Notch signaling deficiency underlies age-dependent depletion of satellite cells in muscular dystrophy

Duchenne muscular dystrophy (DMD) is a devastating disease characterized by muscle wasting, loss of mobility and death in early adulthood. Satellite cells are muscle-resident stem cells responsible for the repair and regeneration of damaged muscles. One pathological feature of DMD is the progressive depletion of satellite cells, leading to the failure of muscle repair. Here, we attempted to explore the molecular mechanisms underlying satellite cell ablation in the dystrophin mutant mdx mouse, a well-established model for DMD. Initial muscle degeneration activates satellite cells, resulting in increased satellite cell number in young mdx mice. This is followed by rapid loss of satellite cells with age due to the reduced self-renewal ability of mdx satellite cells. In addition, satellite cell composition is altered even in young mdx mice, with significant reductions in the abundance of non-committed (Pax7⁺ and Myf5⁻) satellite cells. Using a Notch-reporter mouse, we found that the mdx satellite cells have reduced activation of Notch signaling, which has been shown to be necessary to maintain satellite cell quiescence and self-renewal. Concomitantly, the expression of Notch1, Notch3, Jag1, Hey1 and HeyL are reduced in the mdx primary myoblast. Finally, we established a mouse model to constitutively activate Notch signaling in satellite cells, and show that Notch activation is sufficient to rescue the self-renewal deficiencies of mdx satellite cells. These results demonstrate that Notch signaling is essential for maintaining the satellite cell pool and that its deficiency leads to depletion of satellite cells in DMD.KEY WORDS: Muscular dystrophy, Notch signaling, Stem cell     

TNF-α Mediated Increase of HIF-1α Inhibits VASP Expression,Which Reduces Alveolar-Capillary Barrier Function during Acute Lung Injury (ALI)

Acute lung injury (ALI) is an inflammatory disorder associated with reduced alveolar-capillary barrier function and increased pulmonary vascular permeability. Vasodilator-stimulated phosphoprotein (VASP) is widely associated with all types of modulations of cytoskeleton rearrangement-dependent cellular morphology and function, such as adhesion, shrinkage, and permeability. The present studies were conducted to investigate the effects and mechanisms by which tumor necrosis factor-alpha (TNF-α) increases the tight junction permeability in lung tissue associated with acute lung inflammation. After incubating A549 cells for 24 hours with different concentrations (0–100 ng/mL) of TNF-α, 0.1 to 8 ng/mL TNF-α exhibited no significant effect on cell viability compared with the 0 ng/mL TNF-α group (control group). However, 10 ng/mL and 100 ng/mL TNF-α dramatically inhibited the viability of A549 cells compared with the control group (*p<0.05). Monolayer cell permeability assay results indicated that A549 cells incubated with 10 ng/mL TNF-α for 24 hours displayed significantly increased cell permeability (*p<0.05). Moreover, the inhibition of VASP expression increased the cell permeability (*p<0.05). Pretreating A549 cells with cobalt chloride (to mimic a hypoxia environment) increased protein expression level of hypoxia inducible factor-1α (HIF-1α) (*p<0.05), whereas protein expression level of VASP decreased significantly (*p<0.05). In LPS-induced ALI mice, the concentrations of TNF-α in lung tissues and serum significantly increased at one hour, and the value reached a peak at four hours. Moreover, the Evans Blue absorption value of the mouse lung tissues reached a peak at four hours. The HIF-1α protein expression level in mouse lung tissues increased significantly at four hours and eight hours (**p<0.001), whereas the VASP protein expression level decreased significantly (**p<0.01). Taken together, our data demonstrate that HIF-1α acts downstream of TNF-α to inhibit VASP expression and to modulate the acute pulmonary inflammation process, and these molecules play an important role in the impairment of the alveolar-capillary barrier.     

Schlafen 1 Inhibits the Proliferation and Tube Formation of Endothelial Progenitor Cells

Endothelial progenitor cells (EPCs) are the major source of cells that restore the endothelium during reendothelialization. This study was designed to investigate whether Schlafen 1 (Slfn1) has an effect on the proliferation and tube formation of EPCs in vivo. Slfn1 was expressed in rat EPCs. The overexpression of Slfn1 suppressed the proliferation and tube formation of EPCs; conversely, the knockdown of Slfn1 by shRNA promoted the proliferation and tube formation of EPCs. Furthermore, when Slfn1 was overexpressed, the EPCs were arrested in the G1 phase of the cell cycle. In contrast, when Slfn1 was knocked down, the EPCs progressed into the S phase of the cell cycle. Additionally, the overexpression of Slfn1 decreased the expression of Cyclin D1, whereas the knockdown of Slfn1 increased the expression of Cyclin D1; these findings suggest that Cyclin D1 is downstream of Slfn1 in Slfn1-mediated EPC proliferation. Taken together, these results indicate a key role for Slfn1 in the regulation of EPC biological behavior, which may provide a new target for the use of EPCs during reendothelialization.     

从超声波破碎的蓝藻类囊体膜中分离的叶绿素蛋白复合物

当蓝藻的类囊体膜用超声波进行破碎,并在4℃下用聚丙烯酰胺凝胶电泳进行分离,有6条叶绿素带被分离出来,它们分别是 CPIa,CPIb,CP1,CPa1 CPa2,FC。CP1 在红区和蓝区的吸收峰分别位于674和435 nm 处。在液氮甲该组分在725和680 nm 处有两个荧光发射带。CPa1和 CPa2的吸收光谱相似,其红峰和蓝峰的位置分别位于667和431.5nm 处。它们在77 K 的荧光发射峰都位于684 nm 处。用超声破碎法分离的叶绿素蛋白复合物的光谱特性,除 CPa1和 CPa2在红峰和蓝峰的吸收位置蓝移了3—5 nm 之外,其余与用 SDS 增溶法分离的相应复合物相似。属于光系统Ⅰ的 CPIa-CPI 的叶绿素含量占总叶绿素的40.93%,而属于光系统Ⅱ的 CPa1和 CPa2的叶绿素则占总叶绿素的38.78%,二者之差仅有2.15%。     

Nitrogen addition increases aboveground silicon and phytolith concentrations in understory plants of a tropical forest

Plant and Soil - Silicon (Si) is a beneficial element for plants and plays important roles in the biogeochemical cycle of mineral elements. Yet, few studies have focused on the impact of nitrogen...     

Parthenolide ameliorates tweak-induced podocytes injury

Molecular Biology Reports - Parthenolide (PTL) is a natural product from the shoots of Tanacetum parthenium, which has immunomodulatory effects in multiply type of diseases. This study aimed to...     

Molecular Epidemiologic Characterization of a Clustering HCV Infection Caused by Inappropriate Medical Care in Heyuan City of Guangdong,China

Background

From November 2011 to January 2012, a number of clustering cases of HCV infection were reported in Zijin County, Heyuan City, Guangdong, China. Most patients in the clustering cases suspected that they could be infected due to inappropriate medical care in the clinic located at the Xiangshui road. However, the molecular epidemiology of the clustering cases remains unknown.

Methodology

The residents, living at Xiangshui Road, with HCV antibody positive reported from 2011 and 2012 were recruited. A survey of the HCV infected individuals from the clustering cases was conducted. Each participant underwent a questionnaire defining demographic characteristics and health care history. HCV serological test and viral load test were performed to confirm the infection status. Molecular phylogenetic analysis and Bayesian coalescence analysis were conducted to further confirm the HCV subtype distribution and to reconstruct the associated demographic history and time-scaled phylogeny among the clustering cases.

Principal Findings

The molecular phylogenetic analysis revealed that only two HCV subtypes, 2a and 6a, were found among the clustering cases. There was no close HCV subtype evolutionary relation was observed among patients from the same family. The 6a cluster showed higher viral loads than the 2a cluster. In addition, the Bayesian skyline plot analysis showed that both the HCV 2a and 6a subtype infections among the Heyuan cases experienced an “expansion-diminishment-expansion” featured dissemination. The 2a clustering infection occurred in 2004, and the 6a clustering cases originated in 2006.

Conclusions

The molecular epidemiological characters imply that the inappropriate medical practices were possibly associated with the clustering HCV cases in Heyuan City during 2011, 2012. Latent HCV subtypes 2a and 6a infection may cause the prevalence and become a new public health issue in Guangdong, China.     

Demethylation of the Protein Phosphatase PP2A Promotes Demethylation of Histones to Enable Their Function as a Methyl Group Sink

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蜜蜂脑中5—HT，GABA，Ach免疫反应阳性神经元分布的比较研究

通过免疫细胞化学方法－ＰＡＰ法,研究了中华峰（Ａｐｉｓｓｉｎｅｎｓｉｓ）和意大利峰（ＡｐｉｓｍｅｌｌｉｆｅｒａＬ）脑和视叶中乙酰胆碱（Ａｃｈ）、５－羟色胺（５－ＨＴ）、γ－氨基丁酸（ＧＡＢＡ）免疫反应阳性神经元胞体和纤维的形态、染色强度、分布和各种神经丛之间的联系．一方面将这些阳性分布系统和蜜蜂脑中相应的神经元类型进行比较,另一方面也分析了在一些特殊解剖学通路中存在的可能的神经递质及其作用．