ETHNOPHARMACOLOGICAL RELEVANCE:Traditional Chinese medicine (TCM) has long employed herbal formulas for conditions manifesting as menstrual irregularities, galactorrhea, and infertility-symptom constellations overlapping with hyperprolactinemia (HPRL). Classical formulas such as Peony-Glycyrrhiza Decoction, documented for "liver constraint" patterns associated with amenorrhea, provide an ethnopharmacological rationale for investigating their relevance to antipsychotic-induced HPRL through modern mechanistic studies and network pharmacology. AIM OF THE STUDY:This review critically evaluates the scientific evidence supporting TCM interventions for antipsychotic-induced HPRL, elucidating multi-target mechanisms via network pharmacology and experimental data, thereby linking traditional uses with pharmacological validation. METHODS:This narrative review synthesizes literature from PubMed, CNKI, TCMSP, and HERB databases (January 2000-December 2024) on TCM interventions for antipsychotic-induced HPRL. Network pharmacology analyses, molecular docking studies, experimental validations, and clinical studies of individual herbs and complex formulas were critically evaluated. RESULTS:TCM ameliorates HPRL through multi-dimensional mechanisms: dopaminergic modulation via DRD2 upregulation and MAO inhibition; epigenetic regulation through DNMT inhibition and DRD2 promoter demethylation; restoration of the gut-brain-pituitary axis via microbiota modulation and anti-inflammatory effects; and regulation of key signaling pathways (JAK2/STAT5, NF-κB, PI3K/Akt). Network pharmacology reveals convergent pathway enrichment across formulas, including dopaminergic synapse, TGF-β signaling, and neuroactive ligand-receptor interactions. Clinically, Peony-Glycyrrhiza Decoction reduces prolactin by -32.69 ng/mL (p < 0.00001) with favorable safety. CONCLUSION:TCM represents a promising multi-target approach for antipsychotic-induced HPRL, addressing complex neuroendocrine dysregulation through component synergy. Network pharmacology effectively bridges TCM theory with mechanistic research, supporting evidence-based integration into psychiatric care.

Cutaneous Leishmaniasis (CL) is one of the neglected tropical diseases that causes a significant public health problem for the public in many endemic nations, including Yemen. There has been an absence of new data on the epidemiology of the CL disease in the Ibb governorate. This study aimed to determine the epidemiological status of CL in the Ibb governorate between January 2019 and June 2024. This retrospective study was based on surveillance data registered in the Public Health Office of the Ibb Governorate from January 2019 to June 2023. The required data were gathered and analyzed using SPSS. Out of 1033 registered cases, a high proportion was observed in males (53.6

Tuberculosis (TB) is a major global health issue. Early diagnosis of TB is still a challenge. Studies are seeking non-sputum biomarker-based TB test. Emerging evidence indicates potential significance of blood microbiome signatures for diseases. However, blood microbiome RNA profiles are unknown in TB. We aimed to characterize the blood microbiome of TB patients and identify Mycobacterium tuberculosis (Mtb) genome-derived small RNA molecules to serve as diagnostic biomarkers for TB. RNA sequencing data of the blood from TB patients and healthy controls were retrieved from the NCBI-SRA database for analyzing the blood microbiome and identifying rRNA-derived small RNA (rsRNA) of Mtb. Small RNA-seq was performed on plasma exosomes from TB patients and healthy controls. The levels of the candidate Mtb rsRNAs were determined by real-time quantitative reverse transcription PCR (RT-qPCR) on plasma from a separate cohort of 73 TB patients and 62 healthy controls. The blood microbiome of TB patients consisted of RNA signals from bacteria, fungi, archaea, and viruses, with bacteria accounting for more than 97

Background: Hyperuricemia (HUA), a metabolic disorder resulting from abnormalities in purine metabolism or impaired renal uric acid excretion, has shown a rising global prevalence. Although Chinese herbal medicine (CHM) exhibits therapeutic potential for HUA, strong evidence supporting its efficacy and safety remains limited. Objective: This study aimed to systematically evaluate the efficacy and safety of oral CHM in lowering serum uric acid (SUA) levels. Methods: Randomised controlled trials (RCTs) published between January 2013 and February 2024 were retrieved from PubMed, Embase, Cochrane Library, Web of Science, CNKI, CBM, and Wanfang databases. Metaanalyses were performed using Review Manager 5.4, along with sensitivity analyses, meta-regression, and subgroup analyses to explore heterogeneity. Study quality was assessed using the Cochrane Risk of Bias tool. Results: A total of 53 RCTs involving 5 176 patients were included. CHM monotherapy or CHM combined with Western medicine (WM) significantly reduced SUA levels compared to WM alone (MD = -45.28, 95% CI: -55.06 to -35.50, P < 0.0001). Adverse events occurred in 8.79% of patients receiving CHM or CHM + WM, significantly lower than in the WM control group (RR = 0.63, 95% CI: 0.48-0.83, P = 0.0009). Conclusion: Oral CHM shows significant efficacy and a favourable safety profile in reducing SUA levels, representing a promising alternative for HUA management. However, these findings require confirmation through large-scale, high-quality RCTs due to heterogeneity and methodological limitations in existing studies.

This review signifies the role of circular RNAs (circRNAs) in tuberculosis (TB) and lung cancer (LC), focusing on pathogenesis, diagnosis, and treatment. CircRNAs, a newly discovered type of non-coding RNA, have emerged as key regulators of gene expression and promising biomarkers in various bodily fluids due to their stability. The current review discusses circRNA biogenesis, highlighting their RNase-R resistance due to their loop forming structure, making them effective biomarkers. It details their roles in gene regulation, including splicing, transcription control, and miRNA interactions, and their impact on cellular processes and diseases. For LC, the review identifies circRNA dysregulation affecting cell growth, motility, and survival, and their potential as therapeutic targets and biomarkers. In TB, it addresses circRNAs’ influence on host anti-TB immune responses, proposing their use as early diagnostic markers. The paper also explores the interplay between TB and LC, emphasizing circRNAs as dual biosignatures, and the necessity for differential diagnosis. It concludes that no single circRNA biomarker is universally applicable for both TB and LC. Ultimately, the review highlights the pivotal role of circRNAs in TB and LC, encouraging further research in biomarker identification and therapeutic development concomitant for both diseases.

Morphine withdrawal leads to serious cognitive deficits in which dynorphins are directly involved. Recently, exercise has been shown to prevent and improve cognition dysfunction in a variety of ways. Meanwhile, exercise can regulate the endogenous opioid peptides including dynorphins. However, it remains unclear whether exercise influences cognitive dysfunction caused by morphine withdrawal via dynorphins. In the current study, we investigate the physiological mechanism of exercise prevention and improvement aganist cognition dysfunction caused by morphine withdrawal. Male, adult C57BL/6 mice were randomly divided into 5 groups : Saline control (WT), exercise (EXE), morphine withdrawl (MW), exercise + morphine withdrawl (EMW), morphine withdrawl + exercise (MWE). We established aerobic exercise prevention/improvement models, and conducted behavioral tests including Open field test (OFT), Temporal order memory test (TOM) and Y-maze. Through Western Blotting and immunofluorescence staining, we detected endogenous opioid peptides in hippocampus and mPFC. Compared with MW group, EMW group and MWE group showed the same performance as WT group in TOM and Y-maze, with correct object recognition and memory ability. In Western Blotting and immunofluorescence staining experiments, it indicated that EMW group reduced the expression of PDYN and its fluorescence intensity in hippocampus; MWE group reduced the expression of OPRK1 and its fluorescence intensity in mPFC. Our data suggest that aerobic exercise can both prevent and improve cognitive dysfunction caused by acute morphine withdrawal via respectively down-regulating PDYN in the hippocampus and down-regulating OPRK1 in the mPFC. They may become new targets for drugs development in the future.

Relapse is a major challenge in the treatment of drug addiction, and exercise has been shown to decrease relapse to drug seeking in animal models. However, the neural circuitry mechanisms by which exercise inhibits morphine relapse remain unclear. In this study, we report that 4-week treadmill training prevented morphine conditioned place preference (CPP) expression during abstinence by acting through the nucleus accumbens (NAc)-ventral pallidum (VP) pathway. We found that neuronal excitability was reduced in D2-dopamine receptor-expressing medium spiny neurons (D2-MSNs) following repeated exposure to morphine and forced abstinence. Enhancing the excitability of NAc D2-MSNs via treadmill training decreased the expression of morphine CPP. We also found that the effects of treadmill training were mediated by decreasing enkephalin levels and that restoring opioid modulation of GABA neurotransmission in the VP, which increased neurotransmitter release from NAc D2-MSNs to VP, decreased morphine CPP. Our findings suggest the inhibitory effect of exercise on morphine CPP is mediated by reversing morphine-induced neuroadaptations in the NAc-to-VP pathway.

BACKGROUND:Tuberculosis (TB) as a foremost infectious disease adds massive burden to morbidity and mortality rate, despite of well-structured TB control programs around the globe. Inappropriate health care management system and poor implementation on standard in relevance to TB, remain some reasons causative to TB prevalence and its rising antimicrobial resistance. Health Care Workers (HCWs) laboring as a part of TB control system, are the vital warriors in achieving the goals of TB End Strategy by 2035. Their performance is influenced by their knowledge, attitude, and practices (KAP) toward this infectious disease. This study aimed to signify the role of KAP score of health care Workers in the better control and prevention of TB in the Islamabad Capital Territory (ICT), Pakistan. METHODS:A cross-sectional study on Knowledge, Attitude and Practice study of Tuberculosis (TB) among health care Workers, was done in ICT, which is the capital of Pakistan. The KAP of TB was collected for the 306 Health Care Workers from all the Islamabad TB referring health facilities which refer the TB patients for testing to the National Reference Laboratory, Islamabad Pakistan. Eligible health care workers were requested to respond on KAP questionnaire after informed consent. KAP questionnaire comprised of knowledge, attitude, and practices section including demographic information. All the data was analyzed using IBM SPSS statistics 21. One Way Analysis of Variance (ANOVA) was applied to calculate KAP mean score against different variables. On the significant data sets of ANOVA output, Tukey's Multiple Comparison Test was applied for pairwise comparison. Pearson correlation coefficient was utilized to explore the association between two qualitative variables. The non-parametric tests were applied to evaluate difference of KAP score in relation to demographic covariates individually. RESULTS:From June to July 2023, we conducted TB KAP study among Health Care Workers of ICT, Pakistan. The average age was 33 years (range 26-30 years). Majority of the recruited subjects were not being trained for dealing with TB infection. The results demonstrated that Health Care Workers working were lacking their knowledge about mode of TB transmission, best diagnostic technique, and contraction of TB infections. The mean knowledge, attitude and practices mean scores were 15.05 (SD = 3.96), 83.68 (SD = 15.74) and 6.31 (SD = 2.21), respectively. Mean knowledge score of Health Care Workers were significantly related to their educational level and occupation while no significant association was declared with working experience as TB staff. Pearson coefficient of attitude score with knowledge of Health Care Workers was of weak level (0.28). Practice mean score was correlated to knowledge mean score at a moderate level (r = 0.40). On the other hand, practice score was r = 0.29 with attitude mean score had shown weak level correlation. A number of demographic factors were strongly linked to each of the mean score of knowledge, attitude, and practices. CONCLUSION:These findings highlighted the significant involvement of education, profession, and professional trainings in the better knowledge, attitude, and practices of the TB related health care Workers. For a better management system of infectious diseases like TB, a well-trained and professionally competent staff of Health Care Workers is important so as to achieve the goal of TB-End strategy by 2035 from Pakistan, which is the 5th highest burden country for TB.

BackgroundRisperidone is one of the most reliable and effective antipsychotics for schizophrenia treatment. However, the mechanism of action of risperidone is not yet fully understood. Traf2 and Nck-interacting protein kinase (TNIK), a schizophrenia susceptibility gene, is associated with risperidone treatment response. Our previous in vitro experiments confirmed that downregulated TNIK affected the effect of risperidone on downstream targets. However, the effect of downregulated TNIK on risperidone-induced molecular expression remains to be further explored.MethodsTranscriptome analysis was performed on U251 cells subjected to risperidone, TNIK siRNA, and no treatment, respectively. Compared to the no-treatment group, two groups of DEGs were screened out and then intersected with the schizophrenia-related genes to screen the cross-talk genes. Those DEGs were analyzed using GO and KEGG. STRING and Cytoscape were used to construct a protein-protein interaction (PPI) network for the cross-talk gene.ResultsThe results showed that the parathyroid hormone synthesis, secretion, and action were significantly enriched after risperidone treatment. Downregulated TNIK could have an impact on the collagen-containing extracellular matrix, signaling receptor activator activity, and PI3K-Akt signaling pathway. Interestingly, bone mineralization function and calcium signaling pathway were enriched in the cross-talk genes. Additionally, FGFR2, FGF1, and FGFR might be the potential targets for TNIK affecting the effects of risperidone.ConclusionThe study indicated that risperidone primarily influences functions and/or pathways associated with bone metabolism, potentially contributing to the adverse effect of osteoporosis. Our study may offer a novel perspective on investigating the mechanisms underlying the adverse effects of risperidone.

The rRNA-derived fragment （rRF） is a new type of small non-coding RNA that has entered people’s field of vision in recent years. It is a kind of small RNA fragment produced by cleavage of mature and complete rRNA under specific conditions. The rRF is a new type of small regulatory RNA with different biological functions from its parent rRNA,which plays an important role in cell proliferation, stress response, inflammatory response and metabolic regulation by regulating gene expression. This article summarizes the latest progress in research on rRF in biology, including the biogenesis mechanism and functions, so as to provide reference for the research of rRF.

Physical inactivity is a global epidemic. People who take the initiative to exercise will feel pleasure during the exercise process and stick with it for a long time, while people who passively ask for exercise will feel pain and cannot stick with it. However, the neural mechanisms underlying voluntary and forced exercise remain unclear. Here, we report that voluntary running increased the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSC) but decreased membrane excitability in D1R-MSNs, whereas D2R-MSNs did not change in mEPSC and membrane excitability. Forced running increased the frequency of mEPSC and membrane excitability in D2R-MSNs, but D1R-MSNs did not change, which may be the mechanism by which forced exercise has a non-rewarding effect. These findings provide new insights into how voluntary and forced exercise mediate reward and non-reward effects.

药物滥用带来的公共卫生问题愈加棘手,特别是阿片类药物的滥用可导致成瘾、神经认知障碍、引发传染病等严重危害,甚至可能威胁生命.运动干预作为一种执行成本低、限制条件少、无副作用的治疗手段,目前部分研究已发现其可以对阿片类药物滥用患者产生明显的疗效.有氧运动在改善成瘾、神经认知障碍、免疫力下降、运动功能损伤等多方面都已被证明有效,其中运动强度和运动时间是重要影响因素.抗阻训练与有氧运动相结合后治疗效果更佳,可能是更值得推广的治疗方法.身心运动(包括瑜伽、冥想、太极拳、气功)主要治疗神经认知障碍,在改善病患情绪、生活质量等方面具有独特效果.从生理机制上看,运动通过干预神经环路、突触可塑性、神经递质及其受体对症改善阿片类药物滥用诱发的危害.

Depression has become one of the most important causes of disability worldwide. Although traditional treatment methods such as drug therapy, physical therapy and psychological intervention have positive effects, they still have limitations such as high treatment cost, high drug side effects, high recurrence rate and poor compliance. Exercise therapy, as a treatment recommended by many guidelines, has many advantages such as simple and convenient, few side effects, and strong persistence. Studies have shown that exercise can relieve depression through a variety of mechanisms, but there is still a lack of effective targets for the treatment of depression. Microglia is an innate immune cell in the central nervous system. In recent years, the role of microglia in neuroinflammation in depression and other mental diseases has attracted more and more attention. Thus, microglia may be a key target for exercise to alleviate depression. This article discusses the relationship between exercise and microglia phenotypes as well as depression, and proposes future research directions on microglia-mediated exercise to improve depression, in order to provide new ideas and directions for the clinical treatment of depression.

Abstract Tuberculosis is a major public health issue in Yemen, a country located at the southwestern tip of the Arabian Peninsula, while the situation of tuberculosis had been further exacerbated since the war started in 2015. The objective of this study is to investigate the incidence of tuberculosis in Yemen before the outbreak of COVID-19, from 2006 to 2018. During the 13-year period, 92 482 patients were enrolled in the TB programme records from the 22 governorates. Almost equal number of cases were diagnosed between males and females (a male to female ratio, 1.03:1). A notable rising incidence was observed in all age groups starting from 2011. The sharpest increase occurred in children under age 15, rising by 8.0-fold from 0.5 in the period 2006–2010 to 4.1 in the period 2011–2018. Paediatric TB accounted for 9.6% of all reported cases. In terms of the patient residence, incidence has more than doubled in Sana'a city, Sana'a Gov., Hajjah and Saadah. Concomitant diseases with tuberculosis included diabetes mellitus (14.0%), brucellosis (6.1%), hepatitis (6.0%), rheumatoid arthritis (4.3%), renal disorders (2.5%) and HIV infection (2.5%). Development of interventions to reduce tuberculosis incidence in children and concomitant communicable diseases is urgently needed.

BACKGROUND:Depression is associated with circadian disturbances in which melanopsin was a key mechanism. Further studies have demonstrated that melanopsin gene variations are associated with some depressive disorders and aberrant light can impair mood through melanopsin-expressing retinal ganglion cells (mRGCs). The goal of this study was to explore the direct relationship between depression and melanopsin.METHODS:Adult C57BL/6 male mice were physically restrained for 16 h in a 50-ml polypropylene centrifuge tube and all behavioral tests were performed after CRS treatment. Western blot analysis and immunofluorescence were used to detect melanopsin expression in the retina of C57BL/6 mice. And we observed the change of the electrophysiological function and release of glutamate of mRGCs.RESULTS:The melanopsin expression upregulate in mRGCs of chronic restraint stress (CRS)-treating mice which exhibit depression-like behavior. The frequency of blue light-induced action potentials and light-induced glutamate release mediated by melanopsin also increase significantly. This change of melanopsin is mediated by the CRS-induced glucocorticoid.CONCLUSIONS:CRS may induce the depression-like behavior in mice via glucocorticoid-melanopsin pathway. Our findings provide a novel mechanistic link between CRS-induced depression and melanopsin in mice.

Clinical high-risk psychosis (CHR-P)1 refers to a heterogeneous state where patients exhibit psychotic syndromes such as hallucination and delusion not reaching the diagnostic criteria, with the ability of self-reasoning and help-seeking partially maintained. These characteristics make CHR-P an ideal phase for the early treatment of schizophrenia. Researchers have made great efforts to study peripheral molecular markers with the advantages of feasibility and objectivity2 that could predict CHR-P outcomes, such as using proteome3 and metabolome4 with success. For RNA, studies such as Influence du Cannabis sur l'émergence de symptômes psychopathologiques des Adolescents et jeunes Adultes présentant un état mental à Risque (ICAAR)5 and the NAPLS (North American Prodrome Longitudinal Study) cohort6 have already shown that RNA and microRNA had significant alterations during CHR-P conversion to psychosis, suggesting that blood transcriptome had the potentiality of being used as a biomarker. To evaluate whether blood RNA could serve as CHR-P biomarkers, we collected blood samples of patients with CHR-P from the Shanghai at-risk psychosis (SHARP) longitudinal cohort7 and applied RNA sequencing. Syndrome severity was evaluated by Structured Interview for Prodromal Syndromes (SIPS). We removed 10 samples with RNA integrity number (RIN) <6. With peripheral expression data and clinical assessment at both baseline and at 1- and 2-year follow-up, we built a model to evaluate the psychotic symptom alteration by differential expression analysis and step regression, then explored the biological functions associated with this model by gene set enrichment analysis (GSEA). We then built a model to predict the 2-year prognosis by baseline gene expression, which is achieved by limma-voom8 differential expression and Lasso regression. The model robustness was evaluated by cross-validation and test set validation (for the first model) or premutation (for the second model) (Fig. S1). We obtained RNA expression data of the peripheral blood from 56 patients collected at baseline and at 1-year follow-up. These patients had a mean SIPS-psychotic symptom score of 9.8 (SE of 3.9) at baseline and 4.2 (SE of 4.0) at 1-year follow-up (Table S1). After adjusting for known and surrogate confounders (Figs S2 and S3, Tables S2 and S3), we applied stepwise regression and built a 12-gene model (Fig. 1a and Table S4), including genes such as SDK1 (sidekick cell adhesion molecule 1; standardized coefficient τ = 2.22) and NOTCH4 (Notch receptor 4; τ = 0.86), to reflect symptom alteration (R2 = 0.76, F = 7.84, P = 3.06 × 10−6). This model was robust against subsampling (Fig. 1a) and achieved R2 = 0.56 to 0.70 (P < 10−4) in leave-one-out and cross-validation tests and R2 = 0.40 (P = 0.012) in the test set (Fig. S4). GSEA found that genes showing a negative correlation with model-predicted symptom scores were enriched in synaptic vesicle recycling (Table S5–6, adjusted P = 0.04, Fig. 1b), suggesting that synapse functions were suppressed during CHR-P symptom deterioration. When predicting for the CHR-P conversion, we applied Lasso regression on 10 differential expression genes (Fig. S3) and obtained a five-gene model that included SYP (gene encoding Synaptophysin; P = 6.47 × 10−4) and CNTNAP3 (contactin-associated protein family member 3; P = 1.15 × 10−3) (Fig. 1c, S5, and S6, and Table S7), and achieved area under the curve (AUC) = 0.98. For models containing top 4, 3, 2, and 1 gene, we observed an AUC of 0.96, 0.95, 0.91, and 0.90, respectively. In the leave-one-out and cross-validation tests, the model with top two (SYP and IFNW1 [interferon omega 1]) or top three (by including gene CNTNAP3) genes achieved AUC scores between 0.80 and 0.92 (Fig. 1d). In contrast, the AUC scores of models with more genes dropped to 0.69 from 0.85. Accordingly, the permutation P-value reached the lowest (P = 0.03) at the three-gene model. We concluded that the three-gene model was the optimal predictive model. Additionally, no predictive models using noncoding RNA yielded less accurate results (Figs S7–S10). In this study, we confirmed that blood RNA has the potentiality to serve as a biomarker for CHR-P conversion risk. Thus, blood transcriptome is valuable to CHR-P's clinical intervention, where treatment choices are dependent on the objective evaluation of symptom severity and conversion risk.9 In addition, our symptom association model also reflected the underlying biological mechanism, such as downregulation of synaptic vesicle recycling during CHR-P progression. This result indicated that synaptic functions were significantly suppressed during schizophrenia pathology. Furthermore, the low expression level of a synaptic gene SYN is significantly associated with the future conversion of CHR-P, in line with the previous meta-analysis, which revealed low expression of Synaptophysin in the hippocampus of patients with schizophrenia.10 It should be noted that because of the relatively small sample size and the lack of a validation cohort, we only obtained a suggestive model that was valuable for further validation and could not be considered as immediately applicable. The follow-up period should also be extended to achieve a more precise end point. In sum, our results indicate that blood transcriptome is valuable for the prognosis prediction of CHR-P, and suggests that inhibition of synaptic functions plays an important role in the CHR-P pathology. Highlighted biomarkers and models are highly valuable for future studies. This work is supported by grants from the National Key R&D Program of China (No. 2016YFC1307005 and 2016YFC1306803), the National Natural Science Foundation of China (No. 81971257, 81971292 and 82150610506), the Natural Science Foundation of Shanghai (No. 21ZR1428600), Shanghai Jiao Tong University Medical Engineering (Science) Cross Research Fund (YG2019ZDA30), the Shanghai Municipal Science and Technology Major Project (grant No. 2018SHZDZX01), and the Shanghai Clinical Research Center for Mental Health (No. 19MC1911100). All the authors declared no conflicts of interest. This study was approved by the research ethics committee at the Shanghai Mental Health Centre. Appendix S1. Supplementary Material: Contains supplementary methods, supplementary results. Fig. S1. Flowchart of the study. Fig. S2. Symptom evaluation model of protein-coding genes. Fig. S4. WGCNA result for confounder identification. Fig. S5. Correlation matrix of potential confounders. Fig. S6. Distribution of τ of prediction model in subsampling tests. Fig. S7. Stepwise F test for lincRNA symptom evaluation model. Fig. S8. subsampling test for lincRNA symptom evaluation model. Fig. S9. Prediction model by lincRNA. Fig. S10. Comparison of prediction model of protein-coding genes and lincRNA. Table S2. Result of symptom evaluation model. Table S4. Correlation between confounders and outcome. Table S7. Full result of GSEA. Fig. S3. Prognosis model and its biological interpretations. Table S1. Clinical assessment, demographic characteristics, and confounders of all participants. Table S3. Result of prognosis prediction model. Table S5. Result of confounder selection by MARS. Table S6. Correlation between gene expression, SScore and RScore. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

The ultra-high risk (UHR) paradigm allows the investigation of individuals at increased risk of developing psychotic or other mental disorders with the aim of making prevention and early intervention as specific as possible in terms of the individual outcome.Single-session 1H-/31P-Chemical Shift Imaging of thalamus, prefrontal (DLPFC) and anterior midcingulate (aMCC) cortices was applied to 69 UHR patients for psychosis and 61 matched healthy controls. N-acetylaspartate (NAA), glutamate/glutamine complex (Glx), energy (PCr, ATP) and phospholipid metabolites were assessed, analysed by ANOVA (or ANCOVA [with covariates]) and correlated with symptomatology (SCL-90R).The thalamus showed decreased NAA, inversely correlated with self-rated aggressiveness, as well as increased PCr, and altered phospholipid breakdown. While the aMCC showed a pattern of NAA decrease and PCr increase, the DLPFC showed PCr increase only in the close-to-psychosis patient subgroup. There were no specific findings in transition patients.The results do not support the notion of a specific pre-psychotic neurometabolic pattern, but likely reflect correlates of an “at risk for mental disorders syndrome”. This includes disturbed neuronal (mitochondrial) metabolism in the thalamus and aMCC, with emphasis on left-sided structures, and altered PL remodeling across structures.

Objectives: Genome-wide association studies have identified a significant risk gene, CACNA1C, for schizophrenia. In this study, we comprehensively investigated a large set of CACNA1C single-nucleotide polymorphisms (SNPs) to identify the replicable risk alleles for schizophrenia and explore their biological functions. Methods: One Jewish (1044 cases vs 2052 controls), one European (1350 cases vs 1378 controls) and one exploratory African American samples (98 cases vs 20 controls) were analyzed to identify replicable single-nucleotide polymorphism–schizophrenia associations. The regulatory effects of risk alleles on CACNA1C messenger RNA expression were examined. The most robust risk tagSNP (rs1006737) was meta-analyzed on 17 studies (74,122 cases vs 109,062 controls), and associated with the gray matter volumes of seven subcortical structures in 38,258 Europeans, and the surface areas and thickness of 34 cortical regions in 33,992 Europeans and 2944 non-Europeans. Results: Forty-seven replicable risk single-nucleotide polymorphisms, including a 20-single-nucleotide polymorphism haplotype block, were identified in our samples (1.8 × 10 −4 ⩽ p ⩽ 0.049). This variant block was consistently associated with schizophrenia across four independent Psychiatric Genomics Consortium cohorts (79,645 cases vs 109,590 controls; 2.5 × 10 –17 ⩽ p ⩽ 0.017). This block showed significant expression quantitative trait loci in three independent European brain cohorts (5.1 × 10 –12 ⩽ p ⩽ 8.3 × 10 –3 ) and could be tagged by the most significant risk single-nucleotide polymorphism rs1006737. The minor allele A of rs1006737 significantly increased risk for schizophrenia across the Jewish and European samples ( p = 0.029 and 0.004, respectively), and this association was highly significant in the meta-analysis ( p = 1.62 × 10 –42 ). This allele also significantly altered the CACNA1C messenger RNA expression in five brain regions (5.1 × 10 –12 ⩽ p ⩽ 0.05), decreased the gray matter volume of thalamus ( p = 0.010), the surface area of isthmus cingulate cortex ( p = 0.013) and the thickness of transverse temporal and superior temporal sulcus cortexes (0.005 ⩽ p ⩽ 0.043). Conclusion: We identified an independent, replicable, functional, and significant risk variant block at CACNA1C for schizophrenia, which could be tagged by the most robust risk marker rs1006737, suggesting an important role of CACNA1C in the pathogenesis of schizophrenia.