Mesenchymal stem cells (MSCs) and regulatory T cells (Tregs) are both potent immune-modulators. The aberrant proliferation and function of Tregs plays an important role in the development of asthma. ...Our previous studies have demonstrated the role of MSCs in promoting proliferation and immune-modulating of Tregs, as well as alleviating airway inflammation of asthmatic mice. In the present study, we isolated exosomes secreted by MSCs and investigated their immunomodulation effect on peripheral blood mononuclear cells (PBMCs) of asthmatic patient. We found that MSC exosomes upregulated IL-10 and TGF-β1 from PBMCs, thus promoting proliferation and immune-suppression capacity of Tregs. Furthermore, antigen presenting cells (APCs) but not CD4+ T cells-dependent pathway was shown to be possible mechanism involved in MSC exosome-mediated regulation. Our data elucidated the key role of exosomes in immune-modulation of MSCs, and suggested the therapeutic potential of MSC exosomes for asthma.
•MSC exosomes promote Tregs proliferation by upregulating IL-10 and TGF-β1 in asthma.•MSC exosomes enhance immunosuppression capacity of Tregs from asthmatic patient.•The effect of MSC exosomes on Tregs may be mediated by APCs.
Mortality from hepatitis B virus (HBV)–related acute‐on‐chronic liver failure (ACLF) is high due to limited treatment options. Preclinical and clinical investigations have proved that treatment with ...mesenchymal stromal cells (MSCs) is beneficial for recovery from liver injury. We hypothesized that the outcome of HBV‐related ACLF would be improved by MSC treatment. From 2010 to 2013, 110 patients with HBV‐related ACLF were enrolled in this open‐label, nonblinded randomized controlled study. The control group (n = 54) was treated with standard medical therapy (SMT) only. The experimental group (n = 56) was infused weekly for 4 weeks with 1.0 to 10 × 105 cells/kg allogeneic bone marrow–derived MSCs and then followed for 24 weeks. The cumulated survival rate of the MSC group was 73.2% (95% confidence interval 61.6%‐84.8%) versus 55.6% (95% confidence interval 42.3%‐68.9%) for the SMT group (P = 0.03). There were no infusion‐related side effects, but fever was more frequent in MSC compared to SMT patients during weeks 5‐24 of follow‐up. No carcinoma occurred in any trial patient in either group. Compared with the control group, allogeneic bone marrow–derived MSC treatment markedly improved clinical laboratory measurements, including serum total bilirubin and Model for End‐Stage Liver Disease scores. The incidence of severe infection in the MSC group was much lower than that in the SMT group (16.1% versus 33.3%, P = 0.04). Mortality from multiple organ failure and severe infection was higher in the SMT group than in the MSC group (37.0% versus 17.9%, P = 0.02). Conclusion: Peripheral infusion of allogeneic bone marrow–derived MSCs is safe and convenient for patients with HBV‐related ACLF and significantly increases the 24‐week survival rate by improving liver function and decreasing the incidence of severe infections. (Hepatology 2017;66:209–219).
This article analyzes the current research status and development trend of intelligent technologies for underground metal mines in China, where such technologies are under development for use to ...develop mineral resources in a safe, efficient, and environmentally friendly manner. We analyze and summarize the research status of underground metal mining technology at home and abroad, including some specific examples of equipment, technology, and applications. We introduce the latest equipment and technologies with independent intellectual property rights for unmanned mining, including intelligent and unmanned control technologies for rock-drilling jumbos, down-the-hole (DTH) drills, underground scrapers, underground mining trucks, and underground charging vehicles. Three basic platforms are used for intelligent and unmanned mining: the positioning and navigation platform, information-acquisition and communication platform, and scheduling and control platform. Unmanned equipment was tested in the Fankou Lead-Zinc Mine in China, and industrial tests on the basic platforms of intelligent and unmanned mining were carried out in the mine. The experiment focused on the intelligent scraper, which can achieve autonomous intelligent driving by relying on a wireless communication system, location and navigation system, and data-acquisition system. These industrial experiments indicate that the technology is feasible. The results show that unmanned mining can promote mining technology in China to an intelligent level and can enhance the core competitive ability of China’s mining industry.
Objectives
The purposes of this study were to clarify (i) the prevalence of pneumoconiosis among young adults and (ii) the factors associated with pneumoconiosis among young adults to explore ...targeted solution for control of pneumoconiosis among young adults (aged 24‐44 years).
Methods
The new cases diagnosed from 2001 to 2015 (extracted from the National Occupational Disease and Occupational Health Information Monitoring System) were involved in this research, including information of employer, patient's name, date of birth, gender, date of diagnosis, first year of dust exposure, duration of exposure, aggregation etc
Results
A total of 1519 pneumoconiosis cases were diagnosed among young adults (21.6% of overall cases). Silicosis was the most common type with acute process of disease. Compared with overall cases, the young patients had shorter duration of exposure, more stage II/III cases and higher aggravation rate; and were even more concentrated in small and medium enterprises where more migrant workers were employed and insufficient protective measures were used. Without further regulation, the prevalence of pneumoconiosis among young adults would bring not only disease suffering for 3000 individuals and their families, but also an annual economic loss up to 180 million yuan for Hebei province till 2025.
Conclusions
As a typical heavily industrialized province of China, Hebei has severe situation on pneumoconiosis among young adults. Special attention and effort on silica‐contacting industries, small and medium enterprises, and migrant workers should be focused in future occupational supervision and regulation among young adults.
Among the different initiating events in Alzheimer's disease (AD) pathogenesis, oxidative stress and neuroinflammation are some of the most iimportant. In the central nervous system, the ...12/15Lipoxygenase (12/15LO) enzyme is the source of potent pro-oxidants and inflammatory lipid mediators. Previous works showed that this pathway is up-regulated in AD brains and that its pharmacological targeting modulates the phenotype of transgenic mouse models of the disease. Here we investigate the effect of brain 12/15LO gene delivery on the AD-like phenotype of a mouse model with plaques, tangles and behavioral deficits, the 3xTg mice. Compared with controls, mice over-expressing 12/15LO manifested an exacerbation of spatial learning and memory impairments, which was associated with significant increase in Aβ formation and deposition, and accumulation of hyper-phosphorylated insoluble tau secondary to a down-regulation of autophagy. In addition, the same mice manifested a worsening of neuroinflammation and synaptic pathology. Taken together our study supports the hypothesis that the 12/15LO enzymatic pathway by impairing neuronal autophagy plays a functional role in exacerbating AD-related neuropathologies and cognitive impairments. It provides further critical preclinical evidence to justify developing and testing new and selective 12/15LO inhibitors for AD treatment.
Objective
High level of homocysteine (Hcy) is a recognized risk factor for developing Alzheimer disease (AD). However, the mechanisms involved are unknown. Previously, it was shown that high Hcy ...increases brain β‐amyloid (Aβ) levels in amyloid precursor protein transgenic mice, but no data are available on the effect that it may have on the other main pathologic features of AD such as tau.
Methods
3xTg mice with diet‐induced high Hcy were compared with mice having normal Hcy. Neuronal cells were incubated with and without Hcy.
Results
Diet‐induced high Hcy resulted in an exacerbation of the entire AD‐like phenotype of the 3xTg mice. In particular, we found that compared with controls, mice with high Hcy developed significant memory and learning deficits, and had elevated Aβ levels and deposition, which was mediated by an activation of the γ‐secretase pathway. In addition, the same mice had a significant increase in the insoluble fraction of tau and its phosphorylation at specific epitopes, which was mediated by the cdk5 pathway. In vitro studies confirmed these observations and provided evidence that the effects of Hcy on Aβ and tau are independent from each other.
Interpretation
Taken together, our findings demonstrate that a dietary condition that leads to an elevation of Hcy levels results in an exacerbation of all 3 major pathological features of the AD phenotype: memory deficits, and Aβ and tau neuropathology. They support the concept that this dietary lifestyle can act as a risk factor and actively contribute to the development of the disease. Ann Neurol 2014;75:851–863
The shallow‐water equations (SWEs) are discretized on a spherical multiple‐cell (SMC) grid and validated with classical tests, including steady zonal flow over flat or hill floor, the Rossby–Haurwitz ...wave and the unstable zonal jet. The numerical schemes follow the conventional latitude–longitude (lat‐lon) grid ones at low latitudes but switch to a fixed‐reference direction system to define vector variables at high latitudes for reduction of polar curvature errors. Semi‐implicit schemes are used for both the Coriolis terms and the potential energy gradients. A C‐grid mass‐conserving advection–diffusion scheme is used for the thickness variable and mixed A‐ and D‐grid schemes are applied on the momentum equation. Tests demonstrate that the two reference directions work fine on the SMC grid and the SWEs model is stable as long as numerical noises are suppressed with enough smoothing. This implies that other reduced grids could be used for dynamical models if the vector polar problem is properly solved. The unstructured SMC grid also supports multi‐resolutions in mesh refinement style and a refined area is included to show grid refinement effects. For steady smooth flows, the refinement is almost unnoticeable while in unstable jet case, it may stir up instability ripples in the jet flow unless strong average is applied.
The shallow‐water equations are discretized on a spherical multiple‐cell (SMC) grid and validated with classical tests, including steady zonal flows and the unstable jet. The numerical schemes follow the conventional latitude–longitude (lat‐lon) grid schemes at low latitudes but switch to a fixed‐reference direction system to define vector variables at high latitudes for reduction of polar errors caused by increased curvature near the poles. Tests demonstrate that the two reference directions work well on the SMC grid and the model is stable as long as numerical noise is suppressed with enough smoothing.
A high circulating level of homocysteine (Hcy), also known as hyperhomocysteinemia, is a risk factor for Alzheimer's disease (AD). Previous studies show that elevated Hcy promotes brain amyloidosis ...and behavioral deficits in mouse models of AD. However, whether it directly modulates the development of tau neuropathology independently of amyloid beta in vivo is unknown. Herein, we investigate the effect of diet-induced elevated levels of brain Hcy on the phenotype of a relevant mouse model of human tauopathy. Compared with controls, tau mice fed with low folate and B vitamins diet had a significant increase in brain Hcy levels and worsening of behavioral deficits. The same mice had a significant elevation of tau phosphorylation, synaptic pathology, and astrocytes activation. In vitro studies demonstrated that Hcy effect on tau phosphorylation was mediated by an upregulation of 5-lipoxygenase via cdk5 kinase pathway activation. Our findings support the novel concept that high Hcy level in the central nervous system is a metabolic risk factor for neurodegenerative diseases, specifically characterized by the progressive accumulation of tau pathology, namely tauopathies.
The vacuolar protein sorting 35 (VPS35) is the main component of the retromer recognition core complex system which regulates intracellular cargo protein sorting and trafficking. Downregulation of ...VPS35 has been linked to the pathogenesis of neurodegenerative disorders such Alzheimer's and Parkinson's diseases via endosome dysregulation.
Here we show that the genetic manipulation of VPS35 affects intracellular degradation pathways.
A neuronal cell line expressing human APP Swedish mutant was used. VPS35 silencing was performed treating cells with VPS35 siRNA or Ctr siRNA for 72 h.
Downregulation of VPS35 was associated with alteration of autophagy flux and intracellular accumulation of acidic and ubiquitinated aggregates suggesting that dysfunction of the retromer recognition core leads to a significant alteration in both pathways.
Taken together, our data demonstrate that besides cargo sorting and trafficking, VPS35 by supporting the integral function of the retromer complex system plays an important role also as a critical regulator of intracellular degradation pathways.
Heterogeneous nucleation interface structure of Al-Cu alloys was tuned through solute composition and substrate lattice structure in this study to achieve a sophisticated nucleation control. The ...tuning mechanism at atomic level was systematically investigated using high angle annular dark field scanning transmission electron microscopy (HAADF STEM) and electron energy loss spectroscopy (EELs) techniques. The results show that the solutal element and substrate both can be used to modify the lattice matching of the nucleation interface, where alloying element Cu was found to adsorb at the nucleation interface tuning the lattice matching between new crystal and substrate rather than embed in the matrix distorting the lattice structure of the matrix. The substrate structure can also affect the preferred crystal orientation of new crystals instead. A relationship between the nucleation potency (undercooling) of the alloys and the lattice misfit was further proved, which may lead to a quantitative approach for the nucleation control of Al.
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