Hydrogen selenide (H₂Se), selenium's central metabolic intermediate, is emerging as the candidate fourth gasotransmitter. This membrane permeable gas mediates rapid redox signaling and serves as the obligate precursor for selenoprotein biosynthesis, essential for neuronal redox homeostasis and survival. Engineered selenium donors, designed for controlled H₂Se release or targeted selenoprotein support, exert neuroprotection by attenuating oxidative stress, reducing neuroinflammation, inhibiting ferroptosis, and preserving synaptic integrity across Alzheimer's disease, Parkinson's disease, epilepsy, traumatic brain injury, and stroke. Advances in stimuli-responsive donor chemistry and nanocarrier platforms enable spatiotemporally precise delivery, mitigating selenium's narrow therapeutic window. However, H₂Se is cytoprotective at physiological concentrations but toxic at supraphysiological levels and its clinical translation demands rigorous pharmacokinetic optimization, context-aware targeting, and dynamic biomarkers. This review bridges gasotransmitter biology with translational pharmacology, delineating H₂Se metabolism, donor design principles, and disease-specific applications. By integrating mechanistic insights with precision delivery strategies, we provide a roadmap for harnessing H₂Se and selenium donors as next-generation, clinically viable neurotherapeutics.

Phototherapies play an important role in the treatment of hyperpigmentation. However, the effects of different phototherapies on skin pigmentation have not been comprehensively evaluated to date. We analyzed the efficacy and patient satisfaction of 14 distinct phototherapies for melasma using a network meta-analysis of 22 randomized controlled trials. Cluster analysis revealed that fractional CO2 laser combines the advantages of high efficacy and patient satisfaction. We therefore evaluated the effect of fractional CO2 laser on forearm skin pigmentation in volunteers. Reflectance confocal microscopy showed that fractional CO2 laser effectively inhibited pigmentation, and the inhibitory effect was more pronounced as the scanning spacing decreased. Gene Set Enrichment Analysis revealed that fractional CO2 laser inhibited melanogenesis in photoaging skin. Transcriptome sequencing of skin samples from guinea pigs treated with fractional CO2 laser showed that the key regulators of melanogenesis (microphthalmia-associated transcription factor, tyrosinase and dopachrome tautomerase) were significantly downregulated on the seventh day after treatment with fractional CO2 laser. Gene Set Enrichment Analysis further revealed that the cyclic adenosine monophosphate signaling pathway was inhibited on the third day after treatment, whereas the phosphatidylinositol 3-kinase-protein kinase B pathway was activated on the fifth and seventh days. Fractional CO2 laser effectively reversed hyperpigmentation and may even inhibit skin pigmentation by exfoliating the superficial stratum corneum, destroying melanin granules, and regulating signaling pathways related to melanogenesis.

Vascular adhesion protein-1 (VAP-1), a multifunctional inflammatory mediator, has been implicated in cardiovascular pathology. Current evidence regarding its prognostic relevance in heart failure (HF) is incomplete. This investigation was designed to evaluate circulating VAP-1 as a biomarker for its association with HF progression susceptibility and its clinical prognostic value for adverse cardiovascular events. This retrospective observational cohort study included 356 individuals receiving treatment at Soochow University Hospital from May 2020 to September 2022, among whom 165 were diagnosed with heart failure. During the baseline evaluation, VAP-1 concentrations in blood serum were measured through ELISA testing. Major adverse cardiovascular events (MACE) were designated the principal study endpoints, with data collected from electronic health records and telephone follow-ups. Analytical methods incorporated multiple regression analysis, nonlinear modeling approaches, and Kaplan-Meier survival probability assessments. Additional analyses examined the association between heart failure progression and VAP-1 levels through multiple regression modeling, ROC curve assessment, and AUC calculations to establish VAP-1’s diagnostic potential for heart failure identification. When accounting for potential confounding factors, higher concentrations of VAP-1 showed a correlation with MACE in patients with HF (Q2 versus Q1: hazard ratios [HR] = 1.7, 95

Sleep problems (SPs) frequently occur in patients with schizophrenia patients experiencing cognitive impairments. Thus, this study aimed to investigate the association between SPs and first-episode drug-naive schizophrenia (FDS), and to examine the impact of SPs on their cognitive function. In this cross-sectional study, we enrolled 291 FDS patients (non-SPs/SPs = 197/94) and 685 subjects from the general population (GP, non-SPs/SPs = 577/108) according to the DSM-IV and Pittsburgh Sleep Quality Index (PSQI) grouping. Cognition and sleep quality of subjects were assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the PSQI, respectively. Compared to GP subjects, patients with FDS had a significantly higher prevalence of SPs (15.77

Dopamine β-hydroxylase (DBH) is an enzyme that catalyzes the conversion of dopamine (DA) to norepinephrine (NE). The dysregulation of these neurotransmitters is implicated in the etiology and cognitive impairments of schizophrenia. However, the relationship between DBH and cognitive impairments of schizophrenia, independent of confounding effects of medication and chronic illness, remains unclear. Thus, this case-control study aimed to investigate plasma DBH levels, cognitive performance, and their association in patients with first-episode drug-naïve schizophrenia (FDS). A total of 56 FDS patients and 56 age- and gender-matched healthy controls (HCs) were enrolled. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and plasma DBH levels were measured via sandwich enzyme-linked immunosorbent assays (ELISAs). After adjusting for covariates, plasma Log10DBH levels were significantly lower in FDS patients compared to HCs (F = 9.17, p = 0.003). Moreover, plasma Log10DBH levels showed a positive correlation with immediate memory score in patients (r = 0.27, p = 0.04). Linear regression further confirmed a significant association between Log10DBH levels and immediate memory score in patients (β = 50.18, t = 2.82, p = 0.008). Additionally, FDS patients scored significantly lower than HCs on the RBANS total score and all subdomains, except visuospatial/constructional score (all, p < 0.001). These findings suggest that reduced plasma DBH levels might be strongly associated with schizophrenia and might contribute to immediate memory impairment in FDS patients.

The Disrupted-in-Schizophrenia 1 (DISC1) gene and negative symptoms in schizophrenia are both implicated in neurodevelopmental abnormalities. However, their relationship remains unclear. Thus, this study aimed to compare plasma DISC1 levels and negative symptoms severity between first-episode schizophrenia (FDS) patients and healthy controls (HCs), and examine their association. Sixty-six FDS patients meeting the DSM-IV diagnostic criteria, and 66 age- and sex-matched HCs were enrolled in this case-control study. Plasma DISC1 protein levels were measured by enzyme-linked immunosorbent assay (ELISA). Negative symptoms were assessed using the Clinical Assessment Interview for Negative Symptoms (CAINS). Compared to HCs, patients showed significantly higher CAINS scores for Motivation and Pleasure (MAP, F (1,130) = 5.24, p = 0.02), Expression (EXP, F (1, 130) = 33.89, p < 0.001), and total symptoms (F (1, 130) = 15.14, p < 0.001), alongside lower plasma DISC1 levels (F (1, 130) = 4.622, p = 0.034) after adjusting for convariates. Plasma DISC1 levels were negatively correlated with EXP score in patients (r = -0.30, p = 0.02), but not shown in HCs (r = -0.14, p = 0.26). Multiple linear regression identified lower plasma DISC1 levels as an independent predictor of higher EXP score in patients (β = -3.46, t = 2.23, p = 0.03), but not in HCs (β = 0.15, t = 0.29, p = 0.77). These findings suggest that reduced plasma DISC1 levels in FDS patients are significantly associated with greater expressive deficits, further supporting a potential role for DISC1 in the neurobiology of negative symptoms of schizophrenia.

IntroductionMental disorders pose a major public health challenge in China, with marked urban–rural disparities in resources and outcomes. However, long-term mortality trends, their influencing factors, and future projections across urban and rural areas remain underexplored. This study aimed to analyze these mortality trends, identify relevant factors, and project mortality to 2030 using national data from 2009 to 2021.MethodsData were extracted from the China Health Statistical Yearbook, the China Health and Family Planning Statistical Yearbook, the China Health Statistics Yearbook and the China Statistical Yearbook covering the years 2009–2021. Joinpoint regression was used to analyze temporal trends. A two-way fixed effects panel regression model examined associated factors, with additional sensitivity analyses including Oster’s boundary analysis and the exclusion of dementia-related deaths. GM (1,1), ARIMA, and Lasso models were compared for forecasting, and optimistic and pessimistic scenarios were constructed to reflect uncertainty in projections to 2030.ResultsFrom 2009 to 2021, urban crude mortality rates (CMR) remained stable, whereas rural CMR increased significantly (AAPC = 1.21%, p = 0.02), with a sharp rise during 2019–2021 (APC = 13.23%, p < 0.01). Age-standardized mortality rates (ASMR) declined only in rural areas (AAPC = −3.88%, p < 0.01). Males had higher ASMR than females, and the oldest age groups bore the heaviest burden. The 20–25 years age group showed an increase from 2018 to 2021, although this trend did not reach statistical significance. Aging rate was the strongest factor associated with ASMR (β = 0.650, p < 0.01), and this association persisted after controlling for mental disorder prevalence, suicide-specific mortality, and lifestyle factors. An Oster boundary analysis indicated that unmeasured confounders would need to be substantially stronger than observed covariates to eliminate this association. Scenario projections suggested continued divergence between urban and rural trends, with a wide range between optimistic and pessimistic scenarios.ConclusionThis study reveals significant urban–rural disparities in mental disorder mortality, with rural areas experiencing a marked recent increase. Males, the oldest old, and young adults are particularly vulnerable. Population aging showed the strongest association with mortality, and this association persisted after controlling for additional confounders. Scenario projections indicated continued divergence between urban and rural trends. These findings underscore the need for life-course prevention strategies and differentiated resource allocation between urban and rural areas.

BACKGROUND:Although remnant cholesterol (RC) and residual inflammation are established risk factors for stroke, their joint prognostic value for ischemic stroke remains unclear. OBJECTIVES:The authors aimed to evaluate the combined effects of RC and high-sensitivity C-reactive protein (hs-CRP), as well as a novel index-the remnant cholesterol-inflammation index (RCII)-for long-term clinical outcomes after ischemic stroke. METHODS:We measured RC and hs-CRP levels in 3,008 participants from the China Antihypertensive Trial in Acute Ischemic Stroke. Participants were categorized into 4 groups according to dichotomized RC (≥median, 28.62 mg/dL) and hs-CRP (≥threshold, 2.00 mg/L). RCII was calculated as (RC [mg/dL]×hs-CRP [mg/L])/10 to quantify their joint effects. The study outcomes included all-cause mortality, cardiovascular events, and unfavorable functional outcome at 24 months. RESULTS:Compared with patients with no residual risk, HRs or ORs for those with residual cholesterol and inflammation risk were 2.33 (95% CI: 1.57-3.44) for all-cause mortality, 2.28 (95% CI: 1.49-3.49) for stroke-specific mortality, and 1.91 (95% CI: 1.44-2.53) for unfavorable functional outcome. In addition, the highest quartile of RCII exhibited increased risks of all-cause mortality, cardiovascular events, and unfavorable functional outcome. Both combined RC/hs-CRP and RCII offered substantial risk discrimination and reclassification improvement for study outcomes beyond traditional risk factors, as evidenced by an increase in C-statistics, net reclassification index, and integrated discrimination improvement. CONCLUSIONS:Elevated RC and hs-CRP were synergistically associated with increased risks of long-term all-cause mortality and unfavorable functional outcome, and RCII manifested dose-dependent associations with adverse clinical outcomes and superior predictive capacity.

ObjectiveTo investigate the effect of electroacupuncture （EA） intervention on neuroinflammatory response in rats with ischemic stroke by modulating astrocyte activation， based on the Janus kinase 2/Signal transducer and activator of transcription 3 （JAK2/STAT3） signaling pathway.MethodsForty-five male SD rats were randomly selected as the sham-operation group. The ischemic stroke model was established by occlusion of the middle cerebral artery by referring to the modified Zea Longa’s suture-occlusion method. Ninety successfully modeled rats were randomly assigned to model group and EA group which were further divided into subgroups based on the intervention time points （1， 3 and 7 d）. For rats of the EA group， EA （2 Hz/10 Hz， 1.5 mA） was applied to “Baihui” （GV20） and “Dazhui” （GV14） for 20min （starting 2 hours post-modeling）， once daily for 1， 3 or 7 days. The modified Neurological Severity Score （mNSS） was used to assess neurological deficits， and 2，3，5-Triphenyltetrazolium chloride （TTC） staining employed to measure the cerebral infarction volume. Hematoxylin and Eosin （H&E） staining was used to observe histopathological changes in the ischemic cortex. The protein expression levels of glial fibrillary acidic protein （GFAP）， JAK2， STAT3， phosphorylated-JAK2 （p-JAK2）， p-STAT3， complement component 3 （C3）， and S100 calcium-binding protein A10 （S100A10） in the ischemic brain tissue were detected using western blot. The contents of tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， and IL-6 in the ischemic brain tissue were determined using enzyme-linked immunosorbent assay （ELISA）. The expression levels of GFAP， JAK2， and STAT3 mRNAs in the ischemic brain tissue were detected by using reverse transcription quantitative real-time polymerase chain reaction （RT-qPCR）. The double-staining immunofluorescence intensity of GFAP and STAT3 of the ischemic brain tissue was determined using immunofluorescence staining.ResultsCompared with the sham operation group， the model group showed a significant increase in cerebral infarction volume （P<0.01）， and mNSS score， protein expression levels of GFAP， JAK2， STAT3， p-JAK2， p-STAT3， and C3， contents of TNF-α， IL-1β， and IL-6 and mRNA expression levels of GFAP， JAK2 and STAT3 at the 1st， 3rd and 7th day （P<0.01）， and the immunofluorescence intensity of GFAP and STAT3 co-staining （P<0.01）， and a significant reduction in the expression of S100A10 at the 1st， 3rd and 7th day （P<0.01）. The ischemic cortex exhibited severe neuronal structural damage， characterized by obvious nuclear pyknosis， cellular swelling and rupture， disordered axonal arrangement and vacuolar changes. After EA intervention， all the increased and decreased levels of the indexes mentioned above were reversed （P<0.01）， including obvious improvement of morphology of neurons in the ischemic cortex， characterized by more regular cell arrangement and clearer cellular nucleus.ConclusionEA can improve neurological deficits and reduce cerebral ischemic volume in ischemic stroke rats， which may be related to its functions in inhibiting the activation of the JAK2/STAT3 signaling pathway， mitigating neuroinflammation response mediated by excessive astrocyte activation， and the effects are time-dependent.

DDB1- and CUL4-associated factor 7 (DCAF7) has recently been identified as a critical regulator of tumorigenesis and a potential modulator of ferroptosis. However, the precise function of DCAF7 in regulating the progression of hepatocellular carcinoma (HCC) ferroptosis remains elusive. In this study, we demonstrate that DCAF7 and the deubiquitinase USP2 are highly expressed in HCC. Genetic ablation of DCAF7 or pharmacological inhibition of USP2 sensitizes HCC to ferroptosis and inhibits HCC progression both in vitro and in vivo. Mechanistically, DCAF7 recruits USP2 to inhibit clockophagy (the selective autophagic degradation of core clock protein BMAL1 mediated through p62/SQSTM1) by reducing BMAL1 K63-linked polyubiquitination. Targeting either DCAF7 or USP2 triggers clockophagy-induced ferroptosis through the HIF1α-SLC7A11 axis in HCC cells. Collectively, our study establishes DCAF7 and USP2 as novel suppressors of clockophagy-induced ferroptosis and reveals the potential therapeutic targets for HCC treatment.

Genome-wide association studies (GWASs) have reported multiple risk loci for schizophrenia (SCZ). However, the majority of the associations were from populations of European ancestry. Here we conducted a large-scale GWAS in Eastern Asian populations (29,519 cases and 44,392 controls) and identified ten Eastern Asian-specific risk loci, two of which have not been previously reported. A further cross-ancestry GWAS meta-analysis (96,806 cases and 492,818 controls) including populations from diverse ancestries identified 61 previously unreported risk loci. Systematic variant-level analysis, including fine mapping, functional genomics and expression quantitative trait loci, prioritized potential causal variants. Gene-level analyses, including transcriptome-wide association study, proteome-wide association study and Mendelian randomization, nominated the potential causal genes. By integrating evidence from layers of different analyses, we prioritized the most plausible causal genes for SCZ, such as ACE, CNNM2, SNAP91, ABCB9 and GATAD2A. Finally, drug repurposing showed that ACE, CA14, MAPK3 and MAPT are potential therapeutic targets for SCZ. Our study not only showed the power of cross-ancestry GWAS in deciphering the genetic aetiology of SCZ, but also uncovered new genetic risk loci, potential causal variants and genes and therapeutic targets for SCZ. Luo et al. identify schizophrenia risk loci in East Asians and uncover potential causal genes and therapeutic targets through cross-ancestry GWAS, fine mapping and functional genomics, offering insights into the genetic basis of schizophrenia.

Background Cognitive impairment in individuals with Major Depressive Disorder (MDD) may have an association with the levels of Vascular Endothelial Growth Factor (VEGF). Methods In this case-control study, we recruited 60 patients diagnosed with depression (33 males and 27 females, with a mean age of 41.17 years) from the outpatient or inpatient unit of Suzhou Guangji Hospital. Additionally, 60 healthy controls (28 males and 32 females, with a mean age of 37.20 years) were recruited from the local community in the Suzhou Xiangcheng District. Subsequently, we measured serum VEGF levels using the VEGF ELISA Kit and assessed cognitive performance using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Results This study has received approval from the Institutional Review Board of Suzhou Guangji Hospital, adhering to ethical guidelines and involving the handling of clinical biosamples. Following adjustment for variables such as gender, age, BMI, and other potential confounding factors, it was observed that the serum VEGF levels in individuals with depression were significantly reduced compared to those in the corresponding healthy control group (F = 4.55, p = 0.04). Within the depressive patient cohort, serum VEGF levels negatively correlated with attention scores (r=-0.32, p = 0.01) and RBANS total scores (r=-0.28, p = 0.03). Conversely, no such correlations were observed in the healthy control group (attention scores: r = 0.19, p = 0.15; RBANS total scores: r=-0.03, p = 0.82). Conclusions Our research findings suggest a potential association between serum VEGF levels and the physiological pathology of MDD. This association may have a corresponding impact on the cognitive function of individuals facing MDD.

Background Schizophrenia (SCZ) is a complex and heterogeneous disorder with unclear underlying mechanisms. Identifying key gene diseases and constructing biological regulatory networks were beneficial in expanding our understanding of the pathogenesis of SCZ. Methods We conducted whole transcriptome sequencing of induced pluripotent stem cells (iPSCs) derived from 5 SCZ patients and 5 healthy controls to analyze differences in mRNA and non-coding RNA expression profiles. Differentially expressed mRNAs (DE mRNAs) were explored for their functions and pathways, and lncRNA-miRNA-mRNA regulatory networks were constructed to understand post-transcriptional regulation mechanisms. Additionally, correlation analyses between competitive endogenous RNAs (ceRNAs), hub genes, and clinical phenotypes of SCZ patients (positive/negative and cognitive symptoms) were performed. Results We identified 139 DE mRNAs, 154 lncRNAs, and 19 miRNAs. Significant enrichment of pathways related to apoptosis, inflammatory response, hypoxia, KRAS signaling, and IL6_JAK_STAT3 signaling were observed. Ten hub genes, CCK, CCNA1, CDH5, GATA2, GRPR, NPY, PRKG2, TLE6, ZEB1and ZEB2, were identified, of which ZEB1 and GATA2 were positively correlated with positive symptoms of SCZ, while CDH5 and GRPR were associated with memory. The ceRNA regulatory network (TPM1-AS/ADPGK-AS1/MIRLET7BHG-hsa-mir-3180/3180-3p-LRRC15/TUBA8 and MIRLET7BHG- hsa-mir-3187-3p- CCDC92/ TDRD6/ TMEM26/ ATP1A2) was established, which was also significantly associated with positive, negative and cognitive symptoms of SCZ. Conclusions This study identified potential hub genes, pathways, and lncRNA-miRNA-mRNA regulatory networks in iPSCs that provide new insights into the molecular mechanisms of SCZ. The identified hub genes and ceRNA showed significant correlations with various clinical phenotypes of SCZ, offering potential biomarkers and therapeutic targets.

STUDY OBJECTIVES:Sleep disorders and psychiatric disorders frequently coexist and interact, yet the shared genetic basis linking these two domains remains poorly understood. METHODS:We investigated the genetic correlation and overlap between seven sleep/circadian traits and three psychiatric disorders at the level of genome-wide association studies (GWAS), utilizing LDSC, HDL, and GPA. To identify potential polygenic single nucleotide variations (SNVs) within each trait pair, we used PLACO, while gene-level analyses were performed using MAGMA and POPS. Furthermore, the functions and biological mechanisms, enriched phenotypes, tissues, cellular features, and pathways were thoroughly investigated using FUMA, deTS, and enrichment analyses at the biological pathway level. RESULTS:Our study revealed extensive genetic associations and overlaps in all 21 trait pairs. We identified 18 494 SNVs and 543 independent genomic risk loci, with 113 confirmed as causative through colocalization analysis. These loci collectively spanned 196 unique chromosomal regions. We pinpointed 43 distinct pleiotropic genes exhibiting significant enrichment in behavioral/physiological phenotypes, nervous system phenotypes, and brain tissue. Aberrations in synaptic structure and function, neurogenesis and development, as well as immune responses, particularly involving the MAPK pathway, emerged as potential underpinnings of the biology of sleep/circadian traits and psychiatric disorders. CONCLUSIONS:We identified shared loci and specific sets of genes between sleep/circadian traits and psychiatric disorders, shedding light on the genetic etiology. These discoveries hold promise as potential targets for novel drug interventions, providing valuable insights for the development of therapeutic strategies for these disorders.

Bipolar disorder (BD) and major depressive disorder (MDD) are the most prevalent mood disorders and cause considerable burden worldwide. Compelling evidence suggests a pronounced overlap between these two disorders in clinical symptoms, treatment strategies, and genetic etiology. Here we leverage a BD GWAS (1822 cases and 4650 controls) and a MDD GWAS (5303 cases and 5337 controls), followed by independent replications, to investigate their shared genetic basis among Han Chinese. We have herein identified a lead SNP rs126277 at the 1q32.2 locus, which also exhibited nominal associations with mood disorders and several relevant sub-clinical phenotypes (e.g., mania) in European populations. Bulk tissue and single-cell eQTL analyses suggest that the risk G-allele of rs126277 predicted lower SYT14 mRNA expression in human brains. We generated mice lacking Syt14 (Syt14-/-) and mice with insufficient expression of Syt14 in the hippocampus (Syt14-KD), and found that depletion of Syt14 resulted in mania-like behaviors including hyperactivity and anti-depressive behaviors, resembling aspects of mood disorders. We also confirmed that deficiency of this gene in the hippocampus was sufficient to induce hyperactivity in mice. RNA-sequencing analyses of the hippocampus of Syt14-/- mice revealed significant upregulation of Per1 as well as downregulation of Slc7a11 and Ptprb. Ultrastructural analyses showed significant alteration of the number of vesicles within 50 nm to the active zone and the width of synaptic cleft in the ventral hippocampus of Syt14-/- mice compared with the control mice. Overall, we have identified a novel mood disorder risk gene SYT14, and confirmed its impact on mania-like behaviors. While the current study identifies an essential mood disorder risk gene, further investigations elucidating the detailed mechanisms by which SYT14 contributes to the pathogenesis of the illnesses are needed.

Journal Article Corrected proof Comment on: Incidence and risk factors of mental illnesses among patients with systemic autoimmune rheumatic diseases: an 18-year population-based study Get access Hui Li Hui Li Department of Rheumatology and Immunology, The Second Affiliated Hospital of Shenzhen University, The People's Hospital of Baoan Shenzhen, Shenzhen, Guangdong, China Correspondence to: Hui Li, Department of Rheumatology and Immunology, The Second Affiliated Hospital of Shenzhen University, The People's Hospital of Baoan Shenzhen, 118 Longjing 2nd Road, Shenzhen, Guangdong 518100, China. E-mail: chipperli@163.com https://orcid.org/0000-0002-4837-7515 Search for other works by this author on: Oxford Academic PubMed Google Scholar Rheumatology, keae324, https://doi.org/10.1093/rheumatology/keae324 Published: 06 June 2024 Article history Accepted: 08 May 2024 Published: 06 June 2024 Corrected and typeset: 20 June 2024

BACKGROUND:Bipolar disorder (BD) is a severe mental disorder with high, approximately 70% heritability. Here, to identify novel risk genes of BD, we conducted whole-exome sequencing and pathway enrichment analyses across one multi-affected, southern Chinese Han pedigree. METHODS:Whole-exome sequencing (WES) was performed on five patients with BD and three unaffected members in one multi-affected pedigree. The analyses focused on variants that (i) were shared by affected members but were not present in the unaffected members, and (ii) were rare and damaging. Bioinformatic analyses, including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses, were used for functional annotation and pathway analysis. RESULTS:We identified a rare and potentially damaging single nucleotide variations (SNVs) in NTN1, MYH10, and RILP that were shared by affected family members but were absent in unaffected members. Their functions were predicted to be associated with actin binding, substrate-dependent cell migration, actin cytoskeleton, and nucleotide excision repair. CONCLUSION:Our findings suggest that NTN1, MYH10, and RILP may represent novel candidate risk genes for BD, although further validation in larger cohorts is needed.

Dimethylguanidino valeric acid (DMGV) is a group of endogenous metabolites derived from arginine-containing proteins and is associated with several metabolic disorders. Latest studies have identified the stereoisomers of DMGV: asymmetric dimethylguanidino valeric acid (ADGV) and symmetric dimethylguanidino valeric acid (SDGV), which are derived from asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), respectively. However, the lack of commercial standards has hampered research into the molecular mechanisms of DMGV and its potential clinical application as biomarkers. Reported chemical synthesis methods have low yields and require specialized chemical synthesis skills and apparatus. Therefore, we aimed to develop a practical and efficient method to synthesize DMGV stereoisomers and determine their precise concentration profile in healthy subjects. A novel biocatalytic method for synthesizing DMGV using alanine-glyoxylate aminotransferase 2 (AGXT2) was developed. A metabolite panel including eight DMGV-related metabolites was also established for human plasma samples using HPLC-MS/MS, and its performance was comprehensively evaluated, especially in terms of quantitative sensitivity, precision and accuracy. Compared with the reported chemical synthesis methods, the biocatalytic approach demonstrates superior yield, conversion rate, and product purity, while being easy to implement in biological laboratories. The established DMGV quantification method has been well validated and successfully applied to measure the contents of these metabolites, especially the concentration profile of ADGV in the plasma of healthy individuals. To sum up, this study provides an efficient and practical biocatalytic approach for DMGV synthesis and determines the levels of DMGV in healthy subjects. These findings will undoubtedly promote future mechanistic studies of DMGV and its future clinical applications.