Administration of exosomes derived from mesenchymal stromal cells (MSCs) could improve some neurologic conditions by transferring functional biomolecules to recipient cells. Furthermore, exosomes ...from hypoxic progenitor cells exerted better therapeutic effects in organ injury through specific cargoes. However, there are no related reports about whether exosomes derived from MSCs or hypoxia‐preconditioned MSCs (PC‐MSCs) could prevent memory deficits in Alzheimer disease (AD). In this study, the exosomes derived from MSCs or PC‐MSCs were systemically administered to transgenic APP/PS1 mice. The expression of miR‐21 in MSCs was significantly increased after hypoxic treatment. Injection of exosomes from normoxic MSCs could rescue cognition and memory impairment according to results of the Morris water maze test, reduced plaque deposition, and Aβ levels in the brain; could decrease the activation of astrocytes and microglia; could down‐regulate proinflammatory cytokines (TNF‐α and IL‐1β); and could up‐regulate anti‐inflammatory cytokines (IL‐4 and ‐10) in AD mice, as well as reduce the activation of signal transducer and activator of transcription 3 (STAT3) and NF‐κB. Compared to the group administered exosomes from normoxic MSCs, in the group administered exosomes from PC‐MSCs, learning and memory capabilities were significantly improved; the plaque deposition and Aβ levels were lower, and expression of growth‐associated protein 43, synapsin 1, and IL‐10 was increased; and the levels of glial fibrillary acidic protein, ionized calcium‐binding adaptor molecule 1, TNF‐α, IL‐1β, and activation of STAT3 and NF‐κB were sharply decreased. More importantly, exosomes from PC‐MSCs effectively increased the level of miR‐21 in the brain of AD mice. Additionally, replenishment of miR‐21 restored the cognitive deficits in APP/PS1 mice and prevented pathologic features. Taken together, these findings suggest that exosomes from PC‐MSCs could improve the learning and memory capabilities of APP/PS1 mice, and that the underlying mechanism may lie in the restoration of synaptic dysfunction and regulation of inflammatory responses through regulation of miR‐21.—Cui, G.‐H., Wu, J., Mou, F.‐F., Xie, W.‐H., Wang, F.‐B., Wang, Q.‐L., Fang, J., Xu, Y.‐W., Dong, Y.‐R., Liu, J.‐R., Guo, H.‐D. Exosomes derived from hypoxia‐preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice. FASEB J. 32, 654–668 (2018). www.fasebj.org
Exosomes are lipid-bilayer enclosed nano-sized vesicles that transfer functional cellular proteins, mRNA and miRNAs. Mesenchymal stem cells (MSCs) derived exosomes have been demonstrated to prevent ...memory deficits in the animal model of Alzheimer's disease (AD). However, the intravenously injected exosomes could be abundantly tracked in other organs except for the targeted regions in the brain. Here, we proposed the use of central nervous system-specific rabies viral glycoprotein (RVG) peptide to target intravenously-infused exosomes derived from MSCs (MSC-Exo) to the brain of transgenic APP/PS1 mice. MSC-Exo were conjugated with RVG through a DOPE-NHS linker.
RVG-tagged MSC-Exo exhibited improved targeting to the cortex and hippocampus after being administered intravenously. Compared with the group administered MSC-Exo, in the group administered RVG-conjugated MSC-Exo (MSC-RVG-Exo) plaque deposition and Aβ levels were sharply decreased and activation of astrocytes was obviously reduced. The brain targeted exosomes derived from MSCs was better than unmodified exosomes to improve cognitive function in APP/PS1 mice according to Morris water maze test. Additionally, although MSC-Exo injected intravenously reduced the expression of pro-inflammatory mediators TNF-α, IL-β, and IL-6, but the changes of anti-inflammatory factors IL-10 and IL-13 were not obvious. However, administration of MSC-RVG-Exo significantly reduced the levels of TNF-α, IL-β, and IL-6 while significantly raised the levels of IL-10, IL-4 and IL-13.
Taken together, our results demonstrated a novel method for increasing delivery of exosomes for treatment of AD. By targeting exosomes to the cortex and hippocampus of AD mouse, there was a significant improvement in learning and memory capabilities with reduced plaque deposition and Aβ levels, and normalized levels of inflammatory cytokines.
Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus that affects approximately half of patients with diabetes. Current treatment regimens cannot treat DPN effectively. ...Schwann cells (SCs) are very sensitive to glucose concentration and insulin, and closely associated with the occurrence and development of type 1 diabetic mellitus (T1DM) and DPN. Apoptosis of SCs is induced by hyperglycemia and is involved in the pathogenesis of DPN. This review considers the pathological processes of SCs apoptosis under high glucose, which include the following: oxidative stress, inflammatory reactions, endoplasmic reticulum stress, autophagy, nitrification and signaling pathways (PI3K/AKT, ERK, PERK/Nrf2, and Wnt/β-catenin). The clarification of mechanisms underlying SCs apoptosis induced by high glucose will help us to understand and identify more effective strategies for the treatment of T1DM DPN.
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Induced pluripotent stem cell (iPSC) therapy brings great hope to the treatment of myocardial injuries, while extracellular vesicles may be one of the main mechanisms of its action. iPSC-derived ...small extracellular vesicles (iPSCs-sEVs) can carry genetic and proteinaceous substances and mediate the interaction between iPSCs and target cells. In recent years, more and more studies have focused on the therapeutic effect of iPSCs-sEVs in myocardial injury. IPSCs-sEVs may be a new cell-free-based treatment for myocardial injury, including myocardial infarction, myocardial ischemia-reperfusion injury, coronary heart disease, and heart failure. In the current research on myocardial injury, the extraction of sEVs from mesenchymal stem cells induced by iPSCs was widely used. Isolation methods of iPSCs-sEVs for the treatment of myocardial injury include ultracentrifugation, isodensity gradient centrifugation, and size exclusion chromatography. Tail vein injection and intraductal administration are the most widely used routes of iPSCs-sEV administration. The characteristics of sEVs derived from iPSCs which were induced from different species and organs, including fibroblasts and bone marrow, were further compared. In addition, the beneficial genes of iPSC can be regulated through CRISPR/Cas9 to change the composition of sEVs and improve the abundance and expression diversity of them. This review focused on the strategies and mechanisms of iPSCs-sEVs in the treatment of myocardial injury, which provides a reference for future research and the application of iPSCs-sEVs.
•The changes in maize growth period and soil water content with planting date adjustment.•The suitably delayed planting time can avoid seasonal drought in spring on maize.•A suitable planting date ...have be determined to increase the maize yield and water-use efficiency in rainfed farming systems in arid and semi-arid areas.
Given the frequent drought pressure caused by the unpredictable and limited precipitation concurrent with global climate change, highly efficient cultivation technologies have been increasingly recognized by various levels of scientific communities. Understanding plant–environment relationships in rainfed dry land may help maximize crop productivity while improving water utilization of farmland. Field experiments were conducted in 2012–2014 at the Dryland Maize Experimental Station of the Northwest A&F University, China to determine the effects of possible drought stress and the environmental factors involved during sowing at different sowing dates on maize vegetative growth and grain yield (Zea mays L.), as well as water-use efficiency (WUE=grain yield per unit of seasonal evapotranspiration). Six planting date (PD) treatments with sowing performed for 6 days from April 10 to May 10 were designed. Results showed that the maize growth period was shortened with the postponement of planting time. The vegetative growth stage and the overlapping stages of vegetative and reproductive growth varied by 4–19 days among various PD practices. However, the reproductive growth stage duration was relatively stable and varied by 3–5 days only among the different PD practices. Within a certain time range, dry matter production per plant did not obviously change across the different PD treatments. However, the dry matter accumulation in the ear after flowering, the yield, and the WUE in the treatments under appropriate PDs (April 16–April 28) were 2.2%–28.8%, 2.3%–24.7%, and 6.6%–15.2% higher, respectively, than those in the early or delayed PDs. These findings resulted from the changes in soil water content with PD adjustment. Yield was highly correlated to the soil moisture content during PD, the rainfall before silking, the effective accumulated temperature after silking, and the sunshine hours after silking. Moreover, the thousand-grain weight was highly correlated with the sunshine hours after silking. In the early PDs, the main factor that affected maize yield was the low content of soil moisture, which generated low effective ear number per unit area and seedling emergence ratio. In the late PDs, the main factors that influenced maize yield were the low effective accumulated temperature and the short sunshine hours during the reproductive growth stage, which produced less dry matter accumulation after silking and lower thousand-grain weight. Under suitable sowing time, the actual harvest ear number per hectare and dry matter accumulation of female ear after silking increased. Similarly, the maize yield and WUE increased. By considering the ecological factors and study results, we recommend that the most suitable sowing time for maize should be determined on the basis of the soil moisture content before April 28. As such, we can effectively achieve high yield and avoid drought in the study region. Overall, the results can provide effective cultivation techniques to prevent drought stress in spring maize in the present agro-ecosystem of northern China and other similar areas.
In this work we present the entanglement measures of a tripartite W-State entangled system in noninertial frame through the coordinate transformation between Minkowski and Rindler. Two cases are ...considered, i.e., when one qubit goes in a uniform acceleration a and the others remain stationary and when two qubits undergo in a uniform acceleration and while the other is stationary. The analytical negativities for one-tangle, two-tangle and π-tangle in total are not written out explicitly except for some special cases due to complicated expressions, but we illustrate them in graphics and study their dependencies on the acceleration parameters rb and rc. We find that the negativities of the one-tangle, two-tangle and π-tangle decrease with the acceleration parameters except for the constant NAB=NBA. The negativity NCI(AB) and the πCI decrease faster than NA(BCI) and πA(πB). The negativities NACI (NB(ACI))and NBICI decrease faster than those NAB and NABI, respectively. It is interesting to see there exist turning points for the negativity NA(BICI) at the coordinate position (rb,rc) with rb=rc, which implies that the NA(BICI) has minimum value when Bob and Charlie are on the same position and the degree of the entanglement of the subsystem ρA(BICI) becomes smallest. The von Neumann entropy of tripartite system densities ρABCI and ρABICI are obtained analytically. We notice that they all increase with the acceleration parameters rb and rc.
Taohong Siwu decoction (THSWD) is one of the classic prescriptions for promoting blood circulation and removing blood stasis. With the continuous in-depth excavation in basic and clinical research, ...it has been found that THSWD has made greater progress in the prevention and treatment of cardiovascular diseases. Mechanisms of the current studies have shown that it could prevent and treat the myocardial injury by inhibiting inflammatory reaction, antioxidant stress, inhibiting platelet aggregation, prolonging clotting time, anti-fibrosis, reducing blood lipids, anti-atherosclerosis, improving hemorheology and vascular pathological changes, regulating related signal pathways and other mechanisms to prevent and treat the myocardial injury, so as to protect cardiomyocytes and improve cardiac function. Many clinical studies have shown that THSWD is effective in the prevention and treatment of cardiovascular diseases related to myocardial injuries, such as coronary heart disease angina pectoris (CHD-AP), and myocardial infarction. In clinical practice, it is often used by adding and subtracting prescriptions, the combination of compound prescriptions and combinations of chemicals and so on. However, there are some limitations and uncertainties in both basic and clinical research of prescriptions. According to the current research, although the molecular biological mechanism of various active ingredients needs to be further clarified, and the composition and dose of the drug have not been standardized and quantified, this study still has exploration for scientific research and clinical practice. Therefore, this review mainly discusses the basic mechanisms and clinical applications of THSWD in the prevention and treatment of the myocardial injury caused by CHD-AP and myocardial infarction. The authors hope to provide valuable ideas and references for researchers and clinicians.
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•A novel 3D vertical-flow paper-based device (3VPD) integrated with a sandwich-type fluorescent immunoassay is developed.•The 3VPD can be applied for multiplexed detection of cancer ...biomarkers simultaneously based on the principle of origami.•The proposed 3VPD shows high sensitivity and selectivity for detecting CEA, AFP and CA199 in human serum, respectively.
A novel three-dimensional (3D) vertical-flow paper-based device (3VPD), integrated with a sandwich-type fluorescent immunoassay, was developed for multiplexed detection of cancer biomarkers simultaneously based on the principle of origami. The developed 3VPD, composed of a sample layer, a splitting layer, and a test layer, could be fabricated simply by wax-printing on paper at a large scale. Herein, a vertical-flow immunoassay was introduced into the device, in which fluorescein isothiocyanate labeled antibodies were coated on the splitting layer and mouse monoclonal capture antibodies were functionalized on the test layer. The proposed 3VPD showed high sensitivity and selectivity for detecting three cancer biomarkers, carcinoembryonic antigen (CEA), a-fetoprotein (AFP), and cancer antigen 199 (CA199) with detection limits of 0.03 ng/mL, 0.05 ng/mL, and 0.09 U/mL in human serum, respectively. The results obtained in human serum were compatible with the reference values which were acquired from parallel single-analyte. The developed 3VPD provides a new strategy to develop an inexpensive and sensitive approach for simultaneous detection of multiple analytes and comprehensive clinical diagnosis by a single test.
This paper addresses a flow shop scheduling problem in a production system where the machine setup times depend on their prior states. State-dependent setup times exist widely in thermal facilities ...such as boilers and furnaces. The fuzzy set theory is introduced to describe the uncertainty of processing times and due dates in this study. The goal of the proposed fuzzy flow shop scheduling problem is to dispatch jobs to the machines and to determine the job sequence and state transition of each machine to minimize energy consumption and tardiness. To most efficiently determine the impact of uncertainty, the problem is formulated based on accurate operations of fuzzy numbers, which differ from approximate calculations in the existing literature on scheduling. To solve the problem, two common pattern matching schemes and heuristics are proposed to be combined with the classical genetic algorithm. Computational experiments show that the proposed GA performs better than the random key GA method, especially for large problems. The numerical results also provide practical implications for the proposed problem. The state-dependent setup time constraint significantly influences the scheduling results. In addition, the objective can be improved by reducing the uncertainty of processing times and due dates.
Exposure to relatively low or high temperatures during the entire pregnancy significantly increase the risk of preterm birth, with hazard ratios (HRs) 95% confidence intervals (CIs) of 1.03 (95%CI: ...1.02, 1.04) for relatively low (9.1 ℃, the 5th percentile) temperature and 1.55 (95%CI: 1.48, 1.61) for relatively high (23.0 ℃, the 95th percentile) temperature in comparison with the thresholds (12.0 ℃)
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Little is known about the effect of ambient temperature on preterm birth, especially for the trimester-specific effects.
To evaluate whether exposure to relatively low or high temperature during pregnancy is associated with increasing risk of preterm birth or not.
We analysed the data of a birth cohort with 1,281,859 singleton pregnancies during 2013–2014 and matched the home address of each pregnant women to the model based daily meteorological and air pollution data. Then we used the Cox proportional hazard regression models with random effect to estimate the non-linear associations between exposure to relatively low or high temperature at each trimester of pregnancy and the risk of preterm birth, after controlling for air pollution and individual-level covariates.
The overall preterm birth rate was 8.1% (104,493 preterm births). Exposure to relatively low or high temperatures during the entire pregnancy significantly increase the risk of preterm birth, with hazard ratios (HRs) 95% confidence intervals (CIs) of 1.03 (95%CI: 1.02, 1.04) for relatively low (9.1 ℃, the 5th percentile) temperature and 1.55 (95%CI: 1.48, 1.61) for relatively high (23.0 ℃, the 95th percentile) temperature in comparison with the thresholds (12.0 ℃). Pregnant women at the early pregnancy (the 1st and 2nd trimester) are more susceptible to high temperatures while pregnant women at the late pregnancy (the 3rd trimester) are more susceptible to low temperatures.
These findings provide new evidence that exposure to relatively low or high temperatures during pregnancy increases the risk of preterm birth, which can serve as scientific evidence for prevention of preterm birth.
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