(P〈0.05)。结论:地佐辛用于神经外科患者术后镇痛确切,不良反应少。 相似文献
998.
目的:观察右美托咪定在气管异物取出术中对患儿呼吸、循环及术后恢复情况的影响。方法:40例行气管异物取出术患,随机分为右美托咪定组(D组)(n=20)和生理盐水组(S组)(n=20),分别在麻醉诱导前10min静脉输注右美托咪定0.8μg/kg和等容量的生理盐水,输注时间为10min。术中高频射流呼吸机给氧,保持患儿自主呼吸,泵注丙泊酚和瑞芬太尼维持麻醉。结果:D组患儿术中屏气、咳嗽、喉痉挛、术中SP02〈90%显著低于S组(P〈0.05);D组丙泊酚及瑞芬太尼用量减少(P〈0.05)。结论:在气管异物取出术中应用右美托咪定有很大的优势,对呼吸系统影响小,血流动力学平稳,术后并发症少。 相似文献
999.
A new symmetrical phenylpropanoid glycoside, tangshenoside VIII (1), together with six known tangshenosides (2–7) were isolated from the roots of Codonopsis lanceolata (Campanulaceae). Their structures were established on the basis of spectroscopic data, including two-dimensional NMR analyses. Tangshenosides have chemotaxonomic significance. 相似文献
1000.
Xin Jia Tianshan Zha Bin Wu Yuqing Zhang Wenjing Chen Xiaoping Wang Haiqun Yu Guimei He 《PloS one》2013,8(2)
Although the temperature response of soil respiration (Rs) has been studied extensively, several issues remain unresolved, including hysteresis in the Rs–temperature relationship and differences in the long- vs. short-term Rs sensitivity to temperature. Progress on these issues will contribute to reduced uncertainties in carbon cycle modeling. We monitored soil CO2 efflux with an automated chamber system in a Pinus tabulaeformis plantation near Beijing throughout 2011. Soil temperature at 10-cm depth (Ts) exerted a strong control over Rs, with the annual temperature sensitivity (Q
10) and basal rate at 10°C (Rs
10) being 2.76 and 1.40 µmol m−2 s−1, respectively. Both Rs and short-term (i.e., daily) estimates of Rs
10 showed pronounced seasonal hysteresis with respect to Ts, with the efflux in the second half of the year being larger than that early in the season for a given temperature. The hysteresis may be associated with the confounding effects of microbial population dynamics and/or litter input. As a result, all of the applied regression models failed to yield unbiased estimates of Rs over the entire annual cycle. Lags between Rs and Ts were observed at the diel scale in the early and late growing season, but not in summer. The seasonality in these lags may be due to the use of a single Ts measurement depth, which failed to represent seasonal changes in the depth of CO2 production. Daily estimates of Q
10 averaged 2.04, smaller than the value obtained from the seasonal relationship. In addition, daily Q
10 decreased with increasing Ts, which may contribute feedback to the climate system under global warming scenarios. The use of a fixed, universal Q
10 is considered adequate when modeling annual carbon budgets across large spatial extents. In contrast, a seasonally-varying, environmentally-controlled Q
10 should be used when short-term accuracy is required. 相似文献