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Xuan-qiang Tu,1,* Ze-hua Lai,1,* Yu Zhang,2 Kai-qi Ding,1 Fei-yue Ma,3 Guo-Yuan Yang,1 Ji-rong He,3 Li-li Zeng1 1Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Neurology and Institute of Neurology, Ruijin Hospital North, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Department of Neurology and Institute of Neurology, Ruijin Hospital Luwan Branch, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li-li Zeng No. 197 Ruijin Second Road, Huangpu District, Shanghai, 200025, People’s Republic of ChinaTel +86-13816290607Email llzeng@126.comJi-rong He No. 149 Chongqing South Road, Huangpu District, Shanghai, People’s Republic of ChinaTel +86-13162762045Email kyo3shao@aliyun.comObjective: This study aimed to explore the correlation between white matter hyperintensity (WMH) and post-stroke depression (PSD) at 3 months, and to further investigate sex differences in the pathogenesis of PSD.Methods: A total of 238 consecutive patients with acute cerebral infarction were recruited. PSD was assessed at 2 weeks and at 3 months after stroke onset. All stroke cases were divided into four subgroups according to the diagnosis of depression at two time nodes: continuous depression; depression remission; late-onset PSD; and continuous non-depression. The Fazekas and Scheltens visual rating scales were adopted to assess WMH.Results: Logistic regression revealed that the presence of periventricular white matter hyperintensity (PVWMH) at baseline in male patients was an independent risk factor for PSD at 3 months. Further subgroup analysis revealed that PVWMH was associated with late-onset PSD in males, but not with continuous depression 3 months after stroke. Male acute stroke patients with PVWMH at baseline were more likely to develop PSD at 3 months, especially late-onset PSD.Conclusion: Our data suggest that sex differences may influence the pathogenesis of PSD.Keywords: sex difference, acute cerebral infarction, leukoencephalopathy, affective disorder, post-stroke depression

Vascular cognitive impairment (VCI) is the most common type of dementia after Alzheimer's disease (AD). Effective treatments for VCI are currently lacking. MicroRNA (miR)- 140-5p is associated with cerebral ischemia and poststroke depression, but its relationship with VCI remains unknown. A VCI model was established by bilateral common carotid artery occlusion (BCCAO) for 17 min in mice. Neurogenesis was evaluated by immunostaining for Nestin/bromodeoxyuridine (BrdU), NeuN/BrdU, and doublecortin (DCX)/BrdU. Neuroplasticity was assessed by quantifying synapsin-I and postsynaptic density protein 95 (PSD-95) protein levels. Predicted target genes were screened and verified using the dual luciferase reporter gene system. MiR-140-5p was upregulated in the hippocampus of the BCCAO mice 2 weeks following ischemia. Compared with control groups, the AAV-miR-140-5p group exhibited poorer cognitive performance alongside lower numbers of DCX/BrdU and NeuN/BrdU and less synapsin-I and PSD-95 in the dentate gyrus (P 0.05). MiR-140-5p overexpression decreased the predicted target gene Prox1. Dual luciferase reporter system confirmed that Prox1 was a direct target site for miR-140-5p. In conclusion, our results suggest that miR-140-5p inhibits neurogenesis and neuroplasticity via downregulation of Prox1 and aggravates VCI. Our findings highlight that miR-140-5p is involved in the pathological process of VCI and provides information for the development of new treatments, which may need further inhibition tests to verify.

BACKGROUND: The expression of miR-140-5p increased in the brain tissue of a bilateral common carotid artery ligation model, while the overexpression of miR-140-5p significantly decreased the number of neurons. The luciferase report experiment in the previous study proved that miR-140-5p negatively regulated one of the potential targets of Prospero-related homeobox 1 (Prox1). Therefore, we want to investigate the effect of miR-140-5p on the proliferation and differentiation of neural stem cells (NSCs) and the underlying mechanism. METHODS: Primary NSCs were extracted from pregnant ICR mice aged 16–18 days and induced to differentiate. After transient transfection with miR-140-5p mimic and inhibitor into NSCs, the cells were divided into five groups: blank, mimic normal control, mimic, inhibitor normal control, and inhibitor. Cell Counting Kit-8 (CCK-8) and 5-Bromo-2-deoxyUridine (BrDU), Ki-67 were used, and the diameter of neural spheres was measured to observe proliferation ability 48 h later. Doublecortin (DCX), glial fibrillary acidic protein (GFAP), microtubule-associated proteins 2 (MAP-2), synapsin I (SYN1), and postsynaptic density protein-95 (PSD-95) were stained to identify the effect of miR-140-5p on the differentiation ability of NSCs into neural precursor cells, astrocytes, and neurons and the expression of synapse-associated proteins. The expression of miR-140-5p, Prox1, p-ERK1/2, and ERK1/2 was analyzed by real time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. RESULTS: While the expression of miR-140-5p decreased after NSC differentiation (P0.05). However, the neural spheres were shorter in the miR-140-5p overexpression group (P0.05) in the miR-140-5p overexpression group. CONCLUSIONS: MiR-140-5p reduced the proliferation rate of NSCs, inhibited their differentiation into neurons, produced synapse-associated proteins, and promoted their differentiation into astrocytes. MiR-140-5p negatively regulated downstream target Prox1 and activated the ERK/MAPK signaling pathway.

Kai-qi Ding,* Ze-hua Lai,* Yu Zhang, Guo-yuan Yang, Ji-rong He, Li-li Zeng Department of Neurology and Institute of Neurology, Ruijin Hospital/Luwan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li-li Zeng No. 197 Ruijin Second Road, Huangpu District, Shanghai, 200025, People’s Republic of ChinaTel +86-13816290607Email llzeng@126.comJi-rong He No. 149 Chongqing South Road, Huangpu District, Shanghai, People’s Republic of ChinaTel +86-13162762045Email kyo3shao@aliyun.comPurpose: To explore the relationship between the monocyte-to-lymphocyte ratio (MLR) and depression three months after acute ischemic stroke.Patients and Methods: From May 2013 to September 2014, 203 patients with acute ischemic stroke were recruited within 7 days post-stroke from Shanghai Ruijin Hospital and blood samples were collected after admission. The Hamilton Depression Scale and Clinical Review were evaluated at 3 months after stroke. Based on the Diagnostic and Statistical Manual of Mental Disorders-IV diagnostic criteria, we divided patients into post-stroke depression (PSD) and non-PSD groups. We analyzed the intergroup difference in MLR and the contributing factors. Moreover, dynamic changes in monocytes, lymphocytes and MLR at four different time intervals for all the stroke patients and their relationship with PSD patients were also studied.Results: The NIHSS scores and MLR in the PSD group were significantly higher than in the non-PSD group (p< 0.05). Logistic regression analysis revealed MLR was an independent risk factor for PSD (odds ratio: 18.020, 95% confidence interval: 1.127‒288.195, p=0.041). MLR correlated negatively with cholesterol and low-density lipoprotein (r=− 0.160 and − 0.165, respectively, p< 0.05). Within 7 days post-acute ischemic stroke, monocytes gradually increased while lymphocytes remained unchanged for all the stroke patients. The MLR value was significantly higher in the PSD group than in the non-PSD group within 24 h post-stroke (p< 0.05), but there was no difference in the other three time-intervals between the two groups.Conclusion: The admission MLR, particularly within 24 h post-stroke, was associated with PSD at 3 months, implying that the MLR might be involved in the PSD inflammatory mechanism.Keywords: MLR, depression, inflammation, acute ischemic stroke

Background Many studies among different ethnic populations suggested that angiotensin converting enzyme (ACE) gene polymorphisms were associated with susceptibility to Alzheimer’s disease (AD). However, the results remained inconclusive. In the present meta-analysis, we aimed to clarify the effect of ACE polymorphisms on AD risk using all available relevant data. Methods Systemic literature searches were performed using PubMed, Embase, Alzgene and China National Knowledge Infrastructure (CNKI). Relevant data were abstracted according to predefined criteria. Results Totally, 82 independent cohorts from 65 studies were included, focusing on five candidate polymorphisms. For rs1799752 polymorphism, in overall analyses, the insertion (I) allele conferred increased risk to AD compared to the deletion (D) allele (I vs. D: OR = 1.091, 95% CI = 1.007–1.181, p = 0.032); while the I carriers showed increased AD susceptibility compared with the D homozygotes (II + ID vs. DD: OR = 1.131, 95% CI = 1.008–1.270, p = 0.036). However, none of the positive results passed FDR adjustment. In subgroup analysis restricted to late-onset individuals, the associations between rs1799752 polymorphism and AD risk were identified using allelic comparison (OR = 1.154, 95% CI = 1.028–1.295, p = 0.015, FDR = 0.020), homozygotes comparison, dominant model and recessive model (II vs. ID + DD: OR = 1.272, 95% CI = 1.120–1.444, p < 0.001, FDR < 0.001). Nevertheless, no significant association could be revealed after excluding studies not in accordance with Hardy-Weinberg equilibrium (HWE). In North Europeans, but not in East Asians, the I allele demonstrated increased AD susceptibility compared to the D allele (OR = 1.096, 95% CI = 1.021–1.178, p = 0.012, FDR = 0.039). After excluding HWE-deviated cohorts, significant associations were also revealed under homozygotes comparison, additive model (ID vs. DD: OR = 1.266, 95% CI = 1.045–1.534, p = 0.016, FDR = 0.024) and dominant model (II + ID vs. DD: OR = 1.197, 95% CI = 1.062–1.350, p = 0.003, FDR = 0.018) in North Europeans. With regard to rs1800764 polymorphism, significant associations were identified particularly in subgroup of European descent under allelic comparison (T vs. C: OR = 1.063, 95% CI = 1.008–1.120, p = 0.023, FDR = 0.046), additive model and dominant model (TT + TC vs. CC: OR = 1.116, 95% CI = 1.018–1.222, p = 0.019, FDR = 0.046). But after excluding studies not satisfying HWE, all these associations disappeared. No significant associations were detected for rs4343, rs4291 and rs4309 polymorphisms in any genetic model. Conclusions Our results suggested the significant but modest associations between rs1799752 polymorphism and risk to AD in North Europeans. While rs4343, rs4291 and rs4309 polymorphisms are unlikely to be major factors in AD development in our research.

Endothelial progenitor cells (EPCs) are multipotential stem cells considered to have immense clinical value for revascularization. However, the clinical application of EPCs has been hampered by their clinical potency in ischemic anoxic environments. This study aimed to explore the effect of microRNA-210 (miR-210) on EPCs under oxygen-glucose deprivation (OGD) conditions. We generated a model of EPCs cultured under OGD conditions to simulate ischemia and explore the expression of miR-210 in vitro. With longer exposure to hypoxia, we found that miR-210-3p expression was highly upregulated in OGD groups compared to that in controls from 4 to 24 h, but not miR-210-5p. We then transfected a miR-210-3p mimic and inhibitor into EPCs, and after 24 h, we exposed them to OGD conditions for 4 h to simulate ischemia. We detected miR-210 by real-time polymerase chain reaction (RT-PCR) and tested the proliferation, migration, and tube formation of normal EPCs and OGD-treated EPCs by CCK-8, transwell chamber, and Matrigel assays, respectively. The direct targets of miR-210-3p were predicted using miRWalk. Compared to that in normal EPCs, higher miR-210-3p expression was found in OGD-treated EPCs (p < 0.05). Moreover, upregulation of miR-210-3p was found to promote proliferation, migration, and tube formation in EPCs under normal and OGD conditions (p < 0.05), whereas down-regulation inhibited these abilities in OGD-treated EPCs (p < 0.05). Repulsive guidance molecule A (RGMA), a negative regulator of angiogenesis, was predicted to be a target of miR-210-3p. Accordingly, upregulation of miR-210-3p was found to inhibit its expression at the protein level in OGD-treated EPCs, whereas downregulation of miR-210-3p inhibited its expression (p < 0.05). A dual-luciferase reporter system confirmed that RGMA is a direct target of miR-210-3p. MicroRNA-210-3p overexpression enhances the angiogenic properties of OGD-treated EPCs by inhibiting RGMA.

We aimed to explore the circulating microRNAs biomarkers in the acute stage following cerebral ischemia to earlier warn late-onset post-stroke depression (PSD). A total of 251 consecutive patients with acute ischemic stroke were recruited. They were divided into three groups depending on whether PSD had occurred at 2 weeks or 3 months since stroke: early-onset PSD, late-onset PSD, and non-depressed group. Microarray assay was conducted to identify the different expression profiles of plasma miRNAs. Comprehensive bioinformatics analysis for their integrating putative target genes was performed. The key miRNA was validated in a larger cohort and its function was further studied in ischemic mice brain. We screened three differentially expressed miRNAs in the late-onset PSD individuals, miR-140-5p and miR-221-3p were significantly upregulated while miR-1246 was downregulated. The bioinformatics analysis demonstrated that their predicted target genes were mainly enriched in axon development and Ras signaling pathway. Logistic regression analysis revealed that miR-140-5p was an independent risk factor for late-onset PSD (P = 0.017, OR = 2.313, 95%CI 1.158 to 4.617). The miR-140-5p expression on admission was significantly positively correlated with HDRS scores assessed at 3 months after stroke (P = 0.0007). The predictive value of miR-140-5p for late-onset PSD is 83.3% sensitivity and 72.6% specificity (AUC = 0.8127, P 0.0001). AAV-mediated overexpression of miR-140-5p decreased the protein level of IL1rap, IL1rapl1, VEGF, and MEGF10 in the ischemic mouse hippocampus and inhibited neurogenesis and capillary density. MiR-140-5p might be involved in the pathogenesis of late-onset PSD and used as a novel early warning biomarker.

The Large High Altitude Air Shower Observatory project is proposed to study high energy gamma ray astronomy ( 40 GeV-1 PeV ) and cosmic ray physics ( 20 TeV-1 EeV ). The wide field of view Cherenkov telescope array, as a component of the LHAASO project, will be used to study energy spectrum and compositions of cosmic ray by measuring the total Cherenkov light generated by air showers and shower maximum depth. Two prototype telescopes have been in operation since 2008. The pointing accuracy of each telescope is crucial to the direction reconstruction of the primary particles. On the other hand the primary energy reconstruction relies on the shape of the Cherenkov image on the camera and the unrecorded photons due to the imperfect connections between photomultiplier tubes. UV bright stars are used as point-like objects to calibrate the pointing and to study the optical properties of the camera, the spot size and the fractions of unrecorded photons in the insensitive areas of the camera., 5 pages, 6 figures, submitted to Chinese Physics C