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Amino acid abnormalities have been suggested to be a key pathophysiological mechanism in schizophrenia (SZ). Recently, gut microbes were found to be critically involved in mental and metabolic diseases. However, the relationship between serum amino acid levels and gut microbes in SZ is rarely studied. Here, we analyzed serum amino acid levels in 76 untreated SZ patients and 79 healthy controls (HC). Serum levels of 10 amino acids were significantly altered in patients with SZ. We further classified the cut-off values for serum arginine, leucine, glutamine, and methionine levels to distinguish SZ patients from controls. These classifiers were shown to be effective in another validation cohort (49 SZ and 48 HC). The correlation between serum amino acids and clinical symptoms and cognitive functions was also analyzed. Arginine, leucine, glutamine, and methionine levels were significantly correlated with clinical symptoms and cognitive impairments in SZ patients. By metagenome shotgun sequencing of fecal samples, we found that patients with SZ with a low level of serum amino acids have higher richness and evenness of the gut microbiota. At the genus level, the abundances of Mitsuokella and Oscillibacter are significantly abnormal. At the mOTU level, 15 mOTUs in the low-level SZ group were significantly different from the HC group. In addition, Mitsuokella multacida was correlated with glutamine and methionine, respectively. Our research revealed that alterations in serum amino acid levels are critically related to changes in gut microbiota composition in SZ patients. These findings may shed light on new strategies for the diagnosis and treatment of SZ.

The microbiota-gut-brain axis is a key pathway perturbed by prolonged stressors to produce brain and behavioral disorders. Frontline healthcare workers (FHWs) fighting against COVID-19 typically experience stressful event sequences and manifest some mental symptoms; however, the role of gut microbiota in such stress-induced mental problems remains unclear. We investigated the association between the psychological stress of FHW and gut microbiota.We used full-length 16S rRNA gene sequencing to characterize the longitudinal changes in gut microbiota and investigated the impact of microbial changes on FHWs' mental status.Stressful events induced significant depression, anxiety, and stress in FHWs and disrupted the gut microbiome; gut dysbiosis persisted for at least half a year. Different microbes followed discrete trajectories during the half-year of follow-up. Microbes associated with mental health were mainly Faecalibacterium spp. and [Eubacterium] eligens group spp. with anti-inflammatory effects. Of note, the prediction model indicated that low abundance of [Eubacterium] hallii group uncultured bacterium and high abundance of Bacteroides eggerthii at Day 0 (immediately after the two-month frontline work) were significant determinants of the reappearance of post-traumatic stress symptoms in FHWs.The lack of metabolomic evidence and animal experiments result in the unclear mechanism of gut dysbiosis-related stress symptoms.The stressful event sequences of fighting against COVID-19 induce characteristic longitudinal changes in gut microbiota, which underlies dynamic mental state changes.

Evidence suggests that complex interactions between the immune system and brain have important etiological and therapeutic implications in schizophrenia. However, the detailed cellular and molecular basis of immune dysfunction in schizophrenia remains poorly characterized. To better understand the immune changes and molecular pathways, we systemically compared the cytokine responses of peripheral blood mononuclear cells (PBMCs) derived from patients with schizophrenia and controls against bacterial, fungal, and purified microbial ligands, and identified aberrant cytokine response patterns to various pathogens, as well as reduced cytokine production after stimulation with muramyl dipeptide (MDP) in schizophrenia. Subsequently, we performed single-cell RNA sequencing on unstimulated and stimulated PBMCs from patients and controls and revealed widespread suppression of antiviral and inflammatory programs as well as impaired chemokine/cytokine-receptor interaction networks in various immune cell subpopulations of schizophrenic patients after MDP stimulation. Moreover, serum MDP levels were elevated in these patients and correlated with the course of the disease, suggesting increased bacterial translocation along with disease progression. In vitro assays revealed that MDP pretreatment altered the functional response of normal PBMCs to its re-stimulation, which partially recapitulated the impaired immune function in schizophrenia. In conclusion, we delineated the molecular and cellular landscape of impaired immune function in schizophrenia, and proposed a mutual interplay between innate immune impairment, reduced pathogen clearance, increased MDP translocation along schizophrenia development, and blunted innate immune response. These findings provide new insights into the pathogenic mechanisms that drive systemic immune activation, neuroinflammation, and brain abnormalities in schizophrenia.

OBJECTIVE Sleep disturbances have been recognized as a risk factor for obesity. This study used polysomnography records to investigate associations between sleep fragmentation and obesity. METHODS Objectively measured sleep fragmentation data recorded by in-home polysomnography, including total arousal index (ArI-total), ArI in rapid eye movement (REM) sleep (ArI-REM), ArI in non-REM sleep (ArI-NREM), sleep fragmentation index, sleep efficiency (SE), and wake after sleep onset (WASO), were based on the Sleep Heart Health Study (2,835 men and 2,888 women with a mean [SD] age of 63.2 [11.2] years). Multivariable regression analyses were used to examine the relationship between sleep fragmentation and obesity. RESULTS Multinomial logistic regression showed that participants with obesity have a significantly higher ArI-total (odds ratio [OR] 1.018; 95% CI: 1.010-1.026, p

Although excited behavior in patients with schizophrenia has been linked to brain structural abnormalities, whether cortical abnormalities in this subgroup are related to cognitive impairment or peripheral immune responses is unknown. We included 28 patients with excitability (EC), 28 patients without excitability (NEC), and 48 healthy controls (HCs) to evaluate the associations. Compared with the HC group, the EC and NEC groups showed significant cognitive impairment and increased serum cytokine levels. Analysis of variance in whole-brain grey matter volume (GMV) showed that the volumes of several brain areas, including the superior frontal gyrus (SFG), superior temporal gyrus, and cingulate gyrus, were decreased in patients with schizophrenia. Notably, the left SFG volume was significantly lower in the EC group than in the NEC group. Spearman correlation analysis showed that elevated cytokines were negatively correlated with the GMV of the bilateral SFG, bilateral inferior parietal gyrus, left anterior cingulate gyrus, right fusiform gyrus and parahippocampal gyrus, which were mainly positive correlated with cognitive tests. Moreover, interleukin 4 may contribute to poor scores on Brief Assessment of Cognition and Neuropsychological Assessment Battery by reducing the left SFG volume (17%, P

Psychiatric disorders are the leading cause of disability worldwide while the pathogenesis remains unclear. Genome-wide association studies (GWASs) have made great achievements in detecting disease-related genetic variants. However, functional information on the underlying biological processes is often lacking. Current reports propose the use of metabolic traits as functional intermediate phenotypes (the so-called genetically determined metabotypes or GDMs) to reveal the biological mechanisms of genetics in human diseases. Here we conducted a two-sample Mendelian randomization analysis that uses GDMs to assess the causal effects of 486 human serum metabolites on 5 major psychiatric disorders, which respectively were schizophrenia (SCZ), major depression (MDD), bipolar disorder (BIP), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD). Using genetic variants as proxies, our study has identified 137 metabolites linked to the risk of psychiatric disorders, including 2-methoxyacetaminophen sulfate, which affects SCZ (P = 1.7 × 10–5) and 1-docosahexaenoylglycerophosphocholine, which affects ADHD (P = 5.6 × 10–5). Fourteen significant metabolic pathways involved in the 5 psychiatric disorders assessed were also detected, such as glycine, serine, and threonine metabolism for SCZ (P = .0238), Aminoacyl-tRNA biosynthesis for both MDD (P = .0144) and ADHD (P = .0029). Our study provided novel insights into integrating metabolomics with genomics in order to understand the mechanisms underlying the pathogenesis of human diseases.

The objective of this research was to explore the effect of perioperative anesthesia management for patients based on the concept of enhanced recovery after surgery (ERAS) and the application value of the computed tomography (CT) localization method in lumbar spinal nerve anesthesia, reducing the damage caused by anesthesia. One hundred and twenty patients who underwent the lumbar spinal anesthesia in lower limb surgery were selected as the research subjects. According to puncture positioning and nursing intention, the patients were classified into the control group with 30 patients (method of anatomical landmarks), CT group with 50 patients (the CT localization), and ERAS group with 40 patients (the CT localization and the ERAS management). The effects of the anesthesia positioning method and the ERAS management were compared and analyzed. The results showed that d (0.32) and r (0.27) of exponential filtering function were notably smaller than those of R-L filtering function (d = 0.40, r = 0.39) and of S-R filtering function (d = 0.37, r = 0.36) ( P < 0.05 ). Puncture time ((9.23 ± 0.32) min vs. (13.11 ± 0.45) min), puncture direction change (20% vs. 33.33%), abnormal puncture sensation (22% vs. 40%), and nerve root touch (4% vs. 23.33%) in the CT group were all lower than those in the control group. The proportion of Degree I anesthesia effect (94%) of the CT group was greatly higher than that of the control group (76.67%) ( P < 0.05 ). The VAS score, time of activity and gastrointestinal function recovery, and the incidence of adverse reactions (2.5% vs. 28%) in the ERAS group were lower than those in the CT group ( P < 0.05 ). All in all, the CT localization method can improve the difficulty of anesthesia puncture and improve the anesthetic effect; the ERAS nursing concept can improve the postoperative pain of patients and contribute to the prognosis of patients and have a good clinical value.

The effect of dexmedetomidine on postoperative agitation of patients with craniocerebral injury was investigated based on magnetic resonance imaging (MRI) with the sparse reconstruction algorithm. Sixty patients with craniocerebral injury who underwent tracheal intubation and craniotomy hematoma removal under general anesthesia in hospital were selected as the research objects. Patients were randomly and averagely divided into the normal saline group (group A) and the dexmedetomidine (DEX) group (group B). DEX was added to patients in group A during anesthesia. Other operations in group B were the same as those in group A, where DEX needed to be used was replaced by an equal amount of the normal saline. All patients received the MRI examination, and the images were processed by using the sparse reconstruction algorithm. After the surgery, some indexes, such as hemodynamics (mean arterial pressure (MAP) and hear rate (HR)), the Riker sedation agitation score, the Ramsay sedation score, and the visual analogue scale (VAS) score were recorded and compared. The results showed that the MRI image quality processed by sparse reconstruction algorithm was observably improved. After reconstruction, the sharpness of the image was significantly improved, and the distinction between lesions and tissues was also increased. The Riker sedation agitation score and the incidence of agitation in group A were greatly lower than those in group B (16% VS 76%, P P

The development of artificial intelligence and the Internet of things has motivated extensive research on self-powered flexible sensors. The conventional sensor must be powered by a battery device, while innovative self-powered sensors can provide power for the sensing device. Self-powered flexible sensors can have higher mobility, wider distribution, and even wireless operation, while solving the problem of the limited life of the battery so that it can be continuously operated and widely utilized. In recent years, the studies on piezoelectric nanogenerators (PENGs) and triboelectric nanogenerators (TENGs) have mainly concentrated on self-powered flexible sensors. Self-powered flexible sensors based on PENGs and TENGs have been reported as sensing devices in many application fields, such as human health monitoring, environmental monitoring, wearable devices, electronic skin, human–machine interfaces, robots, and intelligent transportation and cities. This review summarizes the development process of the sensor in terms of material design and structural optimization, as well as introduces its frontier applications in related fields. We also look forward to the development prospects and future of self-powered flexible sensors.

Schizophrenia (SCZ) is associated with several immune dysfunctions, including elevated levels of pro-inflammatory cytokines. Microorganisms and their metabolites have been found to regulate the immune system, and that intestinal microbiota is significantly disturbed in schizophrenic patients. To systematically investigate aberrant gut-metabolome-immune network in schizophrenia, we performed an integrative analysis of intestinal microbiota, serum metabolome, and serum inflammatory cytokines in 63 SCZ patients and 57 healthy controls using a multi-omics strategy. Eighteen differentially abundant metabolite clusters were altered in patients displayed higher cytokine levels, with a significant increase in pro-inflammatory metabolites and a significant decrease in anti-inflammatory metabolites (such as oleic acid and linolenic acid). The bacterial co-abundance groups in the gut displayed more numerous and stronger correlations with circulating metabolites than with cytokines. By integrating these data, we identified that certain bacteria might affect inflammatory cytokines by modulating host metabolites, such as amino acids and fatty acids. A random forest model was constructed based on omics data, and seven serum metabolites significantly associated with cytokines and α-diversity of intestinal microbiota were able to accurately distinguish the cases from the controls with an area under the receiver operating characteristic curve of 0.99. Our results indicated aberrant gut-metabolome-immune network in SCZ and gut microbiota may influence immune responses by regulating host metabolic processes. These findings suggest a mechanism by which microbial-derived metabolites regulated inflammatory cytokines and insights into the diagnosis and treatment of mental disorders from the microbial-immune system in the future.

ObjectiveObservational studies have demonstrated a close relationship between obesity and longevity. The aim of this Mendelian randomization (MR) study is to investigate whether genetic determinants of visceral adipose tissue (VAT) accumulation are causally associated with longevity.MethodsIn this two-sample MR study, we used summary data of genetic determinants (single-nucleotide polymorphisms; p < 5 × 10−8) of VAT accumulation based on genome-wide association studies (GWASs). Longevity was defined as an age beyond the 90th or 99th survival percentile. The causal association of VAT accumulation with longevity was estimated with the inverse variance-weighted (IVW) method. Sensitivity analyses, including weighted median, MR-Egger, and MR–pleiotropy residual sum and outlier (PRESSO), were also employed to assess the stability of the IVW results.ResultsOur MR analysis used 221 genetic variants as instrumental variables to explore the causal association between VAT accumulation and longevity. In the standard IVW methods, VAT accumulation (per 1-kg increase) was found to be significantly associated with lower odds of surviving to the 90th (odds ratio [OR] = 0.69; 95% confidence interval [CI] 0.55 to 0.86, p = 8.32 × 10−4) and 99th (OR = 0.67; 95% CI 0.49 to 0.91, p = 0.011) percentile ages. These findings remained stable in sensitivity analysis.ConclusionThis MR analysis identified a causal relationship between genetically determined VAT accumulation and longevity, suggesting that visceral adiposity may have a negative effect on longevity.

Sleeping habits have been reported to be associated with diabetes mellitus. This study aimed to explore the relationship of sleep efficiency with diabetes mellitus in individuals with or without sleep-disordered breathing based on polysomnography records.We enrolled participants from the Sleep Heart Health Study. Objective indicators of sleep characteristics including sleep efficiency, sleep latency, slow-wave sleep, wake after sleep onset, and total arousal index were monitored via in-home polysomnography. Sleep efficiency was divided into grade 1 (≥85%), grade 2 (80%-84.9%), and grade 3 (80%). Multivariate logistic regression models were utilized to investigate the association between sleep quality and diabetes mellitus.The present study comprised 4737 participants with a mean age of 63.6 ± 11.0 years. The prevalence of diabetes mellitus was higher in those with grade 3 sleep efficiency than that in those with grade 1 and grade 2 sleep efficiency in participants with (10.9% vs 8.5% vs 8.3%, respectively; P =.134) or without (9.5% vs 5.6% vs 3.5%, respectively; P .001) sleep-disordered breathing. After adjusting for potential confounding factors, sleep efficiency80% was associated with the prevalence of diabetes mellitus only in participants without sleep-disordered breathing (odds ratio, 1.894; 95% confidence interval, 1.187-3.022, P =.007).Poor sleep efficiency is associated with diabetes mellitus in those without sleep-disordered breathing. Therefore, the relationship between sleep efficiency and diabetes mellitus is worth further investigation.背景: 前期研究发现睡眠习惯与糖尿病患病有关。本项研究旨在基于睡眠多导图监测探索伴有或不伴有睡眠呼吸暂停的社区人群中睡眠效率与糖尿病患病之间的关系。 方法: 本次研究从睡眠心脏健康研究(Sleep Heart Health Study)中筛选参与者。家庭式睡眠多导图监测下的客观睡眠指标包括睡眠效率、睡眠延迟、慢波睡眠、睡眠总觉醒时间和夜间总觉醒指数。睡眠效率被分为一级(85%), 二级(80%-84.9%), 和三级(80%)。多元逻辑回归分析用来调查睡眠质量与糖尿病之间的关系。 结果: 本研究包含4737名参与者, 平均年龄63.6±11.0岁。整体人群中, 睡眠效率较低的人群具有糖尿病高患病率。三级睡眠效率与一级和二级相比, 糖尿病患病率分别在伴有(10.9% vs. 8.5% vs. 8.3%; P=0.134)或不伴有(9.5% vs. 5.6% vs. 3.5%; P0.001)睡眠呼吸暂停的人群中增高。校正潜在的混杂因素后, 只有在不伴有睡眠呼吸暂停的人群中睡眠效率小于80%与糖尿病的患病率密切相关(OR 1.894, 95% CI 1.187-3.022, P=0.007)。 结论: 不伴有睡眠呼吸暂停的人群中, 较低的睡眠效率与糖尿病患病率密切相关。因此, 睡眠效率与糖尿病之间的关系值得进一步的探究。.

Accumulating evidence suggests that gut microbiota plays a role in the pathogenesis of schizophrenia via the microbiota-gut-brain axis. This study sought to investigate whether transplantation of fecal microbiota from drug-free patients with schizophrenia into specific pathogen-free mice could cause schizophrenia-like behavioral abnormalities. The results revealed that transplantation of fecal microbiota from schizophrenic patients into antibiotic-treated mice caused behavioral abnormalities such as psychomotor hyperactivity, impaired learning and memory in the recipient animals. These mice also showed elevation of the kynurenine-kynurenic acid pathway of tryptophan degradation in both periphery and brain, as well as increased basal extracellular dopamine in prefrontal cortex and 5-hydroxytryptamine in hippocampus, compared with their counterparts receiving feces from healthy controls. Furthermore, colonic luminal filtrates from the mice transplanted with patients' fecal microbiota increased both kynurenic acid synthesis and kynurenine aminotransferase II activity in cultured hepatocytes and forebrain cortical slices. Sixty species of donor-derived bacteria showed significant difference between the mice colonized with the patients' and the controls' fecal microbiota, highlighting 78 differentially enriched functional modules including tryptophan biosynthesis function. In conclusion, our study suggests that the abnormalities in the composition of gut microbiota contribute to the pathogenesis of schizophrenia partially through the manipulation of tryptophan-kynurenine metabolism.

Background There was little evidence about the role of objective sleep efficiency (SE) in the incidence of major cardiovascular disease (CVD) events. The purpose of this study was to investigate the correlation between objective SE and CVD based on polysomnography. Methods and Results A total of 3810 participants from the SHHS (Sleep Heart Health Study) were selected in the current study. CVD was assessed during an almost 11‐year follow‐up period. The primary composite cardiovascular outcome was major adverse cardiovascular events, defined as CVD mortality, congestive heart failure, myocardial infarction, and stroke. The secondary composite cardiovascular outcome was major adverse cardiovascular event plus revascularization. Objective measured SE, including SE and wake after sleep onset, was based on in‐home polysomnography records. Cox regression analysis was used to explore the association between SE and CVD. After multivariate Cox regression analysis, poor SE (P =0.032) and secondary composite cardiovascular outcomes (HR, 1.250; 95% CI, 1.027–1.521; P =0.026); it was also found to be a predictor of CVD mortality (HR, 1.887; 95% CI, 1.224–2.909; P =0.004). Moreover, wake after sleep onset of fourth quartile (>78.0 minutes) was closely correlated with primary (HR, 1.436; 95% CI, 1.066–1.934; P =0.017), secondary composite cardiovascular outcomes (HR, 1.374; 95% CI, 1.103–1.712; P =0.005), and CVD mortality (HR, 2.240; 95% CI, 1.377–3.642; P =0.001). Conclusions Poor SE and long wake after sleep onset, objectively measured by polysomnography, were associated with the increased risk of incident CVD.

Childhood neurodevelopmental disorders, including autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), and Tourette syndrome (TS), comprise a major cause of health-related disabilities in children. However, biomarkers towards pathogenesis or novel drug targets are still limited. Our study aims to provide a comprehensive investigation of the causal effects of the plasma proteome on ASD, ADHD, and TS using the two-sample Mendelian Randomization (MR) approach.Genetic associations with 2994 plasma proteins were selected as exposures and genome-wide association data of ASD, ADHD, TS were utilized as outcomes. MR analyses were carried out using the inverse-variance weighted method, and the MR-Egger and weighted median methods were used for sensitivity analysis.Using single-nucleotide polymorphisms as instruments, the study suggested increased levels of MAPKAPK3 (OR: 1.09; 95% CI: 1.05-1.13; P = 1.43 × 10The study findings support the idea that the MAPK/ERK signaling pathway and mitochondrial dysfunction are involved in the pathogenesis of ASD, while a deficiency in beta-mannosidase might play a role in the development of ADHD.Natural Science Basic Research Program of Shaanxi (2021JQ-390).

Influenza A virus may circulate simultaneously with the SARS-CoV-2 virus, leading to more serious respiratory diseases during this winter. However, the influence of these viruses on disease outcome when both influenza A and SARS-CoV-2 are present in the host remains unclear. Using a mammalian model, sequential infection was performed in ferrets and in K18-hACE2 mice, with SARS-CoV-2 infection following H1N1. We found that co-infection with H1N1 and SARS-CoV-2 extended the duration of clinical manifestation of COVID-19, and enhanced pulmonary damage, but reduced viral shedding of throat swabs and viral loads in the lungs of ferrets. Moreover, mortality was increased in sequentially infected mice compared with single-infection mice. Compared with single-vaccine inoculation, co-inoculation of PiCoVacc (a SARS-CoV-2 vaccine) and the flu vaccine showed no significant differences in neutralizing antibody titers or virus-specific immune responses. Combined immunization effectively protected K18-hACE2 mice against both H1N1 and SARS-CoV-2 infection. Our findings indicated the development of systematic models of co-infection of H1N1 and SARS-CoV-2, which together notably enhanced pneumonia in ferrets and mice, as well as demonstrated that simultaneous vaccination against H1N1 and SARS-CoV-2 may be an effective prevention strategy for the coming winter.

Objectives Sleep timing is related to several risk factors for angina pectoris (AP), such as obesity and diabetes. This study was designed to evaluate the relationship between sleep timing and AP, specifically whether later bedtime was associated with AP in middle-aged and older adults. Methods This community-based study was based on the Sleep Heart Health Study cohort and included 4710 participants (45.9% men, aged 63.3 ± 11.0 years). Lifestyle and epidemiological information were obtained from baseline records. Self-reported sleep measures provided information on bedtime and wake-up time of weekdays and weekends. Individuals were divided into three categories according to bedtime (≤22:00, 22:01–23:00, and >23:00). Odds ratios (OR) and 95% confidence intervals (CIs) of AP for bedtimes were estimated with multivariate logistic regression analysis. Results The prevalence of AP was 44.2% and the distribution of weekday bedtimes ≤22:00, 22:01–23:00, and >23:00 were 36.6%, 47.5% and 46.0%, respectively. After adjusting for potential confounders, weekday bedtimes >23:00 (OR 1.34; 95% CI 1.13–1.60; P = 0.001) and 22:01–23:00 (OR 1.54; 95% CI 1.29–1.82; P 23:00 (OR 1.44; 95% CI 1.20–1.73; P Conclusions Later bedtimes on both weekdays and weekends were significantly associated with an increased prevalence of AP. Early bedtimes may help people decrease the risk of AP.

Background Neuroticism is a strong predictor for a variety of social and behavioral outcomes, but the etiology is still unknown. Our study aims to provide a comprehensive investigation of causal effects of serum metabolome phenotypes on risk of neuroticism using Mendelian randomization (MR) approaches. Methods Genetic associations with 486 metabolic traits were utilized as exposures, and data from a large genome-wide association study of neuroticism were selected as outcome. For MR analysis, we used the standard inverse-variance weighted (IVW) method for primary MR analysis and 3 additional MR methods (MR-Egger, weighted median, and MR pleiotropy residual sum and outlier) for sensitivity analyses. Results Our study identified 31 metabolites that might have causal effects on neuroticism. Of the 31 metabolites, uric acid and paraxanthine showed robustly significant association with neuroticism in all MR methods. Using single nucleotide polymorphisms as instrumental variables, a 1-SD increase in uric acid was associated with approximately 30% lower risk of neuroticism (OR: 0.77; 95% CI: 0.62–0.95; PIVW = 0.0145), whereas a 1-SD increase in paraxanthine was associated with a 7% higher risk of neuroticism (OR: 1.07; 95% CI: 1.01–1.12; PIVW = .0145). Discussion Our study suggested an increased level of uric acid was associated with lower risk of neuroticism, whereas paraxanthine showed the contrary effect. Our study provided novel insight by combining metabolomics with genomics to help understand the pathogenesis of neuroticism.

Intelligence predicts important life and health outcomes, but the biological mechanisms underlying differences in intelligence are not yet understood. The use of genetically determined metabotypes (GDMs) to understand the role of genetic and environmental factors, and their interactions, in human complex traits has been recently proposed. However, this strategy has not been applied to human intelligence. Here we implemented a two-sample Mendelian randomization (MR) analysis using GDMs to assess the causal relationships between genetically determined metabolites and human intelligence. The standard inverse-variance weighted (IVW) method was used for the primary MR analysis and three additional MR methods (MR-Egger, weighted median, and MR-PRESSO) were used for sensitivity analyses. Using 25 genetic variants as instrumental variables (IVs), our study found that 5-oxoproline was associated with better performance in human intelligence tests (PIVW = 9·25×10-5). The causal relationship was robust when sensitivity analyses were applied (PMR-Egger = 0·0001, PWeighted median = 6·29×10-6, PMR-PRESSO = 0·0007), and repeated analysis yielded consistent result (PIVW = 0·0087). Similarly, also dihomo-linoleate (20:2n6) and p-acetamidophenylglucuronide showed robust association with intelligence. Our study provides novel insight by integrating genomics and metabolomics to estimate causal effects of genetically determined metabolites on human intelligence, which help to understanding of the biological mechanisms related to human intelligence.

Background Prophylactic vaccines are critical in preventing hand, foot, and mouth disease (HFMD) primarily caused by human enterovirus 71 (EV71) infection. Children aged less than 5 years are especially susceptible to EV71 infections. In addition to the development of vaccines containing the inactivated virus, those containing virus-like particles (VLPs) with repeated antigens also constitute an effective preventive strategy for EV71 infections, with safety and productivity advantages. We previously developed a fusion protein composed with truncated peptides of the EV71 capsid protein, which assembled into spherical particles. This study aimed to assess the immunoprotective effects of this fusion protein as a vaccine candidate in a mouse model of EV71 infection. Methods To evaluate the protective effect of fusion protein vaccine candidate, neonatal mice born by immunized female mice, as well as normal neonatal mice immunized twice were infected with EV71 virus. Whereafter, the survival rates, clinical scores and viral loads were measured. Results The high dosage and booster immunization helped induce specific serum antibodies with high neutralization titers, which were transferred to neonatal mice, thereby facilitating effective resistance towards EV71 infection. An active immune response was also observed in neonatal mice which generated following immunization. Conclusions The present results suggest that this fusion protein is a suitable vaccine candidate in treating EV71 infections.

Evidence is mounting that the gut-brain axis plays an important role in mental diseases fueling mechanistic investigations to provide a basis for future targeted interventions. However, shotgun metagenomic data from treatment-naïve patients are scarce hampering comprehensive analyses of the complex interaction between the gut microbiota and the brain. Here we explore the fecal microbiome based on 90 medication-free schizophrenia patients and 81 controls and identify a microbial species classifier distinguishing patients from controls with an area under the receiver operating characteristic curve (AUC) of 0.896, and replicate the microbiome-based disease classifier in 45 patients and 45 controls (AUC = 0.765). Functional potentials associated with schizophrenia include differences in short-chain fatty acids synthesis, tryptophan metabolism, and synthesis/degradation of neurotransmitters. Transplantation of a schizophrenia-enriched bacterium, Streptococcus vestibularis, appear to induces deficits in social behaviors, and alters neurotransmitter levels in peripheral tissues in recipient mice. Our findings provide new leads for further investigations in cohort studies and animal models., Gut microbiome has been linked to neurogenerative diseases. Here, the authors present a metagenome-wide association study of schizophrenia (SZ) in human cohorts and identify SZ-associated specific gut-brain functional modules and pathways including SCFAs and neurotransmitters.

Among all psychiatric disorders, anorexia nervosa (AN) has the highest mortality rate. However, there is still no pharmacological therapy for AN. The human plasma proteome may be a great cornerstone for the development of new drugs against AN. Here we performed a Mendelian randomization (MR) analysis to identify causal risk proteins for AN. Exposure data were extracted from a large genome-wide association study (GWAS) of 2994 plasma proteins in 3301 subjects of European descent, while outcome data were obtained from another GWAS of AN (16,992 cases and 55,525 controls of European descent). MR analyses were performed using the inverse-variance weighted (IVW) method and other sensitivity analysis methods. Using single nucleotide polymorphisms as instruments, this study suggested that high TXNDC12 levels were associated with a higher risk of AN (IVW Odd's ratio [OR]: 1.12; 95% confidence interval [CI]: 1.08–1.16; P = 2.35 × 10−10), while another protein ADH1B showed the opposite effect (IVW OR: 0.89; 95% CI: 0.85–0.93; P = 2.99 × 10−7). The causal associations were robust in multivariable models, genome-wide significant models, and with additional MR methods. No pleiotropy was observed. Our findings suggest that TXNDC12 was associated with a high risk of AN, while AHD1B was associated with a low risk of AN. They might both have implications in AN by regulating the brain dopamine reward system. In combination with existing knowledge on AN, these proteins may be novel drug targets for AN treatment.

The CD4(+)CD25(+)FOXP3(+) regulatory T (Treg) cells are critical for maintaining immune tolerance in healthy individuals and are reported to restrict anti-inflammatory responses and thereby promote tumor progression, suggesting them as a target in the development of antitumor immunotherapy. Forkhead box P3 (FOXP3) is a key transcription factor governing Treg lineage differentiation and their immune-suppressive function. Here, using Treg cells, as well as HEK-293T and Jurkat T cells, we report that the stability of FOXP3 is directly and positively regulated by the E3 ubiquitin ligase ring finger protein 31 (RNF31), which catalyzes the conjugation of atypical ubiquitin chains to the FOXP3 protein. We observed that shRNA-mediated RNF31 knockdown in human Treg cells decreases FOXP3 protein levels and increases levels of interferon-γ, resulting in a Th1 helper cell–like phenotype. Human Treg cells that ectopically expressed RNF31 displayed stronger immune-suppressive capacity, suggesting that RNF31 positively regulates both FOXP3 stability and Treg cell function. Moreover, we found that RNF31 is up-regulated in Treg cells that infiltrate human gastric tumor tissues compared with their counterparts residing in peripheral and normal tissue. We also found that elevated RNF31 expression in intratumoral Treg cells is associated with poor survival of gastric cancer patients, suggesting that RNF31 supports the immune-suppressive functions of Treg cells. Our results suggest that RNF31 could be a potential therapeutic target in immunity-based interventions against human gastric cancer.

Glucocorticoid-induced TNFR-related protein (GITR) is constitutively expressed in T regulatory (Treg) cells and regulates their suppressive function. We identified two methylated CpG islands in the Gitr locus. Using a ChIP assay, we demonstrate that both DNMT1 and methyl-CpG-binding domain Protein 4 (MBD4) bind to the Gitr promoter. Moreover, knockdown of DNMT1 decreases the binding activity of MBD4. We observed much higher levels of both DNMT1 and MBD4 in human CD4(+) CD25(-) conventional T (Tconv) cells. Moreover, co-overexpression of DNMT1 and MBD4 in Treg cells significantly inhibits GITR expression and impairs their suppressive activity. Our results reveal a novel molecular mechanism by which MBD4 inhibits GITR expression in a DNMT1-dependent manner.

STUDY OBJECTIVES: The aim of this study was to investigate the association of bedtime with the prevalence of diabetes mellitus (DM) based on a large community-based population. METHODS: In total, 5,420 participants (2,574 males and 2,846 females; aged 63.5 ± 11.0 years) from the Sleep Heart Health Study database were selected in this study. Sleep habit was recorded based on a questionnaire administered to patients upon recruitment. Bedtime was categorized as 11:00 pm and before, 11:00 pm to 12:00 am, and 12:00 am and later in the current study. Multivariate logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) to determine the relationship between bedtime and the prevalence of DM. RESULTS: The distribution of weekday bedtime at 11:00 pm and before, 11:00 pm to 12:00 am, 12:00 am and later was observed in 3,316 participants (61.2%), 991 participants (18.3%), and 1,113 participants (20.5%), respectively. Meanwhile, individuals with weekday bedtime of 12:00 am and later had a higher prevalence of DM than those with bedtime at 11:00 pm to 12:00 am, and 11:00 pm and before (10.6% versus 5.7% versus 6.6%, respectively; P < .001). In the adjusted multivariate logistic regression model, bedtime at 12:00 am and later on a weekday was significantly associated DM prevalence (OR 1.446, 95% CI 1.107–1.888, P = .007). No significant association was found between weekend bedtime and DM. CONCLUSION: Late bedtime at 12:00 am and later on a weekday may be a risk factor for the prevalence of DM. Stable sleep timing leads to lower risk of DM deserves future exploration. CITATION: Yan B, Fan Y, Zhao B, He X, Yang J, Chen C, Ma X. Association between late bedtime and diabetes mellitus: A large community-based study. J Clin Sleep Med. 2019;15(11):1621–1627.

Schizophrenia is a severe mental disorder with high heritability. GWAS had identified multiple susceptible regions associated with schizophrenia. However, a number of variants remained to be explored due to their location in non-coding regions. Enhancers were important DNA elements that positively regulated the expression of target genes. We applied a novel method to conduct pathway enrichment analysis in schizophrenia across 8 brain regions. GWAS summary data and enhancer-target networks of the 8 regions were integrated in this approach. Finally, we identified several genes involving in neurodevelopmental processes across the 8 regions. It is remarkable germinal matrix showed strongest relationship with schizophrenia, which is mainly involved in cells migrate out during brain development. Substantia nigra, dorsolateral prefrontal cortex, inferior temporal lobe and hippocampus middle also showed stronger signals. We also found that schizophrenia was mainly associated with "Immune Diseases", "Gene Expression", "Cell Cycle", "Cellular Component" and "Biological Process" across specific brain regions. Our study supported the argument that schizophrenia is a severe mental disorder with early brain dysplasia or impairment of cognitive and memory related areas, which provided novel insight to the pathophysiology of schizophrenia.

ObjectiveTo investigate whether coronary artery dominance is associated with the severity of coronary artery disease (CAD).DesignCross-sectional study.SettingSingle-centre.ParticipantsBetween July 2015 and February 2017, 1654 patients who underwent coronary angiography (CAG) were recruited into this cross-sectional study.Measurement and methodsAccording to coronary dominance, patients were classified into left dominance (LD), right dominance (RD) and codominance (CD) based on the CAG results. Multiple linear regression analysis was performed to test the association between severity of CAD and coronary dominance.ResultsThe total Gensini score was significantly higher in the RD group than in the left-CD group (42.3±33.6 vs 36.3±29.8; p=0.033). After adjusting for potential confounding factors, the results of multivariate linear regression showed that RD was associated with the severity of CAD (β=6.699, 95% CI 1.193 to 12.205, p=0.017).ConclusionsThe results suggest that right coronary dominance was associated with the severity of CAD.

Purpose Recent reports suggest that Th17 immunity and bone marrow-derived CD34+ fibrocytes contribute to the pathogenesis of Graves' orbitopathy (GO). This study investigated interactions between Th17 cells and fibrocytes in GO inflammation in Chinese subjects. Methods Th17 cells and fibrocytes were derived from blood samples from Chinese GO patients and healthy controls. Proportions and phenotypes of Th17 cells, regulatory T cells (Tregs), and fibrocytes were examined by flow cytometry. Exogenous IL-17A was used to study inflammatory activity of fibrocytes from GO patients and control subjects. Coculture, quantitative RT-PCR, Luminex, and transwell assays were performed to investigate the relationship between Th17 cells and fibrocytes. Results CC-chemokine receptor 6 (CCR6+) Th17 cells were increased in both active (P < 0.001) and inactive (P < 0.05) GO patients, compared with healthy controls. There was a positive correlation between number of CCR6+ Th17 cells and GO clinical activity score (P < 0.0001, r = 0.8176). Further, CD34+ fibrocytes were increased in GO patients, with increased expression of IL-17RA (P < 0.05), CD80 (P < 0.05), and CD86 (P < 0.05). A decreased population of effector Treg cells (P < 0.01) and increased CTLA-4 expression on naive Treg cells (P < 0.05) were observed in GO patients. IL-17A stimulated cytokine production in fibrocytes; GO fibrocytes exhibited more robust production than normal fibrocytes. Autologous Th17 cells promoted inflammatory and antigen-presenting functions of GO fibrocytes; conversely, fibrocytes enhanced Th17 cell-function and recruited Th17 cells in a macrophage inflammatory protein 3 (MIP-3)/CCR6-dependent manner. Conclusions The crosstalk between CCR6+ Th17 cells and fibrocytes plays a role in the pathogenesis of GO. Suppressing these interactions may be a candidate molecular target for therapeutic approaches of GO.

The histone demethylase LSD1 has been known as a key transcriptional coactivator for DNA viruses such as herpes virus. Inhibition of LSD1 was found to block viral genome transcription and lytic replication of DNA viruses. However, RNA virus genomes do not rely on chromatin structure and histone association, and the role of demethylase activity of LSD1 in RNA virus infections is not anticipated. Here, we identify that, contrary to its role in enhancing DNA virus replication, LSD1 limits RNA virus replication by demethylating and activating IFITM3 which is a host restriction factor for many RNA viruses. We have found that LSD1 is recruited to demethylate IFITM3 at position K88 under IFNα treatment. However, infection by either Vesicular Stomatitis Virus (VSV) or Influenza A Virus (IAV) triggers methylation of IFITM3 by promoting its disassociation from LSD1. Accordingly, inhibition of the enzymatic activity of LSD1 by Trans-2-phenylcyclopropylamine hydrochloride (TCP) increases IFITM3 monomethylation which leads to more severe disease outcomes in IAV-infected mice. In summary, our findings highlight the opposite role of LSD1 in fighting RNA viruses comparing to DNA viruses infection. Our data suggest that the demethylation of IFITM3 by LSD1 is beneficial for the host to fight against RNA virus infection., Author summary The viral genomes of DNA viruses but not RNA viruses form chromatin structure during infection. Thus, epigenetic modulators are not expected to have crucial roles in RNA viral infection. However, here, we identify for the first time, that, opposite to its role in enhancing DNA virus replication, LSD1, a histone demethylase, limits RNA virus replication. We show that, under IFNα treatment, LSD1 is involved in the demethylation of IFITM3, a well-known host restriction factor for many RNA viruses. To counteract IFITM3 activation by demethylation, several RNA viruses, such as VSV and IAV, but not Zika virus, have developed strategy to inactive IFITM3 by promoting its dissociation from LSD1. In agreement with our findings, the inhibition of the enzymatic activity of LSD1 by small molecule leads to more severe disease outcomes in IAV-infected mice. Our data suggest that although LSD1 inhibitor is beneficial for treating DNA virus infection, it could be harmful to the host suffering from RNA virus infection. On the contrary, developing strategies to stimulate LSD1 activity to demethylate of IFITM3 is essential to fight RNA viruses.

The purpose of this study was to evaluate the cytokine expression profile of specific IL-1 family members in the aqueous humor and sera of patients with HLA-B27 associated acute anterior uveitis (AAU) and idiopathic AAU. Following informed consent, a total of 13 patients with HLA-B27 associated AAU, 12 patients with idiopathic AAU and 9 controls were recruited to this study from May 2013 to July 2014. Each individual received a complete ophthalmologic examination. Aqueous humor and sera samples were collected and 11 inflammation-related cytokines of the IL-1 family (IL-1α, IL-1β, IL-1 receptor antagonist [IL-1Ra], IL-18, IL-36 receptor antagonist [IL-36Ra], IL-33, IL-36α, IL-36β, IL-36γ, IL-37, IL-38) were quantitatively measured and analyzed for statistical significance between groups. The degree of inflammation, anterior chamber cell or flare, correlated with expression of IL-1β, IL-1Ra, and IL-18. The highest levels of IL-1β, IL-1Ra, IL-18, and IL-36Ra were seen in the aqueous of patients with HLA-B27 associated AAU and this was statically significant when compared to the controls, but not to idiopathic AAU. Expression of IL-18 was statistically higher in the aqueous of patients with HLA-B27 associated AAU in comparison to either idiopathic AAU or controls, but this may reflect greater inflammation in this patient group. In the sera only IL-1α was statistically higher in the HLA-B27 associated AAU in comparison to the control. Cytokine analysis reveals elevation of multiple IL-1 family members in the aqueous humor of patients with AAU as compared to controls. The specific signature of inflammation may potentially be useful in developing new future therapies for AAU.