Effect of visual impairment on subjective cognitive decline in older adults: a cross-sectional study in China.

OBJECTIVE: People with visual impairment have more functional limitations associated with subjective cognitive decline (SCD), and those with SCD are extremely susceptible to transitioning to irreversible cognitive impairment. This study aimed to explore if visual impairment is a significant predictor of SCD compared with other socioeconomic and health factors associated with SCD. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: The investigation aimed to assess the factors influencing SCD among 428 participants aged 60 and above in Zhaoyuan, China. PRIMARY OUTCOME MEASURES: The primary outcome variable was SCD, measured by the Chinese version of SCD questionnaire. Multiple logistic regression and propensity score matching (PSM) were used to analyse the influence of visual impairment on the subjective cognition of the elderly.32.2% of the elderly were experiencing SCD. Older adults with SCD showed a higher prevalence of visual impairment (72.5%) than the elderly without SCD (58.6%) (P=0.006). Multivariate logistic regression analysis showed that bad self-reported health status, lack of physical exercise and visual impairment were the risk factors for SCD in older adults, while more than 9 years of education was a protective factor. In addition, PSM model showed that after eliminating the dominant biases caused by the individual observable heterogeneity of older adults with and without visual impairment, the risk of SCD in the elderly with visual impairment was increased by 13.6%-14.5% and the difference was statistically significant (P<0.05). CONCLUSIONS: It was found that older adults experiencing visual impairments are at an elevated risk of developing SCD compared with their counterparts without such impairments. Additionally, visual impairment remains a significant risk factor for SCD in the elderly, even adjusting for potential biases arising from individual observable heterogeneity.

Decoding the diagnostic potential of T cell repertoires in peripheral blood of patients from amnestic mild cognitive impairment to Alzheimer's disease.

Alzheimer's disease (AD) is currently an incurable neurodegenerative disorder and is the most common etiological cause of dementia. Consequently, it has severe burden on its patients and on their caregivers and represents a global health concern. Clinical investigations have indicated that a dysregulation of peripheral T cell immune homeostasis may be involved in the pathogenesis of AD, as well as in the early stages of AD, characterized by mild cognitive impairment (MCI). However, the characteristics and concomitant feasibility of the use of T-cell receptor (TCR) typing for disease diagnosis remains largely unknown. We employed a high-throughput sequencing and multidimensional bioinformatics analyses for the identification of TCR repertoires present in peripheral blood samples of 10 patients with amnestic MCI (aMCI), 10 patients with AD, and 10 healthy controls (HCs). Based on the characteristics of the TCR repertoires in the amount and diversity of combinations of V-J, the spectrum of immune defense, and differentially expressed genes (DEGs), single and specific TCR profiles were observed in the patient samples of aMCI and AD compared to profiles of HCs. In particular, the diversity of TCR clonotypes manifested a pattern of "decreased first and then increased" pattern during the progression from aMCI to AD, a pattern that was not observed in HC samples. Additionally, a total of 46 and 35 amino acid CDR3 sequences with consistent and reverse expressive abundance with diversity of TCR clonotypes were identified, respectively. Taken together, we provide novel and essential preliminary evidence demonstrating the presence of diversity of T cell repertoires from differentially expressed V-J gene segments and amino acid clonotypes using peripheral blood samples from patients with AD, aMCI, and from HC. Such findings have the potential to reveal potential mechanisms through which aMCI progresses to AD and provide a reference for the future development of immune-related diagnoses and therapies for AD.

Low life satisfaction status among older people with and without an intimate partner: a nationwide cross-sectional study in China.

BACKGROUND: Focusing on older people with and without an intimate partner, this study aimed to evaluate the prevalence of low life satisfaction in both groups, as well as the potential risk factors. METHODS: The 2017-2018 China Health and Retirement Longitudinal Study (CHARLS) data were used, and 9960 individuals aged 60 years and above were included in the analyses. Factors evaluated in this survey included sociodemographic characteristics, clinical variables, physical and social activities, and economic and social factors. The associations of low life satisfaction with independent variables were analysed using multivariate logistic regression. RESULTS: Compared with those with an intimate partner (n = 2025), elders without an intimate partner (n = 7935) showed a higher prevalence of low life satisfaction (15.1 vs. 9.9%, P < 0.001). Multivariate logistic regression showed that ≥2 physical diseases (P = 0.024), poor self-reported health status (P = 0.012), and lack of community care service (P = 0.014) were risk factors for low life satisfaction among elders without an intimate partner, while poor self-reported health status (P < 0.001), ≥2 physical diseases (P = 0.001), being troubled with bodily pain (P < 0.001), lack of light physical activity >10 mins each time (P = 0.011), lack of moderate physical activity >10 mins each time (P = 0.001), lack of social activities in the previous month (P = 0.039), and lack of community care service (P < 0.001) were risk factors for elders with an intimate partner. Regarding the potential reasons for low life satisfaction in the elderly, dissatisfaction with current health status (28.0%) and air quality (15.6%) were most prevalent. CONCLUSIONS: Older people without an intimate partner have lower life satisfaction. Having ≥2 physical diseases, poor self-reported health status, and lack of community care service were common risk factors for low life satisfaction among older adults with or without an intimate partner.

VCAM-1+ hUC-MSCs Exert Considerable Neuroprotection Against Cerebral Infarction in Rats by Suppression of NLRP3-Induced Pyroptosis.

Mesenchymal stem/stromal cells (MSCs) are spindle-like heterogeneous cell populations with advantageous bidirectional immunomodulatory and hematopoietic support effects. Vascular cellular adhesion molecule-1 (VCAM-1)+ MSCs have been reported to exhibit immunoregulatory and proangiogenic capacities. Here, we studied the effects of VCAM-1+ human umbilical cord (hUC)-MSCs on neuroprotection against cerebral infarction. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO), and VCAM-1- and VCAM-1+ hUC-MSCs were intravenously injected into the rat 4 h post-MCAO surgery. Thereafter, modified neurological severity scores (mNSS) were determined, and the Morris water maze test, 2,3,5-triphenyltetrazolium chloride (TTC), hematoxylin and eosin (H&E), Nissl, TUNEL staining, and qRT-PCR were conducted. Following induction of oxygen-glucose deprivation/reoxygenation (OGD/R), SH-SY5Y cells were co-cultured with VCAM-1- and VCAM-1+ hUC-MSCs. CCK-8, flow cytometry, ELISA, and western blot analyses were performed in vitro. Compared with VCAM-1- hUC-MSCs, administration of VCAM-1+ hUC-MSCs revealed improved therapeutic efficacy against cerebral infarction in rats, as confirmed by lower mNSS scores and infarct volumes, as well as improved learning and memory capacities. In addition, VCAM-1+ hUC-MSCs exhibited improved efficacy against neurological defects in rats with cerebral infarction, accompanied by inhibition of the NLRP3-mediated inflammatory response. VCAM-1+ hUC-MSC co-culture improved the viability and diminished NLRP3-mediated inflammatory response in OGD/R-treated SH-SY5Y cells. Moreover, NLRP3 overexpression in SH-SY5Y cells prevented the beneficial effects of VCAM-1+ hUC-MSC co-culture. Overall, our findings demonstrated the relevance of VCAM-1+ hUC-MSC-based cytotherapy for preclinical neuroprotection against cerebral infarction.

Interleukin-33 as a Biomarker Affecting Intrathecal Synthesis of Immunoglobulin in Neuromyelitis Optica Spectrum Disorder and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

INTRODUCTION: The purpose of this study was to analyze IL-33 maybe as a biomarker especially with respect to intrathecal immunoglobulin G (IgG) synthesis which was involved in the immune-mediated process in the demyelinating disease of the central nervous system. METHODS: We aimed to determine the risk association of the serum and CSF levels of IL-33 in aquaporin-4 (AQP4)+neuromyelitis optica spectrum disorder (NMOSD) patients and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) patients compared with the control group. Levels of inflammatory (IL-2, IL-4, IL-6, and IL-10) markers and QAlb, the IgG index, and 24-h IgG synthesis rate were assessed in 28 AQP4+NMOSD patients and 11 MOGAD patients. Disease severity was assessed using the Expanded Disability Status Scale (EDSS). RESULTS: The level of IL-33 in serum decreased first but then increased gradually in AQP4+NMOSD and MOGAD. The serum level of IL-2, IL-4, and IL-10 increased more significantly and decreased more rapidly after methylprednisolone treatment. The level of IL-33 in CSF increased progressively in AQP4+NMOSD and MOGAD, especially in MOGAD. The QAlb levels were increased significantly in the CSF of MOGAD patients and AQP4+NMOSD patients on the acute stage of the disease. The IgG index and 24-h IgG synthesis rate were also increased significantly in the CSF of two groups similarly. CONCLUSIONS: Thus, we concluded that IL-33 may induce dysfunction of the blood-brain barrier and lead to intrathecal synthesis of immunoglobulin in the AQP4+NMOSD and MOGAD, especially in MOGAD. It maybe as a biomarker, at least in part, was involved in the demyelinating diseases of the central nervous system.

Aberrant Dendritic Cell Subsets in Patients with Myasthenia Gravis and Related Clinical Features.

INTRODUCTION: Dendritic cells (DCs) play critical roles in the pathogenesis of myasthenia gravis (MG), and a series of DC-based experimental strategies for MG have recently been developed. However, the definite roles of different DC subsets in the mechanism of MG have scarcely been covered by previous studies. The present study aimed to investigate the levels of three main DC subsets, plasmacytoid DCs (pDCs) (CD303 positive) and two distinct subsets of conventional DCs (cDCs), namely CD1c+ cDCs and CD141+ cDCs, in MG patients and analyze related clinical features. METHODS: From January 2016 to December 2020, 160 newly diagnosed MG patients and matched healthy controls (n = 160) were included in the study, and their clinical data were collected. The blood samples from MG patients before treatment and controls were collected for flow cytometry analysis. A total of 14 MG thymoma, 24 control thymoma, and 3 thymic cysts were used to immunostain the DC subsets. RESULTS: The flow cytometry analysis showed a significantly higher frequency of circulating pDCs, CD1c+ cDCs, and CD141+ cDCs in MG patients than in healthy controls (p < 0.001 for all). Patients with early-onset MG (<50 years old) had a lower frequency of circulating pDCs but a higher frequency of circulating CD1c+ cDCs than those with late-onset MG (≥50 years old) (p = 0.014 and p = 0.025, respectively). The frequency of circulating pDCs was positively associated with the clinical severity of late-onset MG patients (r = 0.613, p < 0.001). 64.3% (9/14) of MG thymoma is of type B2 under the World Health Organization classification, which is higher than that in control thymoma (33.3%, 8/24) (p = 0.019). For type B2 thymoma, there were significantly more pDCs but fewer CD1c+ cDCs in MG thymoma than in the controls. CONCLUSION: The distribution of aberrant pDCs, CD1c+ cDCs, and CD141+ cDCs in MG patients displayed age- and thymoma-related differences, which may contribute to the impaired immune tolerance and lead to the onset of MG.

Differential methylation of circRNA m6A in an APP/PS1 Alzheimer's disease mouse model.

Alzheimer's disease (AD) is a chronic neurological disease characterized by memory loss and progressive cognitive impairment. The characteristic AD pathologies include extracellular senile plaques formed by ß­amyloid protein deposition, neurofibrillary tangles formed by hyper­phosphorylation of τ protein and neuronal loss caused by glial cell proliferation. However, the pathogenesis of AD is still unclear. Dysregulation of RNA methylation is associated with biological processes, including neurodevelopment and neurodegenerative disease. N6­methyladenosine (m6A) is the main modification in eukaryotic RNA and may be associated with the pathophysiology of AD. Circular RNA (circRNA) is a new type of evolutionarily conserved non­coding RNA without 5'­cap and 3'­polyadenylic acid tail. circRNA undergoes m6A RNA methylation and may be involved in the pathogenesis of AD. In the present study, high­throughput sequencing was performed to assess the degree of circRNA m6A methylation in APP/PS1 AD and C57BL/6 mice. These results suggested that circRNA m6A methylation in AD mice was markedly altered compared to the control group. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis was used to predict associated pathways; genes with different circRNA m6A methylation in AD mice were associated with 'axon guidance', 'long­term potentiation', 'glutamatergic synapse', 'cholinergic synapse', 'GABAergic synapse' and 'long­term depression'. Methylated RNA immunoprecipitation reverse transcription­quantitative PCR demonstrated that among the eight selected circRNA m6A genes, there were five genes that demonstrated significantly increased methylation and three demonstrated significantly decreased methylation. In summary, the present study indicated that circRNA m6A methylation may be associated with pathogenesis of AD.

Impact prediction of translocation of the mitochondrial outer membrane 70 as biomarker in Alzheimer's disease.

Mitochondrial dysfunction plays a key role in the pathogenesis of Alzheimer's disease (AD). The translocase of the outer membrane (TOM) complex controls the input of mitochondrial precursor proteins to maintain mitochondrial function under pathophysiological conditions. However, its role in AD development remains unclear. TOM70 is an important translocase present in the TOM complex. In the current study, we found that TOM70 levels were reduced in the peripheral blood and hippocampus of the APP/PS1 mice. In addition, we examined the whole-blood mRNA levels of TOM70 in patients with AD, dementia with Lewy bodies (DLB), and post-stroke dementia (PSD). Our study revealed that the mRNA level of TOM70 was decreased in the blood samples of patients with AD, which was also correlated with the progression of clinical stages. Therefore, we proposed that the expression of TOM70 could be a promising biomarker for AD diagnosis and monitoring of disease progression.

COVID-19 Vaccine Hesitancy Among Older Adolescents and Young Adults: A National Cross-Sectional Study in China.

Background: With promotion of COVID-19 vaccinations, there has been a corresponding vaccine hesitancy, of which older adolescents and young adults represent groups of particular concern. In this report, we investigated the prevalence and reasons for vaccine hesitancy, as well as potential risk factors, within older adolescents and young adults in China. Methods: To assess these issues, an online survey was administered over the period from March 14 to April 15, 2021. Older adolescents (16-17 years old) and young adults (18-21 years old) were recruited nationwide from Wechat groups and results from a total of 2,414 respondents were analyzed. Socio-demographic variables, vaccine hesitancy, psychological distress, abnormal illness behavior, global well-being and social support were analyzed in this report. Results: Compared to young adults (n = 1,405), older adolescents (n = 1,009) showed higher prevalence rates of COVID-19 vaccine hesitancy (16.5 vs. 7.9%, p < 0.001). History of physical diseases (p = 0.007) and abnormal illness behavior (p = 0.001) were risk factors for vaccine hesitancy among older adolescents, while only a good self-reported health status (p = 0.048) was a risk factor for young adults. Concerns over COVID-19 vaccine side effects (67.1%) and beliefs of invulnerability regarding infection risk (41.9%) were the most prevalent reasons for vaccine hesitancy. Providing evidence on the vaccine reduction of COVID-19 infection risk (67.5%), ensuring vaccine safety (56.7%) and the low risk of side effects (52.7%) were the most effective persuasions for promoting vaccinations. Conclusion: In China, older adolescents showed a higher prevalence for vaccine hesitancy than that of young adults. Abnormal illness behavior and history of physical diseases were risk factors for vaccine hesitancy among these older adolescents, while social support represents an important factor which could help to alleviate this hesitancy.

Integrated investigation of DNA methylation, gene expression and immune cell population revealed immune cell infiltration associated with atherosclerotic plaque formation.

BACKGROUND: The clinical consequences of atherosclerosis are significant source of morbidity and mortality throughout the world, while the molecular mechanisms of the pathogenesis of atherosclerosis are largely unknown. METHODS: In this study, we integrated the DNA methylation and gene expression data in atherosclerotic plaque samples to decipher the underlying association between epigenetic and transcriptional regulation. Immune cell classification was performed on the basis of the expression pattern of detected genes. Finally, we selected ten genes with dysregulated methylation and expression levels for RT-qPCR validation. RESULTS: Global DNA methylation profile showed obvious changes between normal aortic and atherosclerotic lesion tissues. We found that differentially methylated genes (DMGs) and differentially expressed genes (DEGs) were highly associated with atherosclerosis by being enriched in atherosclerotic plaque formation-related pathways, including cell adhesion and extracellular matrix organization. Immune cell fraction analysis revealed that a large number of immune cells, especially macrophages, activated mast cells, NK cells, and Tfh cells, were specifically enriched in the plaque. DEGs associated with immune cell fraction change showed that they were mainly related to the level of macrophages, monocytes, resting NK cells, activated CD4 memory T cells, and gamma delta T cells. These genes were highly enriched in multiple pathways of atherosclerotic plaque formation, including blood vessel remodeling, collagen fiber organization, cell adhesion, collagen catalogic process, extractable matrix assembly, and platelet activation. We also validated the expression alteration of ten genes associated with infiltrating immune cells in atherosclerosis. CONCLUSIONS: In conclusion, these findings provide new evidence for understanding the mechanisms of atherosclerotic plaque formation, and provide a new and valuable research direction based on immune cell infiltration.

IFN-γ-Primed hUCMSCs Significantly Reduced Inflammation via the Foxp3/ROR-γt/STAT3 Signaling Pathway in an Animal Model of Multiple Sclerosis.

Our previous study showed that interferon gamma (IFN-γ) might enhance the immunosuppressive properties of mesenchymal stem cells (MSCs) by upregulating the expression of indoleamine 2,3-dioxygenease. Therefore, we treated experimental autoimmune encephalomyelitis (EAE) mice, an animal model of multiple sclerosis (MS), with IFN-γ-primed human umbilical cord MSCs (IFN-γ-hUCMSCs). This study aimed to investigate the potential therapeutic effects of IFN-γ-hUCMSCs transplantation and to identify the biological pathways involved in EAE mice. Firstly, the body weights and clinical scores of EAE mice were recorded before and after treatment. Then, the inflammatory cytokine levels in splenic cell supernatants were quantified by enzyme-linked immunosorbent assay. Finally, the mRNA expression levels of signal transducer and activator of transduction 3 (STAT3), retinoic acid-related orphan receptor gamma t (ROR-γt), and forkhead box P3 (Foxp3) were detected by quantitative reverse transcription polymerase chain reaction. We observed that IFN-γ-hUCMSCs transplantation significantly alleviated body weight loss and decreased the clinical scores of mice. Additionally, IFN-γ-hUCMSCs transplantation could regulate the production of inflammatory cytokines, interleukin (IL)-10 and IL-17, thereby showing more potent treatment efficacy than human umbilical cord MSCs (hUCMSCs) transplantation (p < 0.05). Compared with the EAE group, the expressions of STAT3 and ROR-γt in the transplantation groups were significantly decreased, but the expression of Foxp3 was significantly upregulated in the IFN-γ-hUCMSCs transplantation group compared to that in the hUCMSCs transplantation group. We assumed that IFN-γ-hUCMSCs may affect the balance of T helper 17 (Th17) cells/regulatory T cells (Tregs) through the Foxp3/ROR-γt/STAT3 signaling pathway to reduce the inflammatory response, thereby improving the clinical symptoms of EAE mice. Our study demonstrated that transplantation of IFN-γ-hUCMSCs could reduce inflammation in EAE mice via the Foxp3/ROR-γt/STAT3 signaling pathway, highlighting the therapeutic effects of IFN-γ-hUCMSCs in patients with MS.

A Longitudinal Study on the Mental Health of College Students in Jinan During the Peak Stage of the COVID-19 Epidemic and the Society Reopening.

INTRODUCTION: COVID-19, a continuously emerging human-to-human infectious disease, has exerted a significant impact on the mental health of college students. However, little is known regarding the variations in the mental health issues experienced by college students during the peak versus reopening stages of the COVID-19 epidemic in China. METHODS: To assess these issues, an online longitudinal survey was conducted via a WeChat applet. Undergraduates (n = 300) were recruited from 26 universities throughout Jinan in February 2020 (T1 - the epidemic peak stage) and in January 2021 (T2 - the society reopening stage). Their mental status was determined using the Patient Health Questionnaire-9, the Generalized Anxiety Disorder-7 item, and the Insomnia Severity Index. RESULTS: Of the original 300 college students recruited for this survey, 294 responses at T1 and 285 at T2 were analyzed. Compared with responses obtained at T1, college students at T2 showed a greater prevalence of depression (65.3 vs. 51.0%; p = 0.001) and anxiety (47.7 vs. 38.1%, p = 0.019), and experienced more severe depression (p < 0.001) and anxiety (p < 0.001). Both males (p = 0.03) and females (p < 0.01) showed higher levels of depression at T2 versus T1, while no differences were obtained with regard to anxiety and insomnia. At T1, Grade 4 students showed greater levels of depression (p = 0.005) and anxiety (p = 0.008) than that of Grade 1 students. While at T2, only greater levels of depression (p = 0.004) were present when compared with that of Grade 1 students. Additionally, Grade 4 college students demonstrated a greater prevalence of depression at T2 versus T1 (p = 0.03), but no statistically differences were present for anxiety and insomnia. No statistically significant differences were obtained among the 4 grades of college students for insomnia at either the T1 or T2. CONCLUSION: With progression of the COVID-19 epidemic, college students showed increasing levels of depression and anxiety, with Grade 4 college students being most seriously affected. It is imperative that intervention strategies be implemented to mitigate against these mental health issues resulting from the COVID-19 epidemic.

Long Non-coding RNAs in Pathogenesis of Neurodegenerative Diseases.

Emerging evidence addresses the link between the aberrant epigenetic regulation of gene expression and numerous diseases including neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). LncRNAs, a class of ncRNAs, have length of 200 nt or more, some of which crucially regulate a variety of biological processes such as epigenetic-mediated chromatin remodeling, mRNA stability, X-chromosome inactivation and imprinting. Aberrant regulation of the lncRNAs contributes to pathogenesis of many diseases, such as the neurological disorders at the transcriptional and post-transcriptional levels. In this review, we highlight the latest research progress on the contributions of some lncRNAs to the pathogenesis of neurodegenerative diseases via varied mechanisms, such as autophagy regulation, Aß deposition, neuroinflammation, Tau phosphorylation and α-synuclein aggregation. Meanwhile, we also address the potential challenges on the lncRNAs-mediated epigenetic study to further understand the molecular mechanism of the neurodegenerative diseases.

Methylation of the RIN3 Promoter is Associated with Transient Ischemic Stroke/Mild Ischemic Stroke with Early Cognitive Impairment.

BACKGROUND: Early cognitive impairment after transient ischemic stroke (TIA)/mild ischemic stroke (MIS) is common but easily overlooked. It has been demonstrated that DNA methylation plays a significant role in cognitive impairment and ischemic stroke. Furthermore, it has been reported that the RIN3 gene influences transportation of the amyloid ß-protein. However, to our knowledge, there has been no research related to correlations between RIN3 methylation and early-onset cognitive impairment after TIA/MIS. Therefore, this study aimed to investigate this relationship in TIA/MIS patients. METHODS: This study include 28 control subjects and 84 patients with TIA/MIS who were evaluated within 7 days of TIA/MIS onset using four single-domain cognitive scales. In addition, DNA methylation of whole blood was tested. RIN3 methylation was compared between TIA/MIS and control groups and between TIA/MIS patients with early cognitive impairment and those without early cognitive impairment. Clinical variables and RIN3 methylation sites with statistical differences were then used to construct a predictive model. RESULTS: Hypomethylation of the RIN3 gene was observed in the whole blood of TIA/MIS patients relative to healthy controls. Furthermore, patients with early cognitive impairment after TIA/MIS had hypomethylation of RIN3 relative to those without early cognitive impairment. CONCLUSION: RIN3 methylation is strongly associated with TIA/MIS and TIA/MIS with early cognitive impairment. It is possible to influence the disease process by methylation via appropriate lifestyle and clinical interventions, and methylation of RIN3 gene sites may predict the occurrence of TIA/MIS with early cognitive impairment.

A Cross-Sectional Study on Mental Health Problems of Medical and Nonmedical Students in Shandong During the COVID-19 Epidemic Recovery Period.

Background: The coronavirus disease 2019 (COVID-19) pandemic has resulted in a plethora of psychological problems worldwide since its onset in December 2019. In the upheaval period, compared with medical college students, nonmedical students' psychological state deserves additional concern due to their lack of medical knowledge. Although the epidemic in China has been largely controlled for several months, the mental health problems resulting from the COVID-19 epidemic persist to this day. In this study, we assessed the mental health problems and associated risk factors experienced by nonmedical vs. medical college students in universities of Shandong Province during the COVID-19 epidemic recovery period. Methods: An online survey was conducted over the period from 17 to 19 December 2020. A total of 954 Chinese college students (486 nonmedical and 468 medical students) from three universities of Shandong Province participated in the survey. Mental health variables were assessed with use of Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), and Insomnia Severity Index (ISI). Results: Compared with medical students, nonmedical college students had higher prevalence rates of depression (53.9 vs. 46.4%; p = 0.020) and insomnia (28.0 vs. 22.4%, p = 0.049), as well as higher total scores on the PHQ-9 (p = 0.03) and ISI (p < 0.01). Among nonmedical college students, being female and native of non-Shandong were risk factors for anxiety and depression (p < 0.01), while only native of non-Shandong for insomnia (p < 0.01). Among medical students, age (p < 0.01) and living in rural areas (p = 0.04) were risk factors for depression, while only age (p < 0.05) was a risk factor for anxiety and insomnia. Conclusion: Nonmedical college students in the universities of Shandong Province had more mental health problems and more risk factors for developing them during the COVID-19 epidemic recovery period than medical students. These nonmedical students require additional attention and recovery programs to alleviate the increased incidence of psychological problems related to COVID-19.

IRE1α-XBP1 Affects the Mitochondrial Function of Aß25-35-Treated SH-SY5Y Cells by Regulating Mitochondria-Associated Endoplasmic Reticulum Membranes.

Background: Neurotoxicity induced by the amyloid beta (Aß) peptide is one of the most important pathological mechanisms of Alzheimer's disease (AD). Activation of the adaptive IRE1α-XBP1 pathway contributes to the pathogenesis of AD, making it a potential target for AD therapeutics. However, the mechanism of IRE1α-XBP1 pathway involvement in AD is unclear. We, therefore, investigated the effect of the IRE1α-XBP1 axis in an in vitro AD model and explored its potential mechanism. Methods: The human neuroblastoma cell line, SH-SY5Y, was used. Cells were treated with Aß25-35, with or without 4µ8c, an inhibitor of IRE1α. Cells were collected and analyzed by Western blotting, quantitative real-time PCR, electron microscopy, fluorescence microscopy, calcium imaging, and other biochemical assays. Results: Aß-exposed SH-SY5Y cells showed an increased expression of XBP1s and p-IRE1α. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and calcium imaging analysis showed that the IRE1α inhibitor, 4µ8c, reduced Aß-induced cytotoxicity. Increased levels of ATP, restoration of mitochondrial membrane potential, and decreased production of mitochondrial reactive oxygen species after Aß treatment in the presence of 4µ8c showed that inhibiting the IRE1α-XBP1 axis effectively mitigated Aß-induced mitochondrial dysfunction in SH-SY5Y cells. Furthermore, Aß treatment increased the expression and interaction of IP3R, Grp75, and vdac1 and led to an increased endoplasmic reticulum (ER)-mitochondria association, malfunction of mitochondria-associated ER-membranes (MAMs), and mitochondrial dysfunction. These deficits were rescued by inhibiting the IRE1α-XBP1 axis. Conclusion: These findings demonstrate that Aß peptide induces the activation of the IRE1α-XBP1 axis, which may aggravate cytotoxicity and mitochondrial impairment in SH-SY5Y cells by targeting MAMs. Inhibition of the IRE1α-XBP1 axis provides the protection against Aß-induced injury in SH-SY5Y cells and may, therefore, be a new treatment strategy.

Hypermethylation of Mitochondrial Cytochrome b and Cytochrome c Oxidase II Genes with Decreased Mitochondrial DNA Copy Numbers in the APP/PS1 Transgenic Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia. Increasing evidence shows that mitochondrial DNA (mtDNA) methylation plays an essential role in many diseases related to mitochondrial dysfunction. Since mitochondrial impairment is a key feature of AD, mtDNA methylation may also contribute to AD, but few studies have addressed this issue. Methylation changes of the mitochondrial cytochrome b (CYTB) and cytochrome c oxidase II (COX II) genes in AD have not been reported. We analyzed mtDNA methylation changes of the CYTB and COX II genes in an APP/PS1 transgenic mouse model of AD using pyrosequencing. We examined mtDNA copy numbers and the levels of expression by quantitative real-time PCR. Average methylation levels of different CpG sites were ≤ 4.0%. Methylated mtDNA accounted for only a small part of the total mtDNA. We also observed hypermethylation of mitochondrial CYTB and COX II genes with decreased mtDNA copy numbers and expression in the hippocampi of APP/PS1 transgenic mice. mtDNA methylation may play an important role in AD pathology, which may open a new window for AD therapy.

Vascular endothelial growth factor alleviates mitochondrial dysfunction and suppression of mitochondrial biogenesis in models of Alzheimer's disease.

PURPOSE: Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD). As vascular endothelial growth factor (VEGF) has been shown to be protective in AD, the aim of this study was to investigate the effects of VEGF on mitochondrial function in models of AD. MATERIALS AND METHODS: Adeno associated virus (AAV)-VEGF was injected into the hippocampus of APP/PS1 mice. Cognitive function was assessed in these mice with use of the Morris water maze (MWM) and ß-amyloid (Aß) levels in the hippocampus were also measured. Cell viability and reactive oxygen species (ROS) levels were determined in the SH-SY5Y cells treated with Aß25-35 which served as a cell model of AD. Transmission electron microscopy (TEM) was used to evaluate structural changes in mitochondria and mitochondrial DNA (mtDNA) copy number and mitochondrial membrane potential (MMP) were also recorded. Finally, we investigated the effects of VEGF upon mitochondrial biogenesis, autophagy and mitochondrial autophagy (mitophagy) as determined both in vivo and in vitro with western blots. RESULTS: VEGF treated mice showed improvements in spatial learning and memory along with reduced Aß levels. VEGF protected SH-SY5Y cells against Aß25-35 induced neurotoxicity as demonstrated by increased cell viability and decreased ROS production. Associated with these effects were improvements in mitochondrial structure and function, and increased numbers of mitochondria resulting from stimulation of mitochondrial biogenesis. CONCLUSIONS: VEGF alleviates Aß related patholoy in models of AD. In part, these beneficial effects of VEGF result from protection of mitochondria and stimulation of mitochondrial biogenesis.

Detection and significance of exosomal mRNA expression profiles in the cerebrospinal fluid of patients with meningeal carcinomatosis.

Exosomes are cell-derived membrane vesicles with cargo that can be transported into receiver cells to exert their biological roles. Exosomal RNA signature profiles and exosome-derived proteomics are often used to explore the molecular regulation of diseases, and can mirror the conditional state of their tissue of origin, thus serving as biomarkers. The onset of meningeal carcinomatosis (MC) is concealed, and early diagnosis is difficult. To enable early diagnosis of MC, it is essential to identify new biomarkers. Few studies have investigated the function of exosomes in MC. In this study, high-throughput sequencing was used to examine the mRNA profiles of exosomes in the cerebrospinal fluid (CSF) of patients with MC. We further analyzed the functions and signaling pathways associated with the differentially expressed genes in exosomes to reveal the putative mechanisms by which the exosomal mRNAs function in MC. In summary, this study identified biomarker candidates for MC, and provided new insights into the significant role of exosomal mRNA regulation in MC.

Stem Cell Therapy for Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease caused by eventually aggregated amyloid ß (Aß) plaques in degenerating neurons of the aging brain. These aggregated protein plaques mainly consist of Aß fibrils and neurofibrillary tangles (NFTs) of phosphorylated tau protein. Even though some cholinesterase inhibitors, NMDA receptor antagonist, and monoclonal antibodies were developed to inhibit neurodegeneration or activate neural regeneration or clear off the Aß deposits, none of the treatment is effective in improving the cognitive and memory dysfunctions of the AD patients. Thus, stem cell therapy represents a powerful tool for the treatment of AD. In addition to discussing the advents in molecular pathogenesis and animal models of this disease and the treatment approaches using small molecules and immunoglobulins against AD, we will focus on the stem cell sources for AD using neural stem cells (NSCs); embryonic stem cells (ESCs); and mesenchymal stem cells (MSCs) from bone marrow, umbilical cord, and umbilical cord blood. In particular, patient-specific-induced pluripotent stem cells (iPS cells) are proposed as a future prospective and the challenges for the treatment of AD.