Exosomes derived from human umbilical cord mesenchymal stem cells alleviate Parkinson’s disease and neuronal damage through inhibition of microglia

Microglia-mediated inflammatory responses have been shown to play a crucial role in Parkinson’s disease. In addition, exosomes derived from mesenchymal stem cells have shown anti-inflammatory effects in the treatment of a variety of diseases. However, whether they can protect neurons in Parkinson’s disease by inhibiting microglia-mediated inflammatory responses is not yet known. In this study, exosomes were isolated from human umbilical cord mesenchymal stem cells and injected into a 6-hydroxydopamine-induced rat model of Parkinson’s disease. We found that the exosomes injected through the tail vein and lateral ventricle were absorbed by dopaminergic neurons and microglia on the affected side of the brain, where they repaired nigral-striatal dopamine system damage and inhibited microglial activation. Furthermore, in an in vitro cell model, pretreating lipopolysaccharide-stimulated BV2 cells with exosomes reduced interleukin-1β and interleukin-18 secretion, prevented the adoption of pyroptosis-associated morphology by BV2 cells, and increased the survival rate of SH-SY5Y cells. Potential targets for treatment with human umbilical cord mesenchymal stem cells and exosomes were further identified by high-throughput microRNA sequencing and protein spectrum sequencing. Our findings suggest that human umbilical cord mesenchymal stem cells and exosomes are a potential treatment for Parkinson’s disease, and that their neuroprotective effects may be mediated by inhibition of excessive microglial proliferation.

Evaluation of IMERG, TMPA, ERA5, and CPC precipitation products over China's Mainland: Spatiotemporal patterns and extremes

A comprehensive assessment of representative satellite-retrieved(Integrated Multi-satellite Retrievals for Global Precipitation Measurement(IMERG)and Tropical Rainfall Measuring Mission Multi-satellite Precipitation Analysis(TMPA)),reanalysis-based(fifth generation of atmospheric reanalysis by the European Centre for Medium Range Weather Forecasts(ERA5)),and gauge-estimated(Climate Prediction Center(CPC))precipitation products was conducted using the data from 807 meteorological stations across China's Mainland from 2001 to 2017.Error statistical metrics,precipitation distribution functions,and extreme precipitation indices were used to evaluate the quality of the four precipitation products in terms of multi-timescale accuracy and extreme precipitation estimation.When the timescale increased from daily to seasonal scales,the accuracy of the four precipitation products first increased and then decreased,and all products performed best on the monthly timescale.Their accuracy ranking in descending order was CPC,IMERG,TMPA,and ERA5 on the daily timescale and IMERG,CPC,TMPA,and ERA5 on the monthly and seasonal timescales.IMERG was generally superior to its predecessor TMPA on the three timescales.ERA5 exhibited large statistical errors.CPC provided stable estimated values.For extreme precipitation estimation,the quality of IMERG was relatively consistent with that of TMPA in terms of precipitation distribution and extreme metrics,and IMERG exhibited a significant advantage in estimating moderate and heavy precipitation.In contrast,ERA5 and CPC exhibited poor performance with large systematic underestimation biases.The findings of this study provide insight into the performance of the latest IMERG product compared with the widely used TMPA,ERA5,and CPC datasets,and points to possible directions for improvement of multi-source precipitation data fusion algorithms in order to better serve hydrological applications.

Multiphase convolutional dense network for the classification of focal liver lesions on dynamic contrast-enhanced computed tomography

BACKGROUND The accurate classification of focal liver lesions(FLLs)is essential to properly guide treatment options and predict prognosis.Dynamic contrast-enhanced computed tomography(DCE-CT)is still the cornerstone in the exact classification of FLLs due to its noninvasive nature,high scanning speed,and high-density resolution.Since their recent development,convolutional neural network-based deep learning techniques has been recognized to have high potential for image recognition tasks.AIM To develop and evaluate an automated multiphase convolutional dense network(MP-CDN)to classify FLLs on multiphase CT.METHODS A total of 517 FLLs scanned on a 320-detector CT scanner using a four-phase DCECT imaging protocol(including precontrast phase,arterial phase,portal venous phase,and delayed phase)from 2012 to 2017 were retrospectively enrolled.FLLs were classified into four categories:Category A,hepatocellular carcinoma(HCC);category B,liver metastases;category C,benign non-inflammatory FLLs including hemangiomas,focal nodular hyperplasias and adenomas;and category D,hepatic abscesses.Each category was split into a training set and test set in an approximate 8:2 ratio.An MP-CDN classifier with a sequential input of the fourphase CT images was developed to automatically classify FLLs.The classification performance of the model was evaluated on the test set;the accuracy and specificity were calculated from the confusion matrix,and the area under the receiver operating characteristic curve(AUC)was calculated from the SoftMax probability outputted from the last layer of the MP-CDN.RESULTS A total of 410 FLLs were used for training and 107 FLLs were used for testing.The mean classification accuracy of the test set was 81.3%(87/107).The accuracy/specificity of distinguishing each category from the others were 0.916/0.964,0.925/0.905,0.860/0.918,and 0.925/0.963 for HCC,metastases,benign non-inflammatory FLLs,and abscesses on the test set,respectively.The AUC(95%confidence interval)for differentiating each category from the others was 0.92(0.837-0.992),0.99(0.967-1.00),0.88(0.795-0.955)and 0.96(0.914-0.996)for HCC,metastases,benign non-inflammatory FLLs,and abscesses on the test set,respectively.CONCLUSION MP-CDN accurately classified FLLs detected on four-phase CT as HCC,metastases,benign non-inflammatory FLLs and hepatic abscesses and may assist radiologists in identifying the different types of FLLs.

Comparison of the Immunogenicities of HIV-1 Mutants Based on Structural Modification of env

Eleven env mutants were designed and generated by site-directed mutagenesis of the regions around NAb epitopes and deletions of variable regions in env. The immunogenicities of the generated mutants were evaluated using single-cycle infection neutralization assays with two pseudoviruses and IFN-γ ELISPOT. Overall, five mutants (dWt, M2, M5-2, M5-1 and dM7) induced higher neutralization activities for both pseudoviruses than plasmid Wt, while only two of the mutants (dWt and M5-2) showed significant differences (P<0.05). Two mutants (M2 and dM2) induced more Env-specific T cells than plasmid Wt. Statistically however, significance was only reached for mutant M2. Thus, properly modified HIV-1 Env may have the potential to induce potent cellular and humoral immune responses.

A novel mutation of CYP4V2 gene associated with Bietti crystalline dystrophy complicated by choroidal neovascularization

AIM: To investigate the clinical characteristics and genetic features of a Bietti crystalline dystrophy(BCD) proband in a Chinese family.METHODS: A Chinese female diagnosed with BCD complicated by bilateral choroidal neovascularization(CNV) and her parents underwent complete ophthalmic examinations, including fundus autofluorescence(AF), fundus photography(FP), fundus fluorescein angiography(FFA), visual field testing, full-field electroretinography(ERG), optical coherence tomography(OCT) and optical coherence tomography angiography(OCTA). The sequencing of the CYP4 V2 gene was performed to the whole family.RESULTS: Bilateral tiny glittering crystal-like deposits and differing extent of atrophy of the retinal pigment epithelium(RPE) were found in the posterior pole of her fundus. The diffuse hypo-fluorescence shown on AF images and window defects shown on FFA both indicated the atrophy of the RPE and choriocapillaris. OCT showed the thinning of the RPE and choriocapillaris layer, ellipsoid zone(EZ) band defect and CNV in both eyes. OCTA images proofed bilateral type 2 CNV. The visual field test showed central and paracentral scotoma. ERG showed a slightly decreased b-wave in scotopic ERG. Gene sequencing identified three mutations of the CYP4 V2 gene, c.802_807 del, c.810 del T, and c.1388 G>A. The mutation c.1388 G>A was a novel substitution mutation.CONCLUSION: The novel mutation c.1388 G>A may be a possible cause that could induce the clinical phenotype of BCD.

The Correlation among TIR, HbA1c,1, 5-AG and GA in Patients with 3rd Stage of Diabetic Nephropathy

Objective:To investigate the correlation among time in range(TIR),hemoglobinA1c(HbA1c),1,5-anhydroglucitol(1,5-AG)and glycated albumin(GA)in patients with 3rd stage of diabetic nephropathy.Methods:HbA1c,1,5-AG and GA were detected in120 patients with 3rd stage of diabetic nephropathy and flash glucose monitoring(FGM)was used to observe patients'TIR.The general characteristics,laboratory data and FGM blood glucose data of the groups≥70%and<70%of TIR3.9-10.0 were observed,and the correlation among TIR3.9-10.0,HbA1c,1,5-ag and GA was summarized.Results:There was no significant difference in general information and laboratory data in addition to glycemic monitoring indicators between the two groups of TIR3.9-10.0≥70%and TIR3.9-10.0<70%(P>0.05).After adjusting hemoglobin(HGB),TIR3.9-10.0 was negatively correlated with HbA1c,r=-0.871;after adjusting estimated glomerular filtration rate(eGFR),TIR3.9-10.0 was positively correlated with 1,5-AG concentration,r=0.591;after adjusting serum albumin(ALB),TIR3.9-10.0 was negatively correlated with GA concentration,r=-0.521;all P values were less than 0.05.Conclusion:TIR3.9-10.0 correlated with 1,5-AG and GA in patients with 3rd stage of diabetic nephropathy,which can be considered as an evaluation index of short-term glycemic control in patients with early diabetic nephropathy.

Activity of fibroblast-like synoviocytes in rheumatoid arthritis was impaired by dickkopf-1 targeting siRNA

Background:Fibroblast-like synoviocytes(FLSs),resident mesenchymal cells of synovial joints,play an important role in the pathogenesis of rheumatoid arthritis(RA).Dickkopf-1(DKK-1)has been proposed to be a master regulator of bone remodeling in inflammatory arthritis.Here,potential impairation on the activity of FLSs derived from RA to small interfering RNAs(siRNAs)targeting DKK-1 was investigated.Methods:siRNAs targeting DKK-1 were transfected into FLSs of patients with RA.Interleukin(IL)-1β,IL-6,IL-8,matrix metalloproteinase(MMP)2,MMP3,MMP9,transforming growth factor(TGF)-pi,TGF-β2 and monocyte chemoattractant protein(MCP)-1 levels in the cell culture supernatant were detected by enzyme-linked immunosorbent assay(ELISA).Invasion assay and 3H incorporation assay were utilized to investigate the effects of siRNAs targeting DKK-1 on FLSs invasion and cell proliferation,respectively.Western blotting was performed to analyze the expression of nuclear factor(NF)-kB,interleukin-1 receptor-associared kinase(IRAK)1,extracellular regulated protein kinases(ERK)1,Jun N-terminal kinase(JNK)and p-catenin in FLSs.Results:DKK-1 targeting siRNAs inhibited the expression of DKK-1 in FLSs(P<0.01).siRNAs induced a significant reduction of the levels of IL-6,IL-8,MMP2,MMP3 and MMP9 in FLSs compared to the control group(P<0.05).DKK-1 targeting siRNAs inhibited the proliferation and invasion of FLSs(P<0.05).Important molecules of pro-inflammatory signaling in FLSs,including IRAKI and ERK1,were decreased by the inhibition of DKK-1 in FLSs.In contrast,β-catenin,a pivotal downstream molecule of the Wnt signaling pathway was increased.Conclusions:By inhibiting DKK-1,we were able to inhibit the proliferation,invasion and pro-inflammatory cytokine secretion of FLSs derived from RA,which was mediated by the ERK or the IRAK-1 signaling pathway.These data indicate the application of DKK-1 silencing could be a potential therapeutic approach to RA.