Shandong Mental Health Center

The global population at risk from mosquito-borne diseases-including dengue, yellow fever, chikungunya and Zika-is expanding in concert with changes in the distribution of two key vectors: Aedes aegypti and Aedes albopictus. The distribution of these species is largely driven by both human movement and the presence of suitable climate. Using statistical mapping techniques, we show that human movement patterns explain the spread of both species in Europe and the United States following their introduction. We find that the spread of Ae. aegypti is characterized by long distance importations, while Ae. albopictus has expanded more along the fringes of its distribution. We describe these processes and predict the future distributions of both species in response to accelerating urbanization, connectivity and climate change. Global surveillance and control efforts that aim to mitigate the spread of chikungunya, dengue, yellow fever and Zika viruses must consider the so far unabated spread of these mosquitos. Our maps and predictions offer an opportunity to strategically target surveillance and control programmes and thereby augment efforts to reduce arbovirus burden in human populations globally.

Objectives. Sleep patterns and sleep problems in children are not only influenced by a large number of biological and psychologic factors but also by cultural and social factors. Little is known about similarities and differences in sleep patterns and sleep problems among children across countries. We attempted to compare sleep patterns and sleep problems among schoolchildren from 2 countries with distinctive cultural contexts: the United States and China. Methods. The data come from 2 cross-sectional surveys in 3 elementary schools of Jinan City, People's Republic of China, and 3 elementary schools from a suburban school district in southeastern New England, United States. The Chinese sample consisted of 517 elementary school children (grades 1 to 5), and the US sample consisted of 494 elementary school children (grades kindergarten through 4). We used the Children's Sleep Habits Questionnaire (CSHQ) to assess children's sleep patterns and sleep problems as reported by parents. Parents of the Chinese sample completed a Chinese version of the CSHQ. Results. For children in both the US and Chinese samples, reported bedtime was delayed and sleep duration decreased with increasing age. Compared with the US children (grades 1–4), Chinese children went to bed approximately half an hour later (9:02 vs 8:27 pm) and woke up half an hour earlier (6:28 vs 6:55 am), resulting in an average sleep duration that was 1 hour less (9.25 vs 10.15 hours). Chinese children were rated significantly higher than the US children on almost all CSHQ scales, indicating more sleep problems in Chinese children. Common sleep problems observed for all children were difficulty falling asleep, having a fear of sleeping in the dark, sleep talking, restless sleep, teeth grinding during sleep, and daytime sleepiness. Shorter daily sleep duration was associated with difficulty falling asleep, struggling at bedtime, and trouble sleeping away for the US children, and with going to bed at different times and having a fear of sleeping alone for Chinese children. Short sleep duration was a main predictor of daytime sleepiness for Chinese children, whereas restless sleep and snoring predicted daytime sleepiness for the US children. Conclusions. As reported by parents, children in China went to bed later and woke up earlier and their sleep duration was 1 hour shorter than the US children. Chinese children were reported to have more sleep problems than their US counterparts. Daytime sleepiness was determined by sleep duration only for those who slept insufficiently. Unique school schedules and sleep practices may contribute to the differences in the sleep patterns and sleep problems of children from the United States and China.

OBJECTIVE: To update the prevalence of eating disorders in the general population before 2021 and to analyze the distribution characteristics at different times and in different regions and sexes, as well as the diagnostic criteria. METHODS: Based on the method from a previous report by the authors, studies were identified from the following databases: PubMed/Medline, PsycINFO, ISI Web of Knowledge, Ovid and the 4 most important Chinese databases. Articles in English and Chinese before 2021 were retrieved. The data retrieved at this time were pooled with the data from a previous report for analyses. RESULTS: Thirty-three studies were identified, which included 18 studies supplemented in this retrieval. The pooled lifetime and 12-month prevalence of eating disorders were 0.91% (95% CI, 0.48-1.71) and 0.43% (95% CI, 0.18-0.78), respectively. The pooled lifetime and 12-month prevalence of the subgroup EDs (any), which covers all types of eating disorders, were 1.69% and 0.72%, respectively. The lifetime prevalence of AN, BN and BED was 0.16% (95% CI, 0.06-0.31), 0.63% (95% CI, 0.33-1.02) and 1.53% (95% CI, 1.00-2.17), respectively. The lifetime prevalence of EDs in Western countries was 1.89%, and was high at 2.58% in females. Prevalence studies using DSM-5 criteria were scarce. CONCLUSIONS: The prevalence of eating disorders might be underestimated thus far. Not all types of EDs were included in a majority of epidemiological surveys, and the prevalence rates of the new types of EDs were significantly higher. Eating disorders were especially common in Western countries and in females. New diagnostic criteria should be used to comprehensively assess all types of eating disorders. LEVEL OF EVIDENCE: 1, systematic review and meta-analysis.

Recurrent de novo (DN) and likely gene-disruptive (LGD) mutations contribute significantly to autism spectrum disorders (ASDs) but have been primarily investigated in European cohorts. Here, we sequence 189 risk genes in 1,543 Chinese ASD probands (1,045 from trios). We report an 11-fold increase in the odds of DN LGD mutations compared with expectation under an exome-wide neutral model of mutation. In aggregate, ∼4% of ASD patients carry a DN mutation in one of just 29 autism risk genes. The most prevalent gene for recurrent DN mutations is SCN2A (1.1% of patients) followed by CHD8, DSCAM, MECP2, POGZ, WDFY3 and ASH1L. We identify novel DN LGD recurrences (GIGYF2, MYT1L, CUL3, DOCK8 and ZNF292) and DN mutations in previous ASD candidates (ARHGAP32, NCOR1, PHIP, STXBP1, CDKL5 and SHANK1). Phenotypic follow-up confirms potential subtypes and highlights how large global cohorts might be leveraged to prove the pathogenic significance of individually rare mutations.

BACKGROUND: Hypoxia induces microglial activation which causes damage to the developing brain. Microglia derived inflammatory mediators may contribute to this process. Toll-like receptor 4 (TLR4) has been reported to induce microglial activation and cytokines production in brain injuries; however, its role in hypoxic injury remains uncertain. We investigate here TLR4 expression and its roles in neuroinflammation in neonatal rats following hypoxic injury. METHODS: One day old Wistar rats were subjected to hypoxia for 2 h. Primary cultured microglia and BV-2 cells were subjected to hypoxia for different durations. TLR4 expression in microglia was determined by RT-PCR, western blot and immunofluorescence staining. Small interfering RNA (siRNA) transfection and antibody neutralization were employed to downregulate TLR4 in BV-2 and primary culture. mRNA and protein expression of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and inducible nitric oxide synthase (iNOS) was assessed. Reactive oxygen species (ROS), nitric oxide (NO) and NF-κB levels were determined by flow cytometry, colorimetric and ELISA assays respectively. Hypoxia-inducible factor-1 alpha (HIF-1α) mRNA and protein expression was quantified and where necessary, the protein expression was depleted by antibody neutralization. In vivo inhibition of TLR4 with CLI-095 injection was carried out followed by investigation of inflammatory mediators expression via double immunofluorescence staining. RESULTS: TLR4 immunofluorescence and protein expression in the corpus callosum and cerebellum in neonatal microglia were markedly enhanced post-hypoxia. In vitro, TLR4 protein expression was significantly increased in both primary microglia and BV-2 cells post-hypoxia. TLR4 neutralization in primary cultured microglia attenuated the hypoxia-induced expression of TNF-α, IL-1β and iNOS. siRNA knockdown of TLR4 reduced hypoxia-induced upregulation of TNF-α, IL-1β, iNOS, ROS and NO in BV-2 cells. TLR4 downregulation-mediated inhibition of inflammatory cytokines in primary microglia and BV-2 cells was accompanied by the suppression of NF-κB activation. Furthermore, HIF-1α antibody neutralization attenuated the increase of TLR4 expression in hypoxic BV-2 cells. TLR4 inhibition in vivo attenuated the immunoexpression of TNF-α, IL-1β and iNOS on microglia post-hypoxia. CONCLUSION: Activated microglia TLR4 expression mediated neuroinflammation via a NF-κB signaling pathway in response to hypoxia. Hence, microglia TLR4 presents as a potential therapeutic target for neonatal hypoxia brain injuries.

Adversity, particularly in early life, can cause illness. Clues to the responsible mechanisms may lie with the discovery of molecular signatures of stress, some of which include alterations to an individual's somatic genome. Here, using genome sequences from 11,670 women, we observed a highly significant association between a stress-related disease, major depression, and the amount of mtDNA (p = 9.00 × 10(-42), odds ratio 1.33 [95% confidence interval [CI] = 1.29-1.37]) and telomere length (p = 2.84 × 10(-14), odds ratio 0.85 [95% CI = 0.81-0.89]). While both telomere length and mtDNA amount were associated with adverse life events, conditional regression analyses showed the molecular changes were contingent on the depressed state. We tested this hypothesis with experiments in mice, demonstrating that stress causes both molecular changes, which are partly reversible and can be elicited by the administration of corticosterone. Together, these results demonstrate that changes in the amount of mtDNA and telomere length are consequences of stress and entering a depressed state. These findings identify increased amounts of mtDNA as a molecular marker of MD and have important implications for understanding how stress causes the disease.

Diets rich in SFA have been implicated in Alzheimer's disease (AD). There is strong evidence to suggest that microglial activation augments the progression of AD. However, it remains uncertain whether SFA can initiate microglial activation and whether this response can cause neuronal death. Using the BV-2 microglial cell line and primary microglial culture, we showed that palmitic acid (PA) and stearic acid (SA) could activate microglia, as assessed by reactive morphological changes and significantly increased secretion of pro-inflammatory cytokines, NO and reactive oxygen species, which trigger primary neuronal death. In addition, the mRNA level of these pro-inflammatory mediators determined by RT-PCR was also increased by PA and SA. We further investigated the intracellular signalling mechanism underlying the release of pro-inflammatory mediators from PA-activated microglial cells. The present results showed that PA activated the phosphorylation and nuclear translocation of the p65 subunit of NF-κB. Furthermore, pyrrolidine dithiocarbamate, a NF-κB inhibitor, attenuated the production of pro-inflammatory mediators except for IL-6 in PA-stimulated microglia. Administration of anti-Toll-like receptor (TLR)4-neutralising antibody repressed PA-induced NF-κB activation and pro-inflammatory mediator production. In conclusion, the present in vitro study demonstrates that SFA could activate microglia and stimulate the TLR4/NF-κB pathway to trigger the production of pro-inflammatory mediators, which may contribute to neuronal death.

Oxidative stress plays an important role in the development of aging-related diseases by accelerating the lipid peroxidation of polyunsaturated fatty acids in the cell membrane, resulting in the production of aldehydes, such as malondialdehyde and 4-hydroxy-2-nonenal (4-HNE) and other toxic substances. The compound 4-HNE forms adducts with DNA or proteins, disrupting many cell signaling pathways including the regulation of apoptosis signal transduction pathways. The binding of proteins to 4-HNE (4-HNE-protein) acts as an important marker of lipid peroxidation, and its increasing concentration in brain tissues and fluids because of aging, ultimately gives rise to some hallmark disorders, such as neurodegenerative diseases (Alzheimer's and Parkinson's diseases), ophthalmic diseases (dry eye, macular degeneration), hearing loss, and cancer. This review aims to describe the physiological origin of 4-HNE, elucidate its toxicity in aging-related diseases, and discuss the detoxifying effect of aldehyde dehydrogenase and glutathione in 4-HNE-driven aging-related diseases.

Japanese encephalitis (JE), caused by Japanese encephalitis virus (JEV) infection, is the most important viral encephalitis in the world. Approximately 35,000-50,000 people suffer from JE every year, with a mortality rate of 10,000-15,000 people per year. Although the safety and efficacy of JE vaccines (inactivated and attenuated) have been demonstrated, China still accounts for 50% of the reported JE cases worldwide. In this review, we provide information about the burden of JE in mainland China and the corresponding epidemiology from 1949 to 2010, including the morbidity and mortality of JE; the age, gender, and vocational distribution of JE cases; its regional and seasonal distribution; and JE immunization. In addition, we discuss the relationships among vectors, hosts, and JEV isolates from mainland China; the dominant vector species for JEV transmission; the variety of JEV genotypes and the different biological characteristics of the different JEV genotypes; and the molecular evolution of JEV.

Background: We previously performed targeted sequencing of autism risk genes in probands from the Autism Clinical and Genetic Resources in China (ACGC) (phase I). Here, we expand this analysis to a larger cohort of patients (ACGC phase II) to better understand the prevalence, inheritance, and genotype-phenotype correlations of likely gene-disrupting (LGD) mutations for autism candidate genes originally identified in cohorts of European descent. Methods: We sequenced 187 autism candidate genes in an additional 784 probands and 85 genes in 599 probands using single-molecule molecular inversion probes. We tested the inheritance of potentially pathogenic mutations, performed a meta-analysis of phase I and phase II data and combined our results with existing exome sequence data to investigate the phenotypes of carrier parents and patients with multiple hits in different autism risk genes. Results: ). We identified the transmission of private LGD mutations in genes predominantly associated with DNMs and showed that parental carriers tended to share milder autism-related phenotypes. Patients that carried DNMs in two or more candidate genes show more severe phenotypes. Conclusions: We identify new risk genes and transmission of deleterious mutations in genes primarily associated with DNMs. The fact that parental carriers show milder phenotypes and patients with multiple hits are more severe supports a multifactorial model of risk.

This study examined associations of life events and locus of control with behavioral problems among 1,365 Chinese adolescents by using the Youth Self-Report (YSR), Adolescent Self-Rating Life Events Checklist (ASLEC), and the Nowicki-Strickland Locus of Control Scale for Children. Results indicated that the overall prevalence of behavioral and emotional problems was 10.7% (95% CI = 9.9-11.5%). Logistic-regression analyses showed that a total of 13 negative life events mainly coming from academic domain and interpersonal relationships, high life-stress score, and high external locus score significantly increased the risk for behavioral problems. Life stress and locus of control significantly interacted with behavioral problems. These findings support the linkage between stressful life events and psychopathology in a general population of adolescents from mainland China, and demonstrate the stress-moderating effects of locus of control on psychopathology as well.

China has experienced noticeable changes in climate over the past 100 years and the potential impact climate change has on transmission of mosquito-borne infectious diseases poses a risk to Chinese populations. The aims of this paper are to summarize what is known about the impact of climate change on the incidence and prevalence of malaria, dengue fever and Japanese encephalitis in China and to provide important information and direction for adaptation policy making. Fifty-five papers met the inclusion criteria for this study. Examination of these studies indicates that variability in temperature, precipitation, wind, and extreme weather events is linked to transmission of mosquito-borne diseases in some regions of China. However, study findings are inconsistent across geographical locations and this requires strengthening current evidence for timely development of adaptive options. After synthesis of available information we make several key adaptation recommendations including: improving current surveillance and monitoring systems; concentrating adaptation strategies and policies on vulnerable communities; strengthening adaptive capacity of public health systems; developing multidisciplinary approaches sustained by an new mechanism of inter-sectional coordination; and increasing awareness and mobilization of the general public.

STUDY OBJECTIVES: To examine sleep habits, insomnia, and hypnotic use in the elderly in China. DESIGN AND SETTING: A cross-sectional survey in 5 cities of Shandong, mainland China in 1997. PARTICIPANTS: Among 1,820 individuals aged 65 and older who were sampled, 1,679 (92.2%) were interviewed at home, including 770 men and 909 women. MEASUREMENTS: Asleep and demographic questionnaire that included the Pittsburgh Sleep Quality Index was used for interviews. RESULTS: Average bedtime of participants was 9:18 PM (SD = 2.2 hours), and morning rise time was 5:42 AM (SD = 1.0 hour). Reported night sleep duration was 7.1 hours (SD = 1.6) without age and sex differences. Regular napping was more common in men than in women (44.2% vs 28.0%). Of the sample, 32.9% reported frequent insomnia symptoms, and 8.9% had insomnia symptoms with daytime consequences. Multivariate analysis indicated that age 75 years and older (odds ratio = 2.0), female sex (odds ratio = 1.4), unmarried status (odds ratio = 1.7), frequent napping (odds ratio = 1.5), and poor perceived health (odds ratio, = 2.1) were associated with elevated risks for insomnia. Hypnotic use during the past month was reported by 6.5% of the sample; women were 2 times as likely as men to use hypnotics. CONCLUSION: Sleep patterns in Chinese elderly may be characterized by going to bed early and waking up early. Insomnia symptoms are as common among Chinese as among Western elderly. Further study is warranted to examine the association between insomnia and aging per se in Chinese elderly.

STUDY OBJECTIVES: This study examined the association between bed sharing, sleep habits, and sleep problems among Chinese school-aged children. DESIGN AND SETTING: A questionnaire survey of school-aged children was undertaken in Jinan city, People's Republic of China, in 2001. PARTICIPANTS: A total of 517 elementary-school children (mean age, 10.5 years; 47.4% boys) participated in the survey. MEASUREMENTS: The parents completed the Chinese version of the Children's Sleep Habits Questionnaire and a number of questions that asked about bed sharing and characteristics of the family and child. RESULTS: The prevalence of regular bed sharing in Chinese school-aged children was as high as 18.2%. The rate of bed sharing did not differ between boys and girls but significantly decreased with age from 55.8% in 7-year-olds to 7.2% in 11- to 13-year-olds. Multivariate logistic regression analysis showed that younger age, poor physical health of the child, and crowded housing were associated with an increased likelihood for the child's bed sharing with parents. Bedtime and total sleep duration did not significantly differ between children who shared beds and those who slept alone. Children who shared beds with their parents were reported to have more sleep anxiety and daytime sleepiness than children who slept alone. Bed sharing was not associated with parasomnias and breathing problems during sleep. CONCLUSIONS: Regular bed sharing in Chinese school-aged children was very common and significantly decreased with age. Crowded housing and poor physical health of the child increased the likelihood for children and parents to share beds. Bed sharing may exert influences on sleep quality rather than sleep quantity.

microRNAs (miRNAs) are a novel class of small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. miRNAs can modulate gene expression and thus play important roles in diverse neurobiological processes, such as cell differentiation, growth, proliferation and neural activity, as well as the pathogenic processes of spinal cord injury (SCI) like inflammation, oxidation, demyelination and apoptosis. Results from animal studies have revealed the temporal alterations in the expression of a large set of miRNAs following SCI in adult rats, and the expressional changes in miRNAs following SCI is bidirectional (increase or decrease). In addition, several miRNAs have distinct roles in prognosis of SCI (protective, detrimental and varied). Taken together, the existing evidence suggests that abnormal miRNA expression following SCI contributes to the pathogenesis of SCI, and miRNAs may become potential targets for the therapy of SCI.

Depression is considered a neuropsychiatric disease associated with various neuronal changes within specific brain regions. We previously reported that ginsenoside-Rg1, a potential neuroprotective agent extracted from ginseng, significantly alleviated depressive-like disorders induced by chronic stress in rats. However, the mechanisms by which ginsenoside-Rg1 exerts its neuroprotective effects in depression remain largely uncharacterized. In the present study we confirm that ginsenoside-Rg1 significantly prevented the antidepressant-like effects in a rat model of chronic unpredictable mild stress (CUMS) and report on some of the underlying mechanisms associated with this effect. Specifically, we found that chronic pretreatment with ginsenoside-Rg1 prior to stress exposure significantly suppressed inflammatory pathway activity via alleviating the overexpression of proinflammatory cytokines and the activation of microglia and astrocytes. These effects were accompanied with an attenuation of dendritic spine and synaptic deficits as associated with an upregulation of synaptic-related proteins in the ventral medial prefrontal cortex (vmPFC). In addition, ginsenoside-Rg1 inhibited neuronal apoptosis induced by CUMS exposure, increased Bcl-2 expression and decreased cleaved Caspase-3 and Caspase-9 expression within the vmPFC region. Furthermore, ginsenoside-Rg1 could increase the nuclear factor erythroid 2-related factor (Nrf2) expression and inhibit p38 mitogen-activated protein kinase (p-p38 MAPK) and nuclear factor κB (NF-κB) p65 subunit activation within the vmPFC. Taken together, these results suggest that the neuroprotective effects of ginsenoside-Rg1, which may assume the antidepressant-like effect in this animal model of depression, appears to result from amelioration of a CUMS-dependent neuronal deterioration within the vmPFC. Moreover, they also provide support for the therapeutic potential of ginsenoside-Rg1 in the treatment of stress-related mental disorders.

BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and Aβ-induced neuronal damage is the major pathology of AD. There is increasing evidence that neuroinflammation induced by Aβ is also involved in the pathogenesis of AD. Fasudil is a Rho kinase inhibitor and has been reported to have neuroprotective effects. In this study, the main purpose is to investigate whether fasudil has beneficial effects on cognitive impairment and neuronal toxicity induced by Aβ. METHODS AND RESULTS: In the present study, intracerebroventricular injection of Aβ1-42 to rats resulted in marked cognitive impairment, severe neuronal damage, as well as increased IL-1β, tumor necrosis factor alpha (TNF-α) production, and NF-κB activation. Administration of fasudil significantly ameliorated the spatial learning and memory impairment, attenuated neuronal loss, and neuronal injury induced by Aβ1-42 . In addition, fasudil inhibited IL-1β and TNF-α production and NF-κB activation in the rat brain. CONCLUSIONS: Fasudil can protect against Aβ-induced hippocampal neurodegeneration by suppressing inflammatory response, suggesting that fasudil might be a promising agent for the prevention and treatment of inflammation-related diseases, such as AD.

BACKGROUND: Autism spectrum disorder (ASD) affects many aspects of family life, such as social and economic burden. Little investigation of this phenomenon has been carried out in China. We designed this study to evaluate the employment and financial burdens of families with ASD-diagnosed preschoolers. METHODS: Four hundred and fifty-nine nuclear families of children with ASD, 418 with some other disability (OD) and 424 with typically developing (TD) children were recruited for this study. Employment and financial burdens of families were evaluated using a structured questionnaire; logistic regression was used to examine differences in job change measures by group, and ordinal logistic regression was used to investigate the association between household income and group. RESULTS: Fifty-eight percent of families with ASD children and 19% of families with OD children reported that childcare problems had greatly affected their employment decisions, compared with 9% of families with TD children (p < 0.001). Age of child, parental education and parental age notwithstanding, having a child with ASD and having a child with OD were both associated with increased odds of reporting that childcare greatly interfered with employment (ASD, OR: 15.936; OD, OR: 2.502; all p < 0.001) and decreased the odds of living in a higher-income household (ASD, estimate = -1.271; OD, estimate = -0.569; all p < 0.001). The average loss of annual income associated with having a child with ASD was Chinese RenMinBi (RMB) 44,077 ($7,226), compared with RMB 20,788 ($3,408) for families of OD children. CONCLUSIONS: ASD is associated with severe employment and financial burdens, much more than for OD, in families with preschool children.

Appropriate mitochondrial transport and distribution are essential for neurons because of the high energy and Ca2+ buffering requirements at synapses. Brain-derived neurotrophic factor (BDNF) plays an essential role in regulating synaptic transmission and plasticity. However, whether and how BDNF can regulate mitochondrial transport and distribution are still unclear. Here, we find that in cultured hippocampal neurons, application of BDNF for 15 min decreased the percentage of moving mitochondria in axons, a process dependent on the activation of the TrkB receptor and its downstream PI3K and phospholipase-Cγ signaling pathways. Moreover, the BDNF-induced mitochondrial stopping requires the activation of transient receptor potential canonical 3 and 6 (TRPC3 and TRPC6) channels and elevated intracellular Ca2+ levels. The Ca2+ sensor Miro1 plays an important role in this process. Finally, the BDNF-induced mitochondrial stopping leads to the accumulation of more mitochondria at presynaptic sites. Mutant Miro1 lacking the ability to bind Ca2+ prevents BDNF-induced mitochondrial presynaptic accumulation and synaptic transmission, suggesting that Miro1-mediated mitochondrial motility is involved in BDNF-induced mitochondrial presynaptic docking and neurotransmission. Together, these data suggest that mitochondrial transport and distribution play essential roles in BDNF-mediated synaptic transmission. Appropriate mitochondrial transport and distribution are essential for neurons because of the high energy and Ca2+ buffering requirements at synapses. Brain-derived neurotrophic factor (BDNF) plays an essential role in regulating synaptic transmission and plasticity. However, whether and how BDNF can regulate mitochondrial transport and distribution are still unclear. Here, we find that in cultured hippocampal neurons, application of BDNF for 15 min decreased the percentage of moving mitochondria in axons, a process dependent on the activation of the TrkB receptor and its downstream PI3K and phospholipase-Cγ signaling pathways. Moreover, the BDNF-induced mitochondrial stopping requires the activation of transient receptor potential canonical 3 and 6 (TRPC3 and TRPC6) channels and elevated intracellular Ca2+ levels. The Ca2+ sensor Miro1 plays an important role in this process. Finally, the BDNF-induced mitochondrial stopping leads to the accumulation of more mitochondria at presynaptic sites. Mutant Miro1 lacking the ability to bind Ca2+ prevents BDNF-induced mitochondrial presynaptic accumulation and synaptic transmission, suggesting that Miro1-mediated mitochondrial motility is involved in BDNF-induced mitochondrial presynaptic docking and neurotransmission. Together, these data suggest that mitochondrial transport and distribution play essential roles in BDNF-mediated synaptic transmission.

BACKGROUND: Expression of E2F transcription factor 2 (E2F2), a transcription factor related to the cell cycle, is abnormally high in rheumatoid arthritis synovial fibroblasts (RASFs). Deregulated expression of E2F2 leads to abnormal production of proinflammatory cytokines, such as interleukin (IL)-1α, IL-1β, and tumor necrosis factor (TNF)-α in RASFs. However, the underlying mechanism by which E2F2 regulates expression of IL-1α, IL-1β, and TNF-α has not been fully elucidated. This study aimed to elucidate this mechanism and confirm the pathological roles of E2F2 in rheumatoid arthritis (RA). METHODS: E2f2 knockout (KO) and wild-type (WT) mice were injected with collagen to induce RA. Cytokine production was assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). Western blot and qRT-PCR were performed to evaluate the effect of E2F2 on signaling pathway activity. Chromatin immunoprecipitation (ChIP)-PCR and luciferase assays were used to detect the transcriptional activity of target genes of E2F2. Nuclear translocation of STAT1 and p65 were assayed by Western blot, co-immunoprecipitation (co-IP), and immunofluorescence experiments. RESULTS: The occurrence and severity of collagen-induced arthritis were decreased in E2f2-KO mice compared with WT mice. The expression of IL-1α, IL-1β, and TNF-α was also suppressed in mouse embryonic fibroblasts (MEFs) from E2f2-KO mice and RASFs with E2F2 knocked down. Mechanistically, we found that E2F2 can upregulate the expression of STAT1 and MyD88 through direct binding to their promoters, facilitate the formation of STAT1/MyD88 complexes, and consequently activate AKT. However, silencing STAT1/MyD88 or inactivating AKT significantly attenuated the induction of IL-1α, IL-1β, and TNF-α caused by the introduction of E2F2. CONCLUSIONS: This study confirms the pathological role of E2F2 in RA and found that the E2F2-STAT1/MyD88-Akt axis is closely related with the inflammatory phenotype in RASFs.