Production of species-specific anthocyanins through an inducible system in plant hairy roots.

Anthocyanins are widely distributed pigments in flowering plants with red, purple or blue colours. Their properties in promoting heath make anthocyanins perfect natural colourants for food additives. However, anthocyanins with strong colour and stability at neutral pH, suitable as food colourants are relatively rare in nature. Acylation increases anthocyanin stability and confers bluer colour. In this study, we isolated two anthocyanin regulators SbMyb75 and SbDel from S. baicalensis, and showed that constitutive expression of the two TFs led to accumulation of anthocyanins at high levels in black carrot hairy roots. However, these hairy roots had severe growth problems. We then developed a ß-estradiol inducible system using XVE and a Lex-35S promoter, to initiate expression of the anthocyanin regulators and induced this system in hairy roots of black carrot, tobacco and morning glory. Anthocyanins with various decorations were produced in these hairy roots without any accompanying side-effects on growth. We further produced highly acylated anthocyanins with blue colour in a 5 L liquid culture in a bioreactor of hairy roots from morning glory. We provide here a strategy to produce highly decorated anthocyanins without the need for additional engineering of any of the genes encoding decorating enzymes. This strategy could be transferred to other species, with considerable potential for natural colourant production for the food industries.

Characterization of UDP-glycosyltransferase family members reveals how major flavonoid glycoside accumulates in the roots of Scutellaria baicalensis.

BACKGROUND: Flavonoid glycosides extracted from roots of Scutellaria baicalensis exhibit strong pharmaceutical antitumor, antioxidative, anti-inflammatory, and antiviral activities. UDP glycosyltransferase (UGT) family members are responsible for the transfer of a glycosyl moiety from UDP sugars to a wide range of acceptor flavonoids. Baicalin is the major flavonoid glycoside found in S. baicalensis roots, and its aglycone baicalein is synthesized from a specially evolved pathway that has been elucidated. However, it is necessary to carry out a genome-wide study of genes involved in 7-O-glucuronidation, the final biosynthesis step of baicalin, which might elucidate the relationship between the enzymes and the metabolic accumulation patterns in this medicinal plant. RESULTS: We reported the phylogenetic analysis, tissue-specific expression, biochemical characterization and evolutionary analysis of glucosyltransferases (SbUGTs) and glucuronosyltransferases (SbUGATs) genes based on the recently released genome of S. baicalensis. A total of 124 UGTs were identified, and over one third of them were highly expressed in roots. In vitro enzyme assays showed that 6 SbUGTs could use UDP-glucose as a sugar donor and convert baicalein to oroxin A (baicalein 7-O-glucoside), while 4 SbUGATs used only UDP-glucuronic acid as the sugar donor and catalyzed baicalein to baicalin. SbUGAT4 and SbUGT2 are the most highly expressed SbUGAT and SbUGT genes in root tissues, respectively. Kinetic measurements revealed that SbUGAT4 had a lower Km value and higher Vmax/Km ratio to baicalein than those of SbUGT2. Furthermore, tandem duplication events were detected in SbUGTs and SbUGATs. CONCLUSIONS: This study demonstrated that glucosylation and glucuronidation are two major glycosylated decorations in the roots of S. baicalensis. Higher expression level and affinity to substrate of SbUGAT4, and expansion of this gene family contribute high accumulation of baicalin in the root of S. baicalensis.

Two types of O-methyltransferase are involved in biosynthesis of anticancer methoxylated 4'-deoxyflavones in Scutellaria baicalensis Georgi.

The medicinal plant Scutellaria baicalensis Georgi is rich in specialized 4'-deoxyflavones, which are reported to have many health-promoting properties. We assayed Scutellaria flavones with different methoxyl groups on human cancer cell lines and found that polymethoxylated 4'-deoxyflavones, like skullcapflavone I and tenaxin I have stronger ability to induce apoptosis compared to unmethylated baicalein, showing that methoxylation enhances bioactivity as well as the physical properties of specialized flavones, while having no side-effects on healthy cells. We investigated the formation of methoxylated flavones and found that two O-methyltransferase (OMT) families are active in the roots of S. baicalensis. The Type II OMTs, SbPFOMT2 and SbPFOMT5, decorate one of two adjacent hydroxyl groups on flavones and are responsible for methylation on the C6, 8 and 3'-hydroxyl positions, to form oroxylin A, tenaxin II and chrysoeriol respectively. The Type I OMTs, SbFOMT3, SbFOMT5 and SbFOMT6 account mainly for C7-methoxylation of flavones, but SbFOMT5 can also methylate baicalein on its C5 and C6-hydroxyl positions. The dimethoxylated flavone, skullcapflavone I (found naturally in roots of S. baicalensis) can be produced in yeast by co-expressing SbPFOMT5 plus SbFOMT6 when the appropriately hydroxylated 4'-deoxyflavone substrates are supplied in the medium. Co-expression of SbPFOMT5 plus SbFOMT5 in yeast produced tenaxin I, also found in Scutellaria roots. This work showed that both type I and type II OMT enzymes are involved in biosynthesis of methoxylated flavones in S. baicalensis.

Tracheostomy timing and clinical outcomes in ventilated COVID-19 patients: a systematic review and meta-analysis.

BACKGROUND: The association of tracheostomy timing and clinical outcomes in ventilated COVID-19 patients remains controversial. We performed a meta-analysis to evaluate the impact of early tracheostomy compared to late tracheostomy on COVID-19 patients' outcomes. METHODS: We searched Medline, Embase, Cochrane, and Scopus database, along with medRxiv, bioRxiv, and Research Square, from December 1, 2019, to August 24, 2021. Early tracheostomy was defined as a tracheostomy conducted 14 days or less after initiation of invasive mechanical ventilation (IMV). Late tracheostomy was any time thereafter. Duration of IMV, duration of ICU stay, and overall mortality were the primary outcomes of the meta-analysis. Pooled odds ratios (OR) or the mean differences (MD) with 95%CIs were calculated using a random-effects model. RESULTS: Fourteen studies with a cumulative 2371 tracheostomized COVID-19 patients were included in this review. Early tracheostomy was associated with significant reductions in duration of IMV (2098 patients; MD - 9.08 days, 95% CI - 10.91 to - 7.26 days, p < 0.01) and duration of ICU stay (1224 patients; MD - 9.41 days, 95% CI - 12.36 to - 6.46 days, p < 0.01). Mortality was reported for 2343 patients and was comparable between groups (OR 1.09, 95% CI 0.79-1.51, p = 0.59). CONCLUSIONS: The results of this meta-analysis suggest that, compared with late tracheostomy, early tracheostomy in COVID-19 patients was associated with shorter duration of IMV and ICU stay without modifying the mortality rate. These findings may have important implications to improve ICU availability during the COVID-19 pandemic. Trial registration The protocol was registered at INPLASY (INPLASY202180088).

The prevalence of psychiatric disorders among students aged 6~ 16 years old in central Hunan, China.

BACKGROUND: Though several epidemiological surveys of psychiatric disorders have been carried out in China, only a few of them are concerned about the prevalence of psychiatric disorders in central Hunan and reveal the distribution of common psychiatric disorders and their comorbidities. METHODS: Achenbach's Child Behavior Checklist (CBCL), the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID), and Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) were administered to a stratified sample of 17,071 participants aged 6 to 16 years old from two cities in the central part of Hunan province. Twelve-month prevalence rates were calculated. RESULTS: Twelve-month prevalence of the population was 9.74%. The most common psychiatric disorders were attention deficit hyperactivity disorder (ADHD) (4.96%), oppositional defiant disorder (ODD) (2.98%) and generalized anxiety disorder (GAD) (1.77%). Of those with a 12-month prevalence diagnosis, 34.6% had one or more comorbid psychiatric disorders. Most notably, ADHD had comorbidity rates of 25.15% with ODD, 18.18% with CD, 6.38% with GAD, and 3.66% with MDD. CONCLUSIONS: Psychiatric disorders are common in Chinese children and adolescents. Being the most prevalent mental disorder, ADHD requires continued focus and support in awareness and education.

SbMYB3 transcription factor promotes root-specific flavone biosynthesis in Scutellaria baicalensis.

Scutellaria baicalensis Georgi produces abundant root-specific flavones (RSFs), which provide various benefits to human health. We have elucidated the complete biosynthetic pathways of baicalein and wogonin. However, the transcriptional regulation of flavone biosynthesis in S. baicalensis remains unclear. We show that the SbMYB3 transcription factor functions as a transcriptional activator involved in the biosynthesis of RSFs in S. baicalensis. Yeast one-hybrid and transcriptional activation assays showed that SbMYB3 binds to the promoter of flavone synthase II-2 (SbFNSII-2) and enhances its transcription. In S. baicalensis hairy roots, RNAi of SbMYB3 reduced the accumulation of baicalin and wogonoside, and SbMYB3 knockout decreased the biosynthesis of baicalein, baicalin, wogonin, and wogonoside, whereas SbMYB3 overexpression enhanced the contents of baicalein, baicalin, wogonin, and wogonoside. Transcript profiling by qRT-PCR demonstrated that SbMYB3 activates SbFNSII-2 expression directly, thus leading to more abundant accumulation of RSFs. This study provides a potential target for metabolic engineering of RSFs.

Gap-free genome assembly and CYP450 gene family analysis reveal the biosynthesis of anthocyanins in Scutellaria baicalensis.

Scutellaria baicalensis Georgi, a member of the Lamiaceae family, is a widely utilized medicinal plant. The flavones extracted from S. baicalensis contribute to numerous health benefits, including anti-inflammatory, antiviral, and anti-tumor activities. However, the incomplete genome assembly hinders biological studies on S. baicalensis. This study presents the first telomere-to-telomere (T2T) gap-free genome assembly of S. baicalensis through the integration of Pacbio HiFi, Nanopore ultra-long and Hi-C technologies. A total of 384.59 Mb of genome size with a contig N50 of 42.44 Mb was obtained, and all sequences were anchored into nine pseudochromosomes without any gap or mismatch. In addition, we analysed the major cyanidin- and delphinidin-based anthocyanins involved in the determination of blue-purple flower using a widely-targeted metabolome approach. Based on the genome-wide identification of Cytochrome P450 (CYP450) gene family, three genes (SbFBH1, 2, and 5) encoding flavonoid 3'-hydroxylases (F3'Hs) and one gene (SbFBH7) encoding flavonoid 3'5'-hydroxylase (F3'5'H) were found to hydroxylate the B-ring of flavonoids. Our studies enrich the genomic information available for the Lamiaceae family and provide a toolkit for discovering CYP450 genes involved in the flavonoid decoration.

The genome of Tripterygium wilfordii and characterization of the celastrol biosynthesis pathway.

Tripterygium wilfordii is a vine from the Celastraceae family that is used in traditional Chinese medicine (TCM). The active ingredient, celastrol, is a friedelane-type pentacyclic triterpenoid with putative roles as an antitumor, immunosuppressive, and anti-obesity agent. Here, we report a reference genome assembly of T. wilfordii with high-quality annotation using a hybrid sequencing strategy. The total genome size obtained is 340.12 Mb, with a contig N50 value of 3.09 Mb. We successfully anchored 91.02% of sequences into 23 pseudochromosomes using high-throughput chromosome conformation capture (Hi-C) technology. The super-scaffold N50 value was 13.03 Mb. We also annotated 31,593 structural genes, with a repeat percentage of 44.31%. These data demonstrate that T. wilfordii diverged from Malpighiales species approximately 102.4 million years ago. By integrating genome, transcriptome and metabolite analyses, as well as in vivo and in vitro enzyme assays of two cytochrome P450 (CYP450) genes, TwCYP712K1 and TwCYP712K2, it is possible to investigate the second biosynthesis step of celastrol and demonstrate that this was derived from a common ancestor. These data provide insights and resources for further investigation of pathways related to celastrol, and valuable information to aid the conservation of resources, as well as understand the evolution of Celastrales.

Association of Attention Deficit/Hyperactivity Disorder With Events Occurring During Pregnancy and Perinatal Period.

Background: The relationship of events occurring during pregnancy and perinatal period with attention deficit/hyperactivity disorder (ADHD) is not clear. Thus, the focus of the current study was to examine the effects of events occurring during pregnancy and perinatal period on ADHD. Methods: A two-phase cross-sectional study was performed across 13 schools in Changsha and Yiyang cities from March to December, 2014. We preliminarily screened all students using CBCL and established the diagnosis using Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) and the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). A total of 3,418 questionnaires were effectively completed in this study. Results: History of threatened abortion (TA) [odds ratio (OR): 1.707 (1.201-2.426)] (vs. No-TA) and neonatal asphyxia (NA) [OR: 2.497(1.225-5.09)] (vs. health) showed a positive association with ADHD. On subgroup analysis, TA [OR: 2.216 (1.458-3.369)] (vs. No-TA) was a risk factor for ADHD without comorbidity; instrumental delivery [OR: 2.748 (1.057-7.142)] (vs. natural birth) and NA [OR: 2.789 (1.222-6.361)] (vs. health) were risk factors for ADHD in the subgroup of ADHD with comorbidity; TA (vs. no-TA) and NA (vs. health) were risk factors for ADHD among male students [ORs: 2.232 (1.439-3.462) and 2.808 (1.115-7.068), respectively], while low birth weight (LBW) (vs. normal birth weight) was a risk factor [OR: 2.054 (1.063-3.967)] for ADHD among female students. Conclusion: TA was a risk factor for ADHD in the absence of comorbid conditions; instrumental delivery and NA were risk factors for ADHD in the subgroup of ADHD with comorbidity; TA and NA were risk factors for ADHD among male students. LBW was a risk factor for ADHD among female students.

Altered topographical organization of grey matter structural network in early-onset schizophrenia.

Schizophrenia is characterized by both disrupted neurodevelopmental processes and abnormal brain connectivity. However, few studies have examined the atypical features of brain network topography associated with schizophrenia during childhood and adolescence. We used graph theory to compare the grey matter structural networks of individuals (aged 10-15 years) with early-onset schizophrenia (EOS) (n = 25) and a typically-developing (TD) comparison group (n = 31). Compared with the TD group, EOS patients showed significantly increased clustering and local efficiency across a range of network densities (0.3 - 0.4). The network of EOS patients also had more modules (6 modules in EOS vs. 3 modules in controls), indicating a more segregated network at the cost of functional integration. Although our results were preliminary and failed to survive corrections for multiple comparisons, EOS patients might be characterized by altered nodal centrality in several higher-order associative regions including the prefrontal cortex, the hippocampus and the cerebellum. The EOS structural network also lacked the typical left-hemispheric-dominant hub distribution compared with the TD group. These findings suggest that brain structural network was not only globally but also regionally altered in EOS patients.

Possible Involvement of Tissue Plasminogen Activator/Brain-Derived Neurotrophic Factor Pathway in Anti-Depressant Effects of Electroacupuncture in Chronic Unpredictable Mild Stress-Induced Depression in Rats.

OBJECTIVE: Using a rat model of chronic unpredictable mild stress (CUMS), to investigate the effects of electroacupuncture (EA) on the tissue plasminogen activator (tPA)/brain-derived neurotrophic factor (BDNF) pathway. METHODS: Sixty male Sprague-Dawley rats were randomly divided into four groups: normal, model, fluoxetine (fluox), or EA. Experimental groups were subjected to 28 d of CUMS modeling. One hour after CUMS, the fluox and EA groups were treated with fluox and a 20 min EA intervention, respectively. Depressive-like behaviors were assessed by open field and sucrose preference tests. After the rats were sacrificed, brains were dissected and processed using hematoxylin and eosin (HE) staining to observe changes in the morphology and quantity of neurons in the hippocampal cornu ammonis 3 area. Western blot and real-time polymerase chain reaction (PCR) demonstrated the effects of EA on the tPA/BDNF pathway-related molecules in the hippocampi and raphe nuclei. RESULTS: Compared to the model group, the number of horizontal and vertical movements and the percentage of sucrose consumption in the EA groups were significantly increased (P < 0.01). Compared to the model group, HE staining showed that the hippocampal neurons in the EA and fluox groups were arranged neatly, with rich layers and complete cell structures. The Western blot and real-time PCR showed that the levels of tPA, BDNF, tropomyosin receptor kinase B, and BDNF micro RNA (mRNA) in the hippocampi of the EA group were higher than in the model group (P < 0.01, P < 0.01, P < 0.05, P < 0.01, respectively). The content of p75NTR, proBDNF, and tPA mRNA in the hippocampi of the EA group displayed no significant differences compared to the model group. The tPA mRNA content in the raphe nuclei of the EA group was higher than in the model group (P < 0.01), and the BDNF content in the raphe nuclei was lower than in the model group (P < 0.05). There were no significant differences in tPA and BDNF mRNA between the EA and model groups. CONCLUSION: EA may reverse depressive-like behaviors in CUMS, which may be related to the tPA/BDNF pathway in the hippocampus.

Differential profiles of response inhibition deficit between male children with autism spectrum disorders and schizophrenia.

Autism spectrum disorders (ASD) and schizophrenia (SZ) are both associated with response inhibition impairment. However, the relative pattern of deficits in these two disorders remains unclear. Twenty-three male children with ASD, 23 male children with SZ, and 32 typically developing male controls were recruited to complete a set of tasks measuring response inhibition in the visual, auditory, and verbal domains. We found that visual, auditory, and verbal response inhibitions were impaired in both children with ASD and children with SZ. Compared with typically developing controls, children with ASD made more commission errors whereas children with SZ responded much slower in the visual response inhibition task. Both clinical groups showed comparable impairment in verbal response inhibition, but children with SZ were more impaired in auditory response inhibition than children with ASD. These different patterns of response inhibition deficit between male children with ASD and SZ may help to differentiate between these two disorders and may be potential targets for intervention. Autism Res 2020, 13: 591-602. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: In this study, we found that male children with autism spectrum disorder (ASD) made more commission errors whereas male children with schizophrenia (SZ) responded much slower in the visual response inhibition task. Both clinical groups exhibited comparable impairments in verbal response inhibition, but male children with SZ were more impaired in auditory response inhibition than male children with ASD. Our findings provide potential targets for intervention.

Altered empathy-related resting-state functional connectivity in adolescents with early-onset schizophrenia and autism spectrum disorders.

Empathy refers to the ability to understand other people's feelings and reacting emotionally to others. Impaired empathy has been reported in both individuals with schizophrenia and autism spectrum disorders (ASD). Despite overlaps, few studies have directly examined the neural mechanisms of impaired empathy in these two clinical groups. We used resting-state fMRI to investigate the neural correlates of empathic functioning in adolescents with ASD (N = 11), early-onset schizophrenia (EOS) (N = 20), and typically developing (TD) controls (N = 26). Their parents completed the Griffith Empathy Measure (GEM) to assess the adolescents' empathic capacity. We found that EOS and ASD participants both exhibited impaired empathy as measured by the GEM, especially in cognitive empathy (post-hoc ps < 0.05). Regions-of-interest-based functional connectivity revealed decreased connectivity between the salience network (SN) (i.e., the anterior insula and the anterior cingulate cortex) and core regions of the mentalizing network (e.g., the temporal-parietal junction and the precuneus), and among the SN and the bilateral superior temporal gyri (STG) and the left cerebellum in EOS participants. Subsequent comparisons revealed reduced grey matter volume in the STG bilaterally in both clinical groups. Increased resting-state functional connectivity within the social brain network was correlated with higher parent-reported scores of empathic capacity in TD adolescents, but such a brain-phenotype relationship was absent in the two clinical groups. These findings indicate that structural alterations and disturbed resting-state functional connectivity in the core empathy network may be the neural correlates of social cognitive deficits in individuals with EOS and ASD.

Effect of Electroacupuncture on Reuptake of Serotonin via miRNA-16 Expression in a Rat Model of Depression.

The current study aimed to investigate the effects and mechanisms of electroacupuncture (EA) treatment applied to Bai hui (GV20) and Yin tang (GV29) acupoints (1 mA, 2 Hz, continuous wave, 20 minutes) for 28 days in a rat model of chronic unpredictable mild stress (CUMS) on reuptake of serotonin (5-hydroxytryptamine (5-HT)) and miRNA-16 levels in the hippocampus and serum. Rats were housed in individual cages, and CUMS was used to establish a rat model of depression. After EA treatment for 4 weeks, behavioral changes and indices including 5-HT transporter (SERT), 5-HT, and miRNA-16 levels in the hippocampus and serum were examined. The EA treatment significantly improved base levels of sucrose preference and exploratory behavior and significantly decreased SERT protein and mRNA expression in the hippocampus of depressed rats. Significantly increased 5-HT levels were observed, and miRNA-16 levels were significantly decreased in the hippocampus and serum of depressed rats. In conclusion, the antidepressant effects of EA treatment may be affected via inhibition of 5-HT reuptake, upregulation of 5-HT levels, and inhibition of miRNA-16 expression in the hippocampus and serum.

The Reference Genome Sequence of Scutellaria baicalensis Provides Insights into the Evolution of Wogonin Biosynthesis.

Scutellaria baicalensis Georgi is important in Chinese traditional medicine where preparations of dried roots, "Huang Qin," are used for liver and lung complaints and as complementary cancer treatments. We report a high-quality reference genome sequence for S. baicalensis where 93% of the 408.14-Mb genome has been assembled into nine pseudochromosomes with a super-N50 of 33.2 Mb. Comparison of this sequence with those of closely related species in the order Lamiales, Sesamum indicum and Salvia splendens, revealed that a specialized metabolic pathway for the synthesis of 4'-deoxyflavone bioactives evolved in the genus Scutellaria. We found that the gene encoding a specific cinnamate coenzyme A ligase likely obtained its new function following recent mutations, and that four genes encoding enzymes in the 4'-deoxyflavone pathway are present as tandem repeats in the genome of S. baicalensis. Further analyses revealed that gene duplications, segmental duplication, gene amplification, and point mutations coupled to gene neo- and subfunctionalizations were involved in the evolution of 4'-deoxyflavone synthesis in the genus Scutellaria. Our study not only provides significant insight into the evolution of specific flavone biosynthetic pathways in the mint family, Lamiaceae, but also will facilitate the development of tools for enhancing bioactive productivity by metabolic engineering in microbes or by molecular breeding in plants. The reference genome of S. baicalensis is also useful for improving the genome assemblies for other members of the mint family and offers an important foundation for decoding the synthetic pathways of bioactive compounds in medicinal plants.

Diverse responses of tanshinone biosynthesis to biotic and abiotic elicitors in hairy root cultures of Salvia miltiorrhiza and Salvia castanea Diels f. tomentosa.

Salvia miltiorrhiza (S. miltiorrhiza) and Salvia castanea Diels f. tomentosa (S. castanea) are both used for treatment of cardiovascular diseases. They have the same bioactive compound tanshinones, but whose contents are hugely different. This study illustrated diverse responses of tanshinone biosynthesis to yeast extract (YE) and Ag+ in hairy roots of the two species. YE enhanced both the growth and tanshinone biosynthesis of two hairy roots, and contributed more to tanshinone accumulation in S. castanea than that in S. miltiorrhiza. Genes encoding 1-deoxy-d-xylulose 5-phosphate synthase (DXS2), geranylgeranyl diphosphatesynthase (GGPPS1), copalyl diphosphate synthase (CPS1), and two cytochromes P450 (CYP76AH1 and CYP76AH3) were also more responsive to YE in S. castanea than those in S. miltiorrhiza. Accumulations of dihydrotanshinone I and tanshinone I, and most biosynthetic genes in S. miltiorrhiza were more responsive to Ag+ than those in S. castanea. Accumulations of dihydrotanshinone I and cryptotanshinone were more responsive to YE, while tanshinone IIA accumulation was more responsive to Ag+ in S. miltiorrhiza. However, accumulations of other four tanshinones and related genes in S. castanea were more responsive to YE than Ag+. This study provides foundations for studying diverse specialized metabolism between the related species.

Associations between suicidal behavior and childhood abuse and neglect: A meta-analysis.

BACKGROUND: Relationships of some types of childhood maltreatment and suicidal behavior remain controversial and inconclusive. METHODS: Medline, Embase, PsycINFO and Cochrane library were searched for eligible studies, and the results were synthesized in meta-analyses. RESULTS: childhood maltreatment was associated positively with suicidal behavior in the total population and maltreatment subgroups. Emotional abuse had the strongest effect (OR =2.33, SMD =0.660, P<0.001). Subgroup analyses showed that the effects of childhood abuse (OR =1.55, SMD =0.523) and neglect (OR =1.25, SMD =0.31) were significant. According to the analysis of dichotomous outcomes, childhood maltreatment was associated positively with suicidal behavior in men and women (women: OR =4.84, P<0.001; men: OR =1.03, P<0.001). Among populations, childhood maltreatment had the strongest effect on suicidal behavior in the general population (OR =3.78, P<0.001). However, the analysis of continuous outcomes showed that the effect was strongest in patients with chronic schizophrenia (SMD =0.89, P<0.001). In addition, childhood maltreatment was associated positively with suicide attempt (OR =1.11, SMD =0.48, P<0.001), but not with suicidal ideation. LIMITATIONS: Some subgroup samples were not sufficiently large. CONCLUSIONS: Childhood maltreatment increases the risk of suicidal behavior. Emotional abuse had the strongest effect among the five types of maltreatment. The risk of suicidal behavior is higher in the general population, women, and individuals with chronic schizophrenia who have histories of childhood maltreatment.