Schizophrenia in the genetic era: a review from development history, clinical features and genomic research approaches to insights of susceptibility genes.

Schizophrenia is a devastating neuropsychiatric disorder affecting 1% of the world population and ranks as one of the disorders providing the most severe burden for society. Schizophrenia etiology remains obscure involving multi-risk factors, such as genetic, environmental, nutritional, and developmental factors. Complex interactions of genetic and environmental factors have been implicated in the etiology of schizophrenia. This review provides an overview of the historical origins, pathophysiological mechanisms, diagnosis, clinical symptoms and corresponding treatment of schizophrenia. In addition, as schizophrenia is a polygenic, genetic disorder caused by the combined action of multiple micro-effective genes, we further detail several approaches, such as candidate gene association study (CGAS) and genome-wide association study (GWAS), which are commonly used in schizophrenia genomics studies. A number of GWASs about schizophrenia have been performed with the hope to identify novel, consistent and influential risk genetic factors. Finally, some schizophrenia susceptibility genes have been identified and reported in recent years and their biological functions are also listed. This review may serve as a summary of past research on schizophrenia genomics and susceptibility genes (NRG1, DISC1, RELN, BDNF, MSI2), which may point the way to future schizophrenia genetics research. In addition, depending on the above discovery of susceptibility genes and their exact function, the development and application of antipsychotic drugs will be promoted in the future.

Hydrogen sulfide alleviates osmotic stress-induced root growth inhibition by promoting auxin homeostasis.

Hydrogen sulfide (H2 S) promotes plant tolerance against various environmental cues, and d-cysteine desulfhydrase (DCD) is an enzymatic source of H2 S to enhance abiotic stress resistance. However, the role of DCD-mediated H2 S production in root growth under abiotic stress remains to be further elucidated. Here, we report that DCD-mediated H2 S production alleviates osmotic stress-mediated root growth inhibition by promoting auxin homeostasis. Osmotic stress up-regulated DCD gene transcript and DCD protein levels and thus H2 S production in roots. When subjected to osmotic stress, a dcd mutant showed more severe root growth inhibition, whereas the transgenic lines DCDox overexpressing DCD exhibited less sensitivity to osmotic stress in terms of longer root compared to the wild-type. Moreover, osmotic stress inhibited root growth through repressing auxin signaling, whereas H2 S treatment significantly alleviated osmotic stress-mediated inhibition of auxin. Under osmotic stress, auxin accumulation was increased in DCDox but decreased in dcd mutant. H2 S promoted auxin biosynthesis gene expression and auxin efflux carrier PIN-FORMED 1 (PIN1) protein level under osmotic stress. Taken together, our results reveal that mannitol-induced DCD and H2 S in roots promote auxin homeostasis, contributing to alleviating the inhibition of root growth under osmotic stress.

Positive Association of TEAD1 With Schizophrenia in a Northeast Chinese Han Population.

OBJECTIVE: Schizophrenia is a complex and devastating psychiatric disorder with a strong genetic background. However, much uncertainty still exists about the role of genetic susceptibility in the pathophysiology of schizophrenia. TEA domain transcription factor 1 (TEAD1) is a transcription factor associated with neurodevelopment and has modulating effects on various nervous system diseases. In the current study, we performed a case-control association study in a Northeast Chinese Han population to explore the characteristics of pathogenic TEAD1 polymorphisms and potential association with schizophrenia. METHODS: We recruited a total of 721 schizophrenia patients and 1,195 healthy controls in this study. The 9 single nucleotide polymorphisms (SNPs) in the gene region of TEAD1 were selected and genotyped. RESULTS: The genetic association analyses showed that five SNPs (rs12289262, rs6485989, rs4415740, rs7113256, and rs1866709) were significantly different between schizophrenia patients and healthy controls in allele or/and genotype frequencies. After Bonferroni correction, the association of three SNPs (rs4415740, rs7113256, and rs1866709) with schizophrenia were still evident. Haplotype analysis revealed that two strong linkage disequilibrium blocks (rs6485989-rs4415740-rs7113256 and rs16911710-rs12364619-rs1866709) were globally associated with schizophrenia. Four haplotypes (C-C-C and T-T-T, rs6485989-rs4415740-rs7113256; G-T-A and G-T-G, rs16911710-rs12364619-rs1866709) were significantly different between schizophrenia patients and healthy controls. CONCLUSION: The current findings indicated that the human TEAD1 gene has a genetic association with schizophrenia in the Chinese Han population and may act as a susceptibility gene for schizophrenia.

The role of pregnane X receptor (PXR) in substance metabolism.

As a member of the nuclear receptor (NR) superfamily, pregnane X receptor (PXR; NR1I2) is a ligand-activated transcription factor that plays a crucial role in the metabolism of xenobiotics and endobiotics in mammals. The tissue distribution of PXR is parallel to its function with high expression in the liver and small intestine and moderate expression in the kidney, stomach, skin, and blood-brain barrier, which are organs and tissues in frequent contact with xenobiotics. PXR was first recognized as an exogenous substance receptor regulating metabolizing enzymes and transporters and functioning in detoxification and drug metabolism in the liver. However, further research revealed that PXR acts as an equally important endogenous substance receptor in the metabolism and homeostasis of endogenous substances. In this review, we summarized the functions of PXR in metabolism of different substances such as glucose, lipid, bile acid, vitamin, minerals, and endocrines, and also included insights of the application of PXR ligands (drugs) in specific diseases.

PIN3-mediated auxin transport contributes to blue light-induced adventitious root formation in Arabidopsis.

Adventitious rooting is a heritable quantitative trait that is influenced by multiple endogenous and exogenous factors in plants, and one important environmental factor required for efficient adventitious root formation is light signaling. However, the physiological significance and molecular mechanism of light underlying adventitious root formation are still largely unexplored. Here, we report that blue light-induced adventitious root formation is regulated by PIN-FORMED3 (PIN3)-mediated auxin transport in Arabidopsis. Adventitious root formation is significantly impaired in the loss-of-function mutants of the blue light receptors, PHOTOROPIN1 (PHOT1) and PHOTOROPIN2 (PHOT2), as well as the phototropic transducer, NON-PHOTOTROPIC HYPOCOTYL3 (NPH3). In addition, blue light enhanced the auxin content in the adventitious root, and the pin3 loss-of-function mutant had a reduced adventitious rooting response under blue light compared to the wild type. The PIN3 protein level was higher in plants treated with blue light than in those in darkness, especially in the hypocotyl pericycle, while PIN3-GFP failed to accumulate in nph3 PIN3::PIN3-GFP. Furthermore, the results showed that PIN3 physically interacted with NPH3, a key transducer in phototropic signaling. Taken together, our study demonstrates that blue light induces adventitious root formation through the phototropic signal transducer, NPH3, which regulates adventitious root formation by affecting PIN3-mediated auxin transport.

Osmotic stress represses root growth by modulating the transcriptional regulation of PIN-FORMED3.

Osmotic stress influences root system architecture, and polar auxin transport (PAT) is well established to regulate root growth and development. However, how PAT responds to osmotic stress at the molecular level remains poorly understood. In this study, we explored whether and how the auxin efflux carrier PIN-FORMED3 (PIN3) participates in osmotic stress-induced root growth inhibition in Arabidopsis (Arabidopsis thaliana). We observed that osmotic stress induces a HD-ZIP II transcription factor-encoding gene HOMEODOMAIN ARABIDOPSIS THALIANA2 (HAT2) expression in roots. The hat2 loss-of-function mutant is less sensitive to osmotic stress in terms of root meristem growth. Consistent with this phenotype, whereas the auxin response is downregulated in wild-type roots under osmotic stress, the inhibition of auxin response by osmotic stress was alleviated in hat2 roots. Conversely, transgenic lines overexpressing HAT2 (Pro35S::HAT2) had shorter roots and reduced auxin accumulation compared with wild-type plants. PIN3 expression was significantly reduced in the Pro35S::HAT2 lines. We determined that osmotic stress-mediated repression of PIN3 was alleviated in the hat2 mutant because HAT2 normally binds to the promoter of PIN3 and inhibits its expression. Taken together, our data revealed that osmotic stress inhibits root growth via HAT2, which regulates auxin activity by directly repressing PIN3 transcription.

[Erythropoietin levels in patients with multiple sclerosis complicated with anemia].

OBJECTIVE: To explore the potential decrease of serum erythropoietin (EPO) level in patients with multiple sclerosis (MS) complicated with anemia. METHODS: The serum EPO levels were detected in the patients with MS complicated with anemia (MS group, n=31), patients with iron deficiency anemia (IDA group, n=33), and healthy subjects (normal control group, n=80) by enzyme-linked immunosorbent assay (ELISA). Blood routine test, reticulocyte count, hemoglobin, and indexes of liver and kidney function were also detected. RESULTS: The serum EPO level in MS group was significantly lower than those in IDA group [(101.3±17.6)U/L vs.(166.1±8.7)U/L, P<0.01]. Moreover, the serum EPO level decreased as the severity of anemia in the MS group increased: it was (95.7±9.6), (101.7±8.1), and (123.7±9.3) U/L in patients with mild, moderate, and severe anemia, respectively (P<0.05). Other indicators including blood routine findings, reticulocyte count, hemoglobin, and liver and kidney function parameters showed no significant difference between the MS group and the IDA group (P>0.05). CONCLUSIONS: The serum EPO level decreases in patients with multiple sclerosis complicated with anemia, and the decreasing levels are related with the severity of anemia. Thus EPO therapy may be beneficial for these patients.