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Background: Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) have been reported to exhibit therapeutic effects in various animal models of neurological diseases, such as stroke and hypoxic-ischemic brain injury.Objective: The present study investigated the potential beneficial effect of MSC-derived EVs in an animal model of Alzheimer's disease (AD).Methods: APP/PS1 mice and their non-transgenic littermates (WT) received intracerebroventricle injection of MSC-derived EVs once per two days for two weeks. Then novel object recognition and water maze tasks were carried out to measure the cognitive behaviors. Electrophysiological tests were carried out to measure hippocampal synaptic plasticity. Inducible nitric oxide synthase (iNOS) mRNA and protein levels were measured by qRT-PCR and western blotting in primary cultured neurons treated with amyloid-β peptide (Aβ) or prepared from APP/PS1 mice.Results: Treatment with MSC-derived EVs alleviates exogenous Aβ-induced iNOS mRNA and protein expression. In cultured primary neurons prepared from APP/PS1 pups, iNOS mRNA and protein levels were significantly reduced when treated with MSC-derived EVs. MSC-derived EVs improved cognitive behavior, rescued impairment of CA1 synaptic transmission, and long-term potentiation in APP/PS1 mice.Conclusion: MSC-derived EVs possessed beneficial effects in a mouse model of AD, probably by suppressing Aβ induced iNOS expression. [ABSTRACT FROM AUTHOR]

How climate controls tropical cyclone variability has critical implications for modern human society but is not well understood due to the short length of observational records. To probe this knowledge gap, we present a synthesis of intense typhoon activity from the northwestern Pacific over the past 2000 years, which is supported by a new, wellresolved tidal flat sedimentary record from the Jiangsu coast, eastern China. The record reveals nine intervals of typhoon frequency, indicating that the frequency of intense typhoons has varied on multi-centennial scales over the past 2000 years. Our synthesis shows strong evidence for a seesaw pattern of intense typhoon frequency between southeastern China and Japan and Korea. This pattern can be explained by the El Niño and Southern Oscillation-East Asian Monsoon- sea surface temperature hypothesis, which potentially explains the basin-wide typhoon climate in the northwestern Pacific region. A shift in typhoon activity was identified from 550-280 to 280-50 yr B.P. during the Little Ice Age, when typhoon activity changed from active to quiescent or vice versa. Centennialscale shifts in Intertropical Convergence Zone and Western Pacific Warm Pool sea surface temperature are likely to be the primary forcing mechanisms driving this shift. Results obtained here provide links between typhoon activity and the El Niño and Southern Oscillation, the East Asian Monsoon, and the Western Pacific Warm Pool sea surface temperature, and therefore improve our ability to fully assess intense typhoon activity in future climate warming. [ABSTRACT FROM AUTHOR]

Background: Healthcare resource utilisation for Alzheimer's disease (AD) in China is not well understood. This Delphi panel study aimed to describe the clinical management pathways for moderate and severe AD patients in urban China and to define the amount and cost of healthcare resources used. Methods: A panel of 11 experts was recruited from urban China to participate in two rounds of preparatory interviews. In the first round, 9 physicians specialised in dementia gave a qualitative description of the clinical management of AD patients. In the second round, 2 hospital administrators were asked about the cost of AD management and care. Results from the interviews were discussed by the experts in a Delphi panel meeting, where consensus was reached on quantitative aspects of AD management, including the rate of healthcare resource utilisation, the respective unit costs and caregiving time. Results: Interviewees reported that mild AD is under-recognised in China; most patients are diagnosed with moderate to severe AD. Loss of independence and agitation/aggression are the main drivers for healthcare resource utilisation and contribute to a heavier caregiver burden. It was estimated that 70 % moderate AD patients are independent/non-aggressive at the time of diagnosis, 15 % are independent/aggressive, 10 % are dependent/non-aggressive, and 5 % are dependent/aggressive. Dependent/aggressive AD patients are more likely to be hospitalised (70-90 %) than accepted in a nursing home (0-20 %), while the opposite is true for dependent/non-aggressive patients (5-35 % for hospitalisation vs. 80 % for nursing home). Independent AD patients require 1-3 hours/day of caregiver time, while dependent patients can require up to 12-15 hours/day. Experts agreed that AD complicates the management of age-related comorbidities, found in 70-80 % of all AD patients, increasing the frequency and cost of hospitalisation. Conclusions: The Delphi panel approach was an efficient method of gathering data about the amount of healthcare resources used and associated costs for moderate and severe AD patients in urban China. The results of this study provide a useful source of information for decision makers to improve future healthcare policies and resource planning, as well as to perform economic evaluations of AD therapies. [ABSTRACT FROM AUTHOR]

Background: The genetic basis for avian to mammalian host switching in influenza A virus is largely unknown. The human A/HK/156/1997 (H5N1) virus that transmitted from poultry possesses NS1 gene mutations F103L + M106I that are virulence determinants in the mouse model of pneumonia; however their individual roles have not been determined. The emergent A/Shanghai/patient1/2013(H7N9)-like viruses also possess these mutations which may contribute to their virulence and ability to switch species. Methods: NS1 mutant viruses were constructed by reverse genetics and site directed mutagenesis on human and mouse-adapted backbones. Mouse infections assessed virulence, virus yield, tissue infection, and IFN induction. NS1 protein properties were assessed for subcellular distribution, IFN antagonism (mouse and human), CPSF30 and RIG-I domain binding, host transcription (microarray); and the natural prevalence of 103L and 106I mutants was assessed. Results: Each of the F103L and M106I mutations contributes additively to virulence to reduce the lethal dose by >800 and >3,200 fold respectively by mediating alveolar tissue infection with >100 fold increased infectious yields. The 106I NS1 mutant lost CPSF binding but the 103L mutant maintained binding that correlated with an increased general decrease in host gene expression in human but not mouse cells. Each mutation positively modulated the inhibition of IFN induction in mouse cells and activation of the IFN-β promoter in human cells but not in combination in human cells indicating negative epistasis. Each of the F103L and M106I mutations restored a defect in cytoplasmic localization of H5N1 NS1 in mouse cells. Human H1N1 and H3N2 NS1 proteins bound to the CARD, helicase and RD RIG-I domains, whereas the H5N1 NS1 with the same consensus 103F and 106M mutations did not bind these domains, which was totally or partially restored by the M106I or F103L mutations respectively. Conclusions: The F103L and M106I mutations in the H5N1 NS1 protein each increased IFN antagonism and mediated interstitial pneumonia in mice that was associated with increased cytoplasmic localization and altered host factor binding. These mutations may contribute to the ability of previous HPAI H5N1 and recent LPAI H7N9 and H6N1 (NS1-103L+106M) viruses to switch hosts and cause disease in humans. [ABSTRACT FROM AUTHOR]

The sedimentary environment of a large coastal embayment, Jiaozhou Bay, eastern China, in terms of erosion/siltation, has been assessed on the basis of seabed bathymetry and coastline data sets from sea charts ( 1936-2002) and Landsat-5 TM images (1986-2011). Nine types of sedimentary environment are identified according to the sedimentation rate. The results indicate that slow siltation was generally present from 1936 to 1963, with exceptions of some patchy, slightly eroding areas within the embayment. Transformation to a slow erosion pattern occurred in the main channels over the central embayment in 1963, and such a situation continued until 1982. Subsequently, since 1986, most of the coastlines extended toward the sea at a rate of 101-102 m y-1; this was mainly attributable to human activities, including reclamation over the NW tidal-flat and harbour construction along the east and south coastlines. Using the same data set, patterns of changes in tidal prism and deposition rate within the entrance channel were established. An equivalent friction coefficient (K) is proposed to evaluate the P-A relationship of the large tidal inlets in Jiaozhou Bay. The K value increases gradually over time, indicating a trend toward stable equilibrium in Jiaozhou Bay. This coefficient can be used to examine the status of morphological stability and equilibrium of coastal embayments. [ABSTRACT FROM AUTHOR]