Nanjing Brain Hospital

Background To date, no national‐scale psychiatric epidemiological survey for children and adolescents has been conducted in China. In order to inform government officials and policymakers and to develop a comprehensive plan for service providers, there was a clear need to conduct an up‐to‐date systematic nationwide psychiatric epidemiological survey. Methods We conducted a two‐stage large‐scale psychiatric point prevalence survey. Multistage cluster stratified random sampling was used as the sampling strategy. Five provinces were selected by comprehensively considering geographical partition, economic development, and rural/urban factors. In Stage 1, the Child Behavior Checklist was used as the screening tool. In Stage 2, Mini‐International Neuropsychiatric Interview for Children and Adolescents and a diagnostic process based on the Diagnostic and Statistical Manual were used to make the diagnoses. Sampling weights and poststratification weights were employed to match the population distributions. Exploratory analyses were also performed using socio‐demographic factors. Prevalence in socio‐demographic factor subgroups and overall were estimated. Rao‐Scott adjusted chi‐square tests were utilized to determine if between‐group differences were present. Factor interactions were checked by logistic regression analyses. Results A total of 73,992 participants aged 6–16 years of age were selected in Stage 1. In Stage 2, 17,524 individuals were screened and diagnosed. The weighted prevalence of any disorder was 17.5% (95% CI: 17.2–18.0). Statistically significant differences in prevalence of any psychiatric disorder were observed between sexes [χ 2 (1, N = 71,929) = 223.0, p < .001], age groups [χ 2 (1, N = 71,929) = 18.6, p < .001] and developed vs. developing areas [χ 2 (1, N = 71,929) = 2,129.6, p < .001], while no difference was found between rural and urban areas [χ 2 (1, N = 71,929) = 1.4, p = .239]. Male, younger individuals, children, and adolescents from developed areas had higher prevalence of any psychiatric disorder. The prevalence of any psychiatric disorder was found to decrease with the age in the male group, while the female group increased with the age. Individuals diagnosed with attention‐deficit hyperactivity disorder, oppositional defiant disorder, a tic disorder, conduct disorder, and major depression disorder had the highest rates of comorbidity. Conclusions The prevalence of any psychiatric disorder we found is the highest ever reported in China. These results urgently need to be addressed by public mental health service providers and policymakers in order to provide access to the necessary treatments and to reduce the long‐term negative impact of these conditions on families and the society as a whole.

This study explored students' perceptions of 3 dimensions of school climate (teacher support, student-student support, and opportunities for autonomy in the classroom) and the associations between these dimensions and adolescent psychological and academic adjustment in China and the United States. Data were drawn from 2 studies involving 706 middle school students (M = 12.26) from Nanjing, China, and 709 middle school students (M = 12.36) from New York City. Findings revealed that students in China perceived higher levels of teacher support, student-student support, and opportunities for autonomy in the classroom than students in the United States. Furthermore, students' perceptions of teacher support and student-student support were positively associated with adolescents' self-esteem and grade point average but negatively associated with depressive symptoms for both Chinese and American adolescents.

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.

Abstract Electrochemical reduction of CO 2 (CO 2 R) to formic acid upgrades waste CO 2 ; however, up to now, chemical and structural changes to the electrocatalyst have often led to the deterioration of performance over time. Here, we find that alloying p-block elements with differing electronegativities modulates the redox potential of active sites and stabilizes them throughout extended CO 2 R operation. Active Sn-Bi/SnO 2 surfaces formed in situ on homogeneously alloyed Bi 0.1 Sn crystals stabilize the CO 2 R-to-formate pathway over 2400 h (100 days) of continuous operation at a current density of 100 mA cm −2 . This performance is accompanied by a Faradaic efficiency of 95% and an overpotential of ~ −0.65 V. Operating experimental studies as well as computational investigations show that the stabilized active sites offer near-optimal binding energy to the key formate intermediate *OCHO. Using a cation-exchange membrane electrode assembly device, we demonstrate the stable production of concentrated HCOO – solution (3.4 molar, 15 wt%) over 100 h.

Fast and strong bio-adhesives are in high demand for many biomedical applications, including closing wounds in surgeries, fixing implantable devices, and haemostasis. However, most strong bio-adhesives rely on the instant formation of irreversible covalent crosslinks to provide strong surface binding. Repositioning misplaced adhesives during surgical operations may cause severe secondary damage to tissues. Here, we report hydrogel tapes that can form strong physical interactions with tissues in seconds and gradually form covalent bonds in hours. This timescale-dependent adhesion mechanism allows instant and robust wet adhesion to be combined with fault-tolerant convenient surgical operations. Specifically, inspired by the catechol chemistry discovered in mussel foot proteins, we develop an electrical oxidation approach to controllably oxidize catechol to catecholquinone, which reacts slowly with amino groups on the tissue surface. We demonstrate that the tapes show fast and reversible adhesion at the initial stage and ultrastrong adhesion after the formation of covalent linkages over hours for various tissues and electronic devices. Given that the hydrogel tapes are biocompatible, easy to use, and robust for bio-adhesion, we anticipate that they may find broad biomedical and clinical applications.

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.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous family of myeloid cells that suppress T cell immunity in tumor-bearing hosts. In patients with colon cancer, MDSCs have recently been described as Lin(-/low)HLA-DR(-)CD11b(+)CD33(+) cells correlating with cancer stage, metastasis and chemotherapy response. To learn in more detail the dynamic change and clinical relevance of circulating and tumor-infiltrating Lin(-/low)HLA-DR(-)CD11b(+)CD33(+) MDSC in colorectal cancer, we harvested the blood from 64 patients with varying stage of colorectal cancer and tumor and matched paraneoplastic tissues from 5 patients with advanced colorectal cancer, subjected them to multicolor flow cytometric analysis of percentage, absolute number and phenotype of MDSC and finally characterized their immunosuppressive functions. Our results demonstrate that peripheral blood from colorectal cancer patients contains markedly increased percentage and absolute number of Lin(-/low)HLA-DR(-)CD11b(+)CD33(+) MDSCs compared with healthy individuals, and this increase is closely correlated with clinical cancer stage and tumor metastasis but not primary tumor size and serum concentrations of cancer biomarker. A similar increase of MDSCs was also observed in the tumor tissues. Phenotyping MDSCs shows that they express high CD13 and CD39, low CD115, CD117, CD124 and PD-L1, and devoid of CD14, CD15 and CD66b, reminiscent of precursor myeloid cells. MDSCs from cancer patients but not healthy donors have the immunosuppressive activity and were able to inhibit in vitro autologous T-cell proliferation. Collectively, this study substantiates the presence of increased immunosuppressive circulating and tumor-resident Lin(-/low)HLA-DR(-)CD11b(+)CD33(+) MDSCs in patients with colorectal cancers correlating with cancer stage and metastasis, and suggests that pharmacologic blockade of MDSCs should be considered in future clinical trials.

OBJECTIVE: Uncertainty exists over the size of potential beneficial effects of medical treatments targeting hematoma growth in intracerebral hemorrhage (ICH). We report associations of hematoma growth parameters on clinical outcomes in the pilot phase, Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT1) (ClinicalTrials.gov NCT00226096). METHODS: In randomized patients with both baseline and 24-hour brain CT (n = 335), associations between measures of absolute and relative hematoma growth and 90-day poor outcomes of death and dependency (modified Rankin Scale score 3-5) were assessed in logistic regression models, with data reported as odds ratios (OR) and 95% confidence intervals (CI). RESULTS: A total of 10.7 mL (1 SD) increase in hematoma volume over 24 hours was strongly associated with poor outcome (adjusted OR 1.72, 95% CI 1.19-2.49; p = 0.004). An association was also evident for relative growth (adjusted OR 1.67, 95% 1.22-2.27; p = 0.001 for 1 SD increase). The analyses were adjusted for age, sex, achieved systolic blood pressure, elevated NIH Stroke Scale score (≥ 14), hematoma location, baseline hematoma volume, intraventricular extension, antithrombotic therapy, baseline glucose, time from ICH to baseline CT scan, and time from baseline to repeat CT scan. A 1 mL increase in hematoma growth was associated with a 5% (95% CI 2%-9%) higher risk of death or dependency. CONCLUSION: Medical treatments, such as rapid intensive blood pressure lowering, could achieve ∼2-4 mL absolute attenuation of hematoma growth. There is hope that this could translate into modest but still clinically worthwhile (∼10%-20% better chance) outcome from ICH.

BACKGROUND AND PURPOSE: Recent clinical trials report that metformin, an activator of AMP-activated protein kinase (AMPK) used to treat type 2 diabetes, significantly reduces the risk of stroke by actions that are independent of its glucose-lowering effects. However, the underlying molecular mechanisms are not known. Here, we tested the possibility that acute metformin preconditioning confers neuroprotection by pre-activation of AMPK-dependent autophagy in a rat model of permanent middle cerebral artery occlusion (pMCAO). EXPERIMENTAL APPROACH: Male Sprague-Dawley rats were pretreated with either vehicle, an AMPK inhibitor, Compound C, or an autophagy inhibitor, 3-methyladenine, and were injected with a single dose of metformin (10 mg kg(-1), i.p.). Then, AMPK activity and autophagy biomarkers in the brain were assessed. At 24 h after metformin treatment, rats were subjected to pMCAO; infarct volume, neurological deficits and cell apoptosis were evaluated 24 and 96 h later. KEY RESULTS: A single dose of metformin significantly activated AMPK and induced autophagy in the brain. The enhanced autophagic activity was inhibited by Compound C pretreatment. Furthermore, acute metformin preconditioning significantly reduced infarct volume, neurological deficits and cell apoptosis during a subsequent focal cerebral ischaemia. The neuroprotection mediated by metformin preconditioning was fully abolished by Compound C and partially inhibited by 3-methyladenine. CONCLUSIONS AND IMPLICATIONS: These results provide the first evidence that acute metformin preconditioning induces autophagy by activation of brain AMPK, which confers neuroprotection against subsequent cerebral ischaemia. This suggests that metformin, a well-known hypoglycaemic drug, may have a practical clinical use for stroke prevention.

We conducted a cross-trait meta-analysis of genome-wide association study on schizophrenia (SCZ) (n = 65,967), bipolar disorder (BD) (n = 41,653), autism spectrum disorder (ASD) (n = 46,350), attention deficit hyperactivity disorder (ADHD) (n = 55,374), and depression (DEP) (n = 688,809). After the meta-analysis, the number of genomic loci increased from 14 to 19 in ADHD, from 3 to 10 in ASD, from 45 to 57 in DEP, from 8 to 54 in BD, and from 64 to 87 in SCZ. We observed significant enrichment of overlapping genes among different disorders and identified a panel of cross-disorder genes. A total of seven genes were found being commonly associated with four out of five psychiatric conditions, namely GABBR1, GLT8D1, HIST1H1B, HIST1H2BN, HIST1H4L, KCNB1, and DCC. The SORCS3 gene was highlighted due to the fact that it was involved in all the five conditions of study. Analysis of correlations unveiled the existence of two clusters of related psychiatric conditions, SCZ and BD that were separate from the other three traits, and formed another group. Our results may provide a new insight for genetic basis of the five psychiatric disorders.

Autism spectrum disorder (ASD) is a prevalent and complex neurodevelopmental disorder which has strong genetic basis. Despite the rapidly rising incidence of autism, little is known about its aetiology, risk factors, and disease progression. There are currently neither validated biomarkers for diagnostic screening nor specific medication for autism. Over the last two decades, there have been remarkable advances in genetics, with hundreds of genes identified and validated as being associated with a high risk for autism. The convergence of neuroscience methods is becoming more widely recognized for its significance in elucidating the pathological mechanisms of autism. Efforts have been devoted to exploring the behavioural functions, key pathological mechanisms and potential treatments of autism. Here, as we highlight in this review, emerging evidence shows that signal transduction molecular events are involved in pathological processes such as transcription, translation, synaptic transmission, epigenetics and immunoinflammatory responses. This involvement has important implications for the discovery of precise molecular targets for autism. Moreover, we review recent insights into the mechanisms and clinical implications of signal transduction in autism from molecular, cellular, neural circuit, and neurobehavioural aspects. Finally, the challenges and future perspectives are discussed with regard to novel strategies predicated on the biological features of autism.

The circadian rhythm is crucial for physiological and behavioral functions. Chronotype, which represents individual preferences for activity and performance, is associated with human health issues, particularly psychiatric disorders. This narrative review, which focuses on the relationship between chronotype and mental disorders, provides an insight into the potential mechanism. Recent evidence indicates that (1) the evening chronotype is a risk factor for depressive disorders and substance use disorders, whereas the morning chronotype is a protective factor. (2) Evening chronotype individuals with bipolar disorder tend to have more severe symptoms and comorbidities. (3) The evening chronotype is only related to anxiety symptoms. (4) The relationship between chronotype and schizophrenia remains unclear, despite increasing evidence on their link. (5) The evening chronotype is significantly associated with eating disorders, with the majority of studies have focused on binge eating disorders. Furthermore, the underlying mechanisms or influence factors are described in detail, including clock genes, brain characteristics, neuroendocrinology, the light/dark cycle, social factors, psychological factors, and sleep disorders. These findings provide the latest evidence on chronotypes and psychiatric disorders and serve as a valuable reference for researchers.

BACKGROUND: Weight gain is a common consequence of antipsychotic drug treatment and can lead to further morbidity. AIMS: To assess the effects of antipsychotic drug therapy on abdominal fat deposition, on insulin and leptin secretion, and on circulating glucose and lipids. METHOD: Abdominal body fat was determined by magnetic resonance imaging in a group of previously untreated patients with schizophrenia, before and after 10 weeks' antipsychotic drug treatment. Body mass and blood concentrations of glucose, insulin, leptin and lipids were also measured. RESULTS: Significant increases in both subcutaneous and intra-abdominal fat were identified after antipsychotic drug treatment. A three-fold increase in leptin secretion as well as significant increases in levels of circulating lipids and non-fasting glucose were also identified. CONCLUSIONS: Patients first receiving antipsychotic drugs experience substantial deposition of both subcutaneous and intra-abdominal fat, reflecting a loss of the normal inhibitory control of leptin on body mass. Along with fat deposition, the increase in levels of fasting lipids and in non-fasting glucose may provide early signs of drug-induced progression towards the metabolic syndrome.

Methylating drugs such as temozolomide (TMZ) are widely used in the treatment of brain tumors including malignant glioblastoma. The mechanism of TMZ-induced glioblastoma cell death and apoptosis, however, is not fully understood. Here, we tested the potential involvement of AMP-activated protein kinase (AMPK) in this process. We found that methylating agents TMZ and N-methyl-N′-nitro-N-nitrosoguanidine induce AMPK activation in primary cultured human glioblastoma and glioblastoma cell lines. TMZ-induced O6-methylguanine production is involved in AMPK activation. O6-benzylguanine, an O6-methylguanine-DNA methyltransferase inhibitor, enhances TMZ-induced O6-methylguanine production, leading to enhanced reactive oxygen species production, which serves as an upstream signal for AMPK activation. Activation of AMPK is involved in TMZ-induced glioblastoma cell death and apoptosis. AMPK inhibitor (Compound C) or AMPKα siRNA knockdown inhibits TMZ-induced glioblastoma cell death and apoptosis, whereas AMPK activator 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside enhances it. In further studies, we found that activation of AMPK is involved in TMZ-induced p53 activation and subsequent p21, Noxa, and Bax up-regulation. Activation of AMPK by TMZ also inhibits mTOR complex 1 (mTORC1) signaling and promotes anti-apoptosis protein Bcl-2 down-regulation, which together mediate TMZ-induced pro-cell apoptosis effects. Our study suggests that activation of AMPK by TMZ contributes to glioblastoma cell apoptosis, probably by promoting p53 activation and inhibiting mTORC1 signaling. Methylating drugs such as temozolomide (TMZ) are widely used in the treatment of brain tumors including malignant glioblastoma. The mechanism of TMZ-induced glioblastoma cell death and apoptosis, however, is not fully understood. Here, we tested the potential involvement of AMP-activated protein kinase (AMPK) in this process. We found that methylating agents TMZ and N-methyl-N′-nitro-N-nitrosoguanidine induce AMPK activation in primary cultured human glioblastoma and glioblastoma cell lines. TMZ-induced O6-methylguanine production is involved in AMPK activation. O6-benzylguanine, an O6-methylguanine-DNA methyltransferase inhibitor, enhances TMZ-induced O6-methylguanine production, leading to enhanced reactive oxygen species production, which serves as an upstream signal for AMPK activation. Activation of AMPK is involved in TMZ-induced glioblastoma cell death and apoptosis. AMPK inhibitor (Compound C) or AMPKα siRNA knockdown inhibits TMZ-induced glioblastoma cell death and apoptosis, whereas AMPK activator 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside enhances it. In further studies, we found that activation of AMPK is involved in TMZ-induced p53 activation and subsequent p21, Noxa, and Bax up-regulation. Activation of AMPK by TMZ also inhibits mTOR complex 1 (mTORC1) signaling and promotes anti-apoptosis protein Bcl-2 down-regulation, which together mediate TMZ-induced pro-cell apoptosis effects. Our study suggests that activation of AMPK by TMZ contributes to glioblastoma cell apoptosis, probably by promoting p53 activation and inhibiting mTORC1 signaling.

Alzheimer's disease (AD) is the most common type of dementia, and promptly diagnosis of AD is crucial for delaying the development of disease and improving patient quality of life. However, AD detection, particularly in the early stages, remains a substantial challenge due to the lack of specific biomarkers. The present study was undertaken to identify and validate the potential of circulating miRNAs as novel biomarkers for AD. Solexa sequencing was employed to screen the expression profile of serum miRNAs in AD and controls. RT-qPCR was used to confirm the altered miRNAs at the individual level. Moreover, candidate miRNAs were examined in the serum samples of patients with mild cognitive impairment (MCI) and vascular dementia (VD). The results showed that four miRNAs (miR-31, miR-93, miR-143, and miR-146a) were markedly decreased in AD patients' serum compared with controls. Receiver operating characteristic curve analysis demonstrated that this panel of four miRNAs could be used as potential biomarker for AD. Furthermore, miR-93, and miR-146a were significantly elevated in MCI compared with controls, and the panel of miR-31, miR-93 and miR-146a can be used to discriminate AD from VD. We established a panel of four serum miRNAs as a novel noninvasive biomarker for AD diagnosis.

BACKGROUND: Adolescent depression is becoming one of the major public health concerns, because of its increased prevalence and risk of significant functional impairment and suicidality. Clinical depression commonly emerges in adolescence; therefore, the prevention and intervention of depression at this stage is crucial. Recent evidence supports the importance of the gut microbiota (GM) in the modulation of multiple functions associated with depression through the gut-brain axis (GBA). However, the underlying mechanisms remain poorly understood. Therefore, in the current study, we aimed to screen the microbiota out from healthy and depressive adolescents, delineate the association of the targeted microbiota and the adolescent depression, address the salutary effects of the targeted microbiota on anti-depressive behaviors in mice involving the metabolism of the tryptophan (Trp)-derived neurotransmitters along the GBA. RESULTS: Here, we found the gut microbiota from healthy adolescent volunteers, first diagnosis patients of adolescent depression, and sertraline interveners after first diagnosis displayed significant difference, the relative abundance of Faecalibacterium, Roseburia, Collinsella, Blautia, Phascolarctobacterium, Lachnospiraceae-unclassified decreased in adolescent depressive patients, while restored after sertraline treatment. Of note, the Roseburia abundance exhibited a high efficiency in predicting adolescent depression. Intriguingly, transplantation of the fecal microbiota from healthy adolescent volunteers to the chronic restraint stress (CRS)-induced adolescent depressed mice significantly ameliorated mouse depressive behaviors, in which the Roseburia exerted critical roles, since its effective colonization in the mouse colon resulted in remarkably increased 5-HT level and reciprocally decreased kynurenine (Kyn) toxic metabolites quinolinic acid (Quin) and 3-hydroxykynurenine (3-HK) levels in both the mouse brain and colon. The specific roles of the Roseburia were further validated by the target bacteria transplantation mouse model, Roseburia intestinalis (Ri.) was gavaged to mice and importantly, it dramatically ameliorated CRS-induced mouse depressive behaviors, increased 5-HT levels in the brain and colon via promoting tryptophan hydroxylase-2 (TPH2) or -1 (TPH1) expression. Reciprocally, Ri. markedly restrained the limit-step enzyme responsible for kynurenine (indoleamine2,3-dioxygenase 1, IDO1) and quinolinic acid (3-hydroxyanthranilic acid 3,4-dioxygenase, 3HAO) generation, thereby decreased Kyn and Quin levels. Additionally, Ri. administration exerted a pivotal role in the protection of CRS-induced synaptic loss, microglial activation, and astrocyte maintenance. CONCLUSIONS: This study is the first to delineate the beneficial effects of Ri. on adolescent depression by balancing Trp-derived neurotransmitter metabolism and improving synaptogenesis and glial maintenance, which may yield novel insights into the microbial markers and therapeutic strategies of GBA in adolescent depression. Video Abstract.

Intracranial aneurysm is a common life-threatening disease. Computed tomography angiography is recommended as the standard diagnosis tool; yet, interpretation can be time-consuming and challenging. We present a specific deep-learning-based model trained on 1,177 digital subtraction angiography verified bone-removal computed tomography angiography cases. The model has good tolerance to image quality and is tested with different manufacturers. Simulated real-world studies are conducted in consecutive internal and external cohorts, in which it achieves an improved patient-level sensitivity and lesion-level sensitivity compared to that of radiologists and expert neurosurgeons. A specific cohort of suspected acute ischemic stroke is employed and it is found that 99.0% predicted-negative cases can be trusted with high confidence, leading to a potential reduction in human workload. A prospective study is warranted to determine whether the algorithm could improve patients' care in comparison to clinicians' assessment.

The current study investigated the mechanism and changes in psychopathology symptoms throughout the COVID-19 outbreak and after peak. Two studies were conducted separately in China during outbreak and the after peak stages, with 2540 participants were recruited from February 6 to 16, 2020, and 2543 participants were recruited from April 25 to May 5, 2020. The network models were created to explore the relationship between psychopathology symptoms both within and across anxiety and depression, with anxiety measured by the Generalized Anxiety Disorder-7 and depression measured by the Patient Health Questionnaire-9. Symptom network analysis was conducted to evaluate network and bridge centrality, and the network properties were compared between the outbreak and after peak. Noticeably, psychomotor symptoms such as impaired motor skills, restlessness, and inability to relax exhibited high centrality during the outbreak, which still relatively high but showed substantial remission during after peak stage (in terms of strength, betweenness, or bridge centrality). Meanwhile, symptoms of irritability (strength, betweenness, or bridge centrality) and loss of energy (bridge centrality) played an important role in the network after the peak of the pandemic. This study provides novel insights into the changes in central features during the different COVID-19 stages and highlights motor-related symptoms as bridge symptoms, which could activate the connection between anxiety and depression. The results revealed that restrictions on movement were associated with worsen in psychomotor symptoms, indicating that future psychological interventions should target motor-related symptoms as priority.

T cells (double-negative T cells; DNTs) have diverse functions in peripheral immune-related diseases by regulating immunological and inflammatory homeostasis. However, the functions of DNTs in the central nervous system remain unknown. Here, we found that the levels of DNTs were dramatically increased in both the brain and peripheral blood of stroke patients and in a mouse model in a time-dependent manner. The infiltrating DNTs enhanced cerebral immune and inflammatory responses and exacerbated ischemic brain injury by modulating the FasL/PTPN2/TNF-α signaling pathway. Blockade of this pathway limited DNT-mediated neuroinflammation and improved the outcomes of stroke. Our results identified a critical function of DNTs in the ischemic brain, suggesting that this unique population serves as an attractive target for the treatment of ischemic stroke.

Ischemic stroke is a debilitating clinical disorder that affects millions of people, yet lacks effective neuroprotective treatments. Fish oil is known to exert beneficial effects against cerebral ischemia. However, the underlying protective mechanisms are not fully understood. The present study tests the hypothesis that omega-3 polyunsaturated fatty acids (n-3 PUFAs) attenuate ischemic neuronal injury by activating nuclear factor E2-related factor 2 (Nrf2) and upregulating heme oxygenase-1 (HO-1) in both in vitro and in vivo models. We observed that pretreatment of rat primary neurons with docosahexaenoic acid (DHA) significantly reduced neuronal death following oxygen-glucose deprivation. This protection was associated with increased Nrf2 activation and HO-1 upregulation. Inhibition of HO-1 activity with tin protoporphyrin IX attenuated the protective effects of DHA. Further studies showed that 4-hydroxy-2E-hexenal (4-HHE), an end-product of peroxidation of n-3 PUFAs, was a more potent Nrf2 inducer than 4-hydroxy-2E-nonenal derived from n-6 PUFAs. In an in vivo setting, transgenic mice overexpressing fatty acid metabolism-1, an enzyme that converts n-6 PUFAs to n-3 PUFAs, were remarkably resistant to focal cerebral ischemia compared with their wild-type littermates. Regular mice fed with a fish oil-enhanced diet also demonstrated significant resistance to ischemia compared with mice fed with a regular diet. As expected, the protection was associated with HO-1 upregulation, Nrf2 activation, and 4-HHE generation. Together, our data demonstrate that n-3 PUFAs are highly effective in protecting the brain, and that the protective mechanisms involve Nrf2 activation and HO-1 upregulation by 4-HHE. Further investigation of n-3 PUFA neuroprotective mechanisms may accelerate the development of stroke therapies.