From Inorganic to Organic Iodine: Stabilization of I+ Enabling High-Energy Lithium-Iodine Battery.

Organic materials have been considered a class of promising cathodes for metal-ion batteries because of their sustainability in preparation and source. However, organic batteries with high energy density and application potential require high discharge voltage, multielectron transfer, and long cycling performance. Here, we report an exceptional lithium-iodine (Li//I2) battery, in which the organic iodine (BPD-HI) cathode formed by the Lewis acid-base coordination between hydroiodic acid (HI) and 4,4'-bipyridine (BPD) allows 2e- transfer via the I-/I0 and I0/I+ redox couples. The I+ stabilized by BPD exhibits a high discharge voltage plateau at ∼3.4 V. Remarkably, from inorganic to organic iodine, it realizes a 2-fold increase in the achieved capacity, up to ∼400 mA h gI-1 (Theor. 422 mA h gI-1 and 245.6 mA h g-1 based on the mass of BPD-HI), and an over 2-fold energy density, reaching 1160 W h kgI-1 (Theor. 1324 W h kgI-1). More importantly, a capacity retention rate of 85% over 850 cycles is attained for the Li//BPD-HI battery at a current density of 2 A gI-1. This facile strategy enables positively charged I+ to be electrochemically active in a rechargeable lithium battery. The new redox chemistry discovered provides new insights for developing organic batteries with high energy density.

Epigenetic inactivation of ERF reactivates γ-globin expression in ß-thalassemia.

The fetal-to-adult hemoglobin switch is regulated in a developmental stage-specific manner and reactivation of fetal hemoglobin (HbF) has therapeutic implications for treatment of ß-thalassemia and sickle cell anemia, two major global health problems. Although significant progress has been made in our understanding of the molecular mechanism of the fetal-to-adult hemoglobin switch, the mechanism of epigenetic regulation of HbF silencing remains to be fully defined. Here, we performed whole-genome bisulfite sequencing and RNA sequencing analysis of the bone marrow-derived GYPA+ erythroid cells from ß-thalassemia-affected individuals with widely varying levels of HbF groups (HbF ≥ 95th percentile or HbF ≤ 5th percentile) to screen epigenetic modulators of HbF and phenotypic diversity of ß-thalassemia. We identified an ETS2 repressor factor encoded by ERF, whose promoter hypermethylation and mRNA downregulation are associated with high HbF levels in ß-thalassemia. We further observed that hypermethylation of the ERF promoter mediated by enrichment of DNMT3A leads to demethylation of γ-globin genes and attenuation of binding of ERF on the HBG promoter and eventually re-activation of HbF in ß-thalassemia. We demonstrated that ERF depletion markedly increased HbF production in human CD34+ erythroid progenitor cells, HUDEP-2 cell lines, and transplanted NCG-Kit-V831M mice. ERF represses γ-globin expression by directly binding to two consensus motifs regulating γ-globin gene expression. Importantly, ERF depletion did not affect maturation of erythroid cells. Identification of alterations in DNA methylation of ERF as a modulator of HbF synthesis opens up therapeutic targets for ß-hemoglobinopathies.

An Organic Molecular Cathode Composed of Naphthoquinones Bridged by Organodisulfide for Rechargeable Lithium Battery.

Organic electrodes that embrace multiple electron transfer and efficient redox reactions are desirable for green energy storage batteries. Here, a novel organic electrode material is synthesized, i.e., 2, 2'-((disulfanediylbis (4, 1-phenylene)) bis(azanediyl)) bis (naphthalene-1, 4-dione) (MNQ), through a simple click reaction between common carbonyl and organosulfur compounds and demonstrate its application potential as a high-performance cathode material in rechargeable lithium batteries. MNQ exhibits the aggregation effect of redox-active functional groups, the advantage of fast reaction kinetics from molecular structure evolution, and the decreased solubility in aprotic electrolytes resulting from intermolecular interactions. As expected, the MNQ electrode exhibits a high initial discharge capacity of 281.2 mA h g-1 at 0.5 C, equivalent to 97.9% of its theoretical capacity, and sustains stable long-term cycling performance of over 1000 cycles at 1 C. This work adds a new member to the family of organic electrode materials, providing performance-efficient organic molecules for the design of rechargeable battery systems, which will undoubtedly spark great interest in their applications.

Transition of allele-specific DNA hydroxymethylation at regulatory loci is associated with phenotypic variation in monozygotic twins discordant for psychiatric disorders.

BACKGROUND: Major psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BPD) are complex genetic mental illnesses. Their non-Mendelian features, such as those observed in monozygotic twins discordant for SCZ or BPD, are likely complicated by environmental modifiers of genetic effects. 5-Hydroxymethylcytosine (5hmC) is an important epigenetic mark in gene regulation, and whether it is linked to genetic variants that contribute to non-Mendelian features remains largely unexplored. METHODS: We combined the 5hmC-selective chemical labeling method (5hmC-seq) and whole-genome sequencing (WGS) analysis of peripheral blood DNA obtained from monozygotic (MZ) twins discordant for SCZ or BPD to identify allelic imbalances in hydroxymethylome maps, and examined association of allele-specific hydroxymethylation (AShM) transition with disease susceptibility based on Bayes factors (BF) derived from the Bayesian generalized additive linear mixed model. We then performed multi-omics integrative analysis to determine the molecular pathogenic basis of those AShM sites. We finally employed luciferase reporter, CRISPR/Cas9 technology, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), PCR, FM4-64 imaging analysis, and RNA sequencing to validate the function of interested AShM sites in the human neuroblastoma SK-N-SH cells and human embryonic kidney 293T (HEK293T) cells. RESULTS: We identified thousands of genetic variants associated with AShM imbalances that exhibited phenotypic variation-associated AShM changes at regulatory loci. These AShM marks showed plausible associations with SCZ or BPD based on their effects on interactions among transcription factors (TFs), DNA methylation levels, or other epigenomic marks and thus contributed to dysregulated gene expression, which ultimately increased disease susceptibility. We then validated that competitive binding of POU3F2 on the alternative allele at the AShM site rs4558409 (G/T) in PLLP-enhanced PLLP expression, while the hydroxymethylated alternative allele, which alleviated the POU3F2 binding activity at the rs4558409 site, might be associated with the downregulated PLLP expression observed in BPD or SCZ. Moreover, disruption of rs4558409 promoted neural development and vesicle trafficking. CONCLUSION: Our study provides a powerful strategy for prioritizing regulatory risk variants and contributes to our understanding of the interplay between genetic and epigenetic factors in mediating SCZ or BPD susceptibility.

Allele-specific DNA methylation maps in monozygotic twins discordant for psychiatric disorders reveal that disease-associated switching at the EIPR1 regulatory loci modulates neural function.

The non-Mendelian features of phenotypic variations within monozygotic twins are likely complicated by environmental modifiers of genetic effects that have yet to be elucidated. Here, we performed methylome and genome analyses of blood DNA from psychiatric disorder-discordant monozygotic twins to study how allele-specific methylation (ASM) mediates phenotypic variations. We identified that thousands of genetic variants with ASM imbalances exhibit phenotypic variation-associated switching at regulatory loci. These ASMs have plausible causal associations with psychiatric disorders through effects on interactions between transcription factors, DNA methylations, and other epigenomic markers and then contribute to dysregulated gene expression, which eventually increases disease susceptibility. Moreover, we also experimentally validated the model that the rs4854158 alternative C allele at an ASM switching regulatory locus of EIPR1 encoding endosome-associated recycling protein-interacting protein 1, is associated with demethylation and higher RNA expression and shows lower TF binding affinities in unaffected controls. An epigenetic ASM switching induces C allele hypermethylation and then recruits repressive Polycomb repressive complex 2 (PRC2), reinforces trimethylation of lysine 27 on histone 3 and inhibits its transcriptional activity, thus leading to downregulation of EIPR1 in schizophrenia. Moreover, disruption of rs4854158 induces gain of EIPR1 function and promotes neural development and vesicle trafficking. Our study provides a powerful framework for identifying regulatory risk variants and contributes to our understanding of the interplay between genetic and epigenetic variants in mediating psychiatric disorder susceptibility.

LncRNA-AC006129.1 reactivates a SOCS3-mediated anti-inflammatory response through DNA methylation-mediated CIC downregulation in schizophrenia.

Schizophrenia is a complex genetic disorder, the non-Mendelian features of which are likely complicated by epigenetic factors yet to be elucidated. Here, we performed RNA sequencing of peripheral blood RNA from monozygotic twins discordant for schizophrenia, and identified a schizophrenia-associated upregulated long noncoding RNA (lncRNA, AC006129.1) that participates in the inflammatory response by enhancing SOCS3 and CASP1 expression in schizophrenia patients and further validated this finding in AC006129.1-overexpressing mice showing schizophrenia-related abnormal behaviors. We find that AC006129.1 binds to the promoter region of the transcriptional repressor Capicua (CIC), facilitates the interactions of DNA methyltransferases with the CIC promoter, and promotes DNA methylation-mediated CIC downregulation, thereby ameliorating CIC-induced SOCS3 and CASP1 repression. Derepression of SOCS3 enhances the anti-inflammatory response by inhibiting JAK/STAT-signaling activation. Our findings reveal an epigenetic mechanism with etiological and therapeutic implications for schizophrenia.

A female carrier of a novel DMD mutation with slightly skewed X-chromosome inactivation shows a suspected case of Becker muscular dystrophy in a Chinese family.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are both caused by mutations in DMD gene effecting the expression of dystrophin. Generally female carriers are asymptomatic; however, it has been suggested that carriers may exhibit symptoms. We investigated a 6-year-old Chinese girl exhibiting a suspected BMD phenotype, including persistently elevated creatine kinase and creatine kinase isoenzyme levels. The proband harbored a novel heterozygous mutation, c.3458_3459insAA, within exon 26 of the DMD gene inherited from her mother who had a completely normal phenotype and presented with mosaicism in her lymphocytes with 45, X [17%]/46, XX [83%]. In addition, X-chromosome inactivation (XCI) patterns in the peripheral blood of the child were slightly skewed: proband with 62% (mutant allele)/38% (normal allele) when compared with her mother with 32/68%. Amplification of regions of the cDNA revealed different ratios for the expression of these alleles: proband with 50/50% and her mother with 20/80%. Real-time PCR showed that mRNA expression was significantly decreased in both. We proposed that a frameshift or nonsense mutation may contribute to the development of symptoms in carriers. These phenotypes correlate with nonrandom XCI patterns and are compounded by the locus of the mutation. For incompletely skewed XCI patterns, although the mutant allele could suppress the expression of a normal allele, carriers would remain asymptomatic as long as there was adequate compensation from the normal allele. We also proposed a mechanism where mRNA from the mutant allele may be unstable and easily degraded, allowing for phenotypic compensation by the wildtype allele.

A Hybrid Rao-NM Algorithm for Image Template Matching.

This paper proposes a hybrid Rao-Nelder-Mead (Rao-NM) algorithm for image template matching is proposed. The developed algorithm incorporates the Rao-1 algorithm and NM algorithm serially. Thus, the powerful global search capability of the Rao-1 algorithm and local search capability of NM algorithm is fully exploited. It can quickly and accurately search for the high-quality optimal solution on the basis of ensuring global convergence. The computing time is highly reduced, while the matching accuracy is significantly improved. Four commonly applied optimization problems and three image datasets are employed to assess the performance of the proposed method. Meanwhile, three commonly used algorithms, including generic Rao-1 algorithm, particle swarm optimization (PSO), genetic algorithm (GA), are considered as benchmarking algorithms. The experiment results demonstrate that the proposed method is effective and efficient in solving image matching problems.

Mutations in C1orf194, encoding a calcium regulator, cause dominant Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease is a hereditary motor and sensory neuropathy exhibiting great clinical and genetic heterogeneity. Here, the identification of two heterozygous missense mutations in the C1orf194 gene at 1p21.2-p13.2 with Charcot-Marie-Tooth disease are reported. Specifically, the p.I122N mutation was the cause of an intermediate form of Charcot-Marie-Tooth disease, and the p.K28I missense mutation predominately led to the demyelinating form. Functional studies demonstrated that the p.K28I variant significantly reduced expression of the protein, but the p.I122N variant increased. In addition, the p.I122N mutant protein exhibited the aggregation in neuroblastoma cell lines and the patient's peroneal nerve. Either gain-of-function or partial loss-of-function mutations to C1ORF194 can specify different causal mechanisms responsible for Charcot-Marie-Tooth disease with a wide range of clinical severity. Moreover, a knock-in mouse model confirmed that the C1orf194 missense mutation p.I121N led to impairments in motor and neuromuscular functions, and aberrant myelination and axonal phenotypes. The loss of normal C1ORF194 protein altered intracellular Ca2+ homeostasis and upregulated Ca2+ handling regulatory proteins. These findings describe a novel protein with vital functions in peripheral nervous systems and broaden the causes of Charcot-Marie-Tooth disease, which open new avenues for the diagnosis and treatment of related neuropathies.

Platinized spherical supramolecular nanoassemblies of a porphyrin: facile synthesis and excellent catalytic recyclability.

Porphyrin-based supramolecular nanoassemblies of a spherical morphology have been attracting broad interest owing to their wide application possibilities in numerous fields of paramount significance. Most of the existing assembly protocols, however, either suffer from the requirement of elaborately-designed yet tediously-synthesized ad hoc porphyrins, the use of surfactant templates, or accurate consideration of the experimental parameters etc. The initiation of a facile surfactant-free fabrication protocol performable under ambient conditions using commercial porphyrins as building blocks is strongly desired. We herein report that a commercial metal-free porphyrins, 5,10,15,20-tetrakis(4-aminophenyl)porphyrin (TPPNH2), could be facilely organized to form well-defined discrete spherical nanoassemblies at room temperature by means of a simple reprecipitation method. We further find that the as-manufactured TPPNH2 nanospheres could work as photocatalysts towards the reduction of potassium tetrachloroplatinate(ii), leading to their self-platinization and the production of platinum/porphyrin nanosphere nanocomposites, wherein ultrathin Pt nanoparticles of a size of ca. 3 nm are immobilized on the porphyrin nanospheres. Significantly, by taking the advantage of their easy sedimentation from aqueous suspensions, we show that the as-produced composites could serve as qualified heterogeneous nanocatalysts in terms of their excellent catalytic stability and recyclability towards the reduction of 4-nitrophenol, where the catalytic reactivity exhibits only trivial changes even after the reactions have been repeated 8 times continuously. Taking into account the general concerns of porphyrins- and Pt-based nanostructures, this might provide a facile method for the construction of spherical porphyrin nanostructures with self-platinization capability. Meanwhile, considering the high cost and scarcity of Pt, our nanocomposites with excellent stability and recyclability likely have a bright future of potential uses.

Fluorescence polarization-based method with bisulfite conversion-specific one-label extension for quantification of single CpG dinucleotide methylation.

To quantify the methylation at individual CpG dinucleotide sites in large biological or clinical samples, we developed a bisulfite conversion-specific one-label extension (BS-OLE) method using visualization by fluorescence polarization (FP) measurement of methylation at single CpG sites in small amounts of genomic DNA. Genomic DNA was treated with sodium bisulfite to convert unmethylated cytosine to uracil leaving 5-methylcytosine unaltered, and BS-PCR was used to generate DNA template containing target CpG sites. BS-OLE uses a BS-primer hybridized immediately upstream of the target CpG site being examined and then fluorescent dCTP or dUTP is incorporated into the methylated (CpG) or unmethylated (TpG) form of the target site through single-nucleotide chain extension, yielding an FP ratio between the fluorescent dCTP- and dUTP-incorporated products as a measure of methylation. This provides stable estimates of the methylation level of human genomic DNA and of a 250-bp plasmid DNA segment containing a single TCGA TaqI cleavage site, in accordance with the results of a combined bisulfite restriction analysis method. We used BS-OLE to measure dose-dependent DNA hypomethylation in human embryonic kidney 293T cells treated with the DNA methyltransferase inhibitor 5-aza-dC. BS-OLE is well suited to high-throughput multi-sample applications in biological and medical studies.

Activation of γ-globin expression by LncRNA-mediated ERF promoter hypermethylation in ß-thalassemia.

The mechanism that drives the switch from fetal to adult hemoglobin (Hb) provides a therapeutic target for ß-thalassemia. We have previously identified that hypermethylation of transcription factor ERF promoter reactivated γ-globin expression. To uncover the mechanism underlying the hypermethylation of ERF promoter, we performed RNA sequencing in ß0/ß0-thalassemia patients and identified an upregulated long noncoding RNA (RP11-196G18.23) associated with HbF production. RP11-196G18.23 bound to the ERF promoter and recruited DNA methyltransferase 3A to promote DNA hypermethylation-mediated ERF downregulation, thereby ameliorating ERF-induced γ-globin inactivation. The identification of RP11-196G18.23 provides an epigenetic mechanism for the reactivation of fetal γ-globin expression for ß-hemoglobinopathies.

Biredox-Ionic Anthraquinone-Coupled Ethylviologen Composite Enables Reversible Multielectron Redox Chemistry for Li-Organic Batteries.

Organic compounds bearing redox-active ionic pairs as electrode materials for high-performance rechargeable batteries have gained growing attention owing to the properties of synthetic tunability, high theoretical capacity, and low solubility. Herein, an innovative biredox-ionic composite, i.e., ethylviologen dianthraquinone-2-sulfonate (EV-AQ2 ), affording multiple and reversible active sites as a cathode material in lithium-organic batteries is reported. EV-AQ2 exhibits a high initial capacity of 199.2 mAh g-1 at 0.1 C rate, which corresponds to the transfer of two electrons from one redox couple EV2+ /EV0 and four electrons from two redox-active AQ- anions. It is notable that EV-AQ2 shows remarkably improved cyclability compared to the precursors. The capacity retention is 89% and the Coulombic efficiency approaches 100% over 120 cycles at 0.5 C rate. The results offer evidence that AQ- into the EV2+ scaffold with multiple redox sites are promising in developing high-energy-density organic rechargeable batteries.

Dielectric property measurements for the rapid differentiation of thoracic lymph nodes using XGBoost in patients with non-small cell lung cancer: a self-control clinical trial.

Background: One of the important criteria for thoracic surgeons in making surgical strategies is whether the thoracic lymph nodes (LNs) are metastatic. Frozen section (FS) is widely used as an intraoperative diagnostic method, which is time-consuming and expensive. The dielectric property, including permittivity and conductivity, varies with different tissues. The extreme gradient boosting (XGBoost) is a powerful classifier and widely used. Thus, this study aims to develop the rapid differentiation method combining dielectric property and XGBoost, and assess its efficacy on the thoracic LNs in patients with non-small cell lung cancer (NSCLC). Methods: This was a single center self-control clinical trial with paraffin pathology section (PPS) results as gold diagnosis. The LNs from the pathologically diagnosed patients with NSCLC were recruited, which were measured by open-ended coaxial probe for the dielectric property within 1-4,000 MHz after removal from the patients and then were sent to perform FS and PPS diagnosis. The XGBoost combining with dielectric property was developed to differentiate malignant LNs from benign LNs. The classified efficacy was determined using the receiver operator characteristic (ROC) curve and area under the curve (AUC). Results: A total of 204 LNs from 67 NSCLC patients were analyzed. The mean values of the two parameters differed significantly (P<0.001) between benign and malignant LNs. The AUC for permittivity and conductivity were 0.850 [95% confidence interval (CI): 0.786 to 0.915; P<0.001] and 0.887 (95% CI: 0.828 to 0.946; P<0.001), respectively. The AUC was 0.893 (95% CI: 0.834 to 0.951; P<0.001) when the two parameters were combined. After the application of the XGBoost, the AUC was 0.968 (95% CI: 0.918 to 1.000; P<0.001), and the accuracy was 87.80%. Its sensitivity was 58.33% and the specificity was 100%. When the Synthetic Minority Oversampling Technique (SMOTE) algorithm was used, the AUC was 0.954 (95% CI: 0.883 to 1.000; P<0.001) and the accuracy was 92.68%. Its sensitivity was 83.33% and the specificity was 96.55%. Conclusions: This method might be useful for thoracic surgeons during surgery, for its relatively high efficacy in rapid differentiation of LNs for patients with NSCLC.

LncRNA RP5-998N21.4 promotes immune defense through upregulation of IFIT2 and IFIT3 in schizophrenia.

Schizophrenia is a complex polygenic disease that is affected by genetic, developmental, and environmental factors. Accumulating evidence indicates that environmental factors such as maternal infection and excessive prenatal neuroinflammation may contribute to the onset of schizophrenia by affecting epigenetic modification. We recently identified a schizophrenia-associated upregulated long noncoding RNA (lncRNA) RP5-998N21.4 by transcriptomic analysis of monozygotic twins discordant for schizophrenia. Importantly, we found that genes coexpressed with RP5-998N21.4 were enriched in immune defense-related biological processes in twin subjects and in RP5-998N21.4-overexpressing (OE) SK-N-SH cell lines. We then identified two genes encoding an interferon-induced protein with tetratricopeptide repeat (IFIT) 2 and 3, which play an important role in immune defense, as potential targets of RP5-998N21.4 by integrative analysis of RP5-998N21.4OE-induced differentially expressed genes (DEGs) in SK-N-SH cells and RP5-998N21.4-coexpressed schizophrenia-associated DEGs from twin subjects. We further demonstrated that RP5-998N21.4 positively regulates the transcription of IFIT2 and IFIT3 by binding to their promoter regions and affecting their histone modifications. In addition, as a general nuclear coactivator, RMB14 (encoding RNA binding motif protein 14) was identified to facilitate the regulatory role of RP5-998N21.4 in IFIT2 and IFIT3 transcription. Finally, we observed that RP5-998N21.4OE can enhance IFIT2- and IFIT3-mediated immune defense responses through activation of signal transducer and activator of transcription 1 (STAT1) signaling pathway in U251 astrocytoma cells under treatment with the viral mimetic polyinosinic: polycytidylic acid (poly I:C). Taken together, our findings suggest that lncRNA RP5-998N21.4 is a critical regulator of immune defense, providing etiological and therapeutic implications for schizophrenia.

Loss of schizophrenia-related miR-501-3p in mice impairs sociability and memory by enhancing mGluR5-mediated glutamatergic transmission.

Schizophrenia is a polygenetic disease, the heterogeneity of which is likely complicated by epigenetic modifications yet to be elucidated. Here, we performed transcriptomic analysis of peripheral blood RNA from monozygotic twins discordant for schizophrenia and identified a schizophrenia-associated down-regulated microRNA, miR-501-3p. We showed that the loss of miR-501-3p in germline knockout (KO) male mice resulted in dendritic structure defects, glutamatergic transmission enhancement, and sociability, memory, and sensorimotor gating disruptions, which were attenuated when miR-501 expression was conditionally restored in the nervous system. Combining the results of proteomic analyses with the known genes linked to schizophrenia revealed that metabotropic glutamate receptor 5 (mGluR5) was one of the miR-501-3p targets and was elevated in vivo upon loss of miR-501. Treatment with the mGluR5 negative allosteric modulator 3-2((-methyl-4-thiazolyl) ethynyl) pyridine or the N-methyl-d-aspartate receptor antagonist 2-amino-5-phosphonopentanoic acid ameliorated the deficits observed in Mir501-KO mice. The epigenetic and pathophysiological mechanism that links miR-501-3p to the modulation of glutamatergic transmission provides etiological implications for schizophrenia.

Epigenetic Age Acceleration Was Delayed in Schizophrenia.

Schizophrenia is a serious neuropsychiatric disorder with abnormal age-related neurodevelopmental (or neurodegenerative) trajectories. Although an accelerated aging hypothesis of schizophrenia has been proposed, the quantitative study of the disruption of the physiological trajectory caused by schizophrenia is inconclusive. In this study, we employed 3 "epigenetic clock" methods to quantify the epigenetic age of a large sample size of whole blood (1069 samples from patients with schizophrenia vs 1264 samples from unaffected controls) and brain tissues (500 samples from patients with schizophrenia vs 711 samples from unaffected controls). We observed significant positive correlations between epigenetic age and chronological age in both blood and brain tissues from unaffected controls and patients with schizophrenia, as estimated by 3 methods. Furthermore, we observed that epigenetic age acceleration was significantly delayed in schizophrenia from the whole blood samples (aged 20-90 years) and brain frontal cortex tissues (aged 20-39 years). Intriguingly, the genes regulated by the epigenetic clock also contained schizophrenia-associated genes, displaying differential expression and methylation in patients with schizophrenia and involving in the regulation of cell activation and development. These findings were further supported by the dysregulated leukocyte composition in patients with schizophrenia. Our study presents quantitative evidence for a neurodevelopmental model of schizophrenia from the perspective of a skewed "epigenetic clock." Moreover, landmark changes in an easily accessible biological sample, blood, reveal the value of these epigenetic clock genes as peripheral biomarkers for schizophrenia.

Downregulation by CNNM2 of ATP5MD expression in the 10q24.32 schizophrenia-associated locus involved in impaired ATP production and neurodevelopment.

Genome-wide association studies (GWAS) have accelerated the discovery of numerous genetic variants associated with schizophrenia. However, most risk variants show a small effect size (odds ratio (OR) <1.2), suggesting that more functional risk variants remain to be identified. Here, we employed region-based multi-marker analysis of genomic annotation (MAGMA) to identify additional risk loci containing variants with large OR value from Psychiatry Genomics Consortium (PGC2) schizophrenia GWAS data and then employed summary-data-based mendelian randomization (SMR) to prioritize schizophrenia susceptibility genes. The top-ranked susceptibility gene ATP5MD, encoding an ATP synthase membrane subunit, is observed to be downregulated in schizophrenia by the risk allele of CNNM2-rs1926032 in the schizophrenia-associated 10q24.32 locus. The Atp5md knockout (KO) in mice was associated with abnormal startle reflex and gait, and ATP5MD knockdown (KD) in human induced pluripotent stem cell-derived neurons disrupted the neural development and mitochondrial respiration and ATP production. Moreover, CNNM2-rs1926032 KO could induce downregulation of ATP5MD expression and disruptions of mitochondrial respiration and ATP production. This study constitutes an important mechanistic component that links schizophrenia-associated CNNM2 regions to disruption in energy adenosine system modulation and neuronal function by long-distance chromatin domain downregulation of ATP5MD. This pathogenic mechanism provides therapeutic implications for schizophrenia.

Schizophrenia-associated rs4702 G allele-specific downregulation of FURIN expression by miR-338-3p reduces BDNF production.

Genome-wide association studies (GWAS) reveal numerous schizophrenia (SCZ)-associated single-nucleotide polymorphisms (SNPs); however, functional characterizations of the risk variants remain to be established. Using data from 108 SCZ GWAS loci, we performed systematic miRNA binding site screening of 128 SCZ-associated SNPs and found that 2 out of 3 SNPs located in the 3'UTR were predicted to alter 3 miRNAs' binding sites in 2 target genes. Of the identified SNPs, the most genome-wide significant SNP rs4702 (A/G) in the FURIN 3'UTR, previously identified as an SCZ-associated cis-expression quantitative trait loci (downregulated by the risk G allele), is located in the binding site of miR-338-3p in the presence of the risk G allele. Allele-specific downregulation of FURIN by miR-338-3p was validated with a luciferase reporter assay. Furthermore, we demonstrated that miR-338-3p-mediated FURIN inhibition reduced brain-derived neurotrophic factor (BDNF) maturation and secretion in human embryonic kidney 293T cells. Our data reveal that schizophrenia-associated rs4702 G allele-specific downregulation of FURIN by miR-338-3p reduces mature BDNF production. These data help elucidate the mechanism of genetic predisposition toward schizophrenia or other neurodevelopmental diseases.

Hypomethylation of LINE-1 elements in schizophrenia and bipolar disorder.

Schizophrenia (SCZ) and bipolar disorder (BPD) are severe mental illnesses with evidence of significant genetic and environmental etiological elements in their complex etiologies. 5'-Methylcytosine is the main epigenetic DNA modification that mediates the interplay between genetic and environmental components. In humans, most 5'-methylcytosine modifications are observed in CpG-rich regions within the long interspersed nuclear element (LINE-1). LINE-1 is a mobile retrotransposon that comprises ∼17% of the human genome, and its methylation levels are highly correlated with global DNA methylation levels. LINE-1 insertions are also reported to be mental illnesses-associated genomic risk factors. To examine the LINE-1 methylation levels in SCZ and BPD, this study employed a bisulfite conversion-specific one-label extension (BS-OLE) method to detect the methylation levels at three CpG sites (S1, S2 and S3) of LINE-1 in peripheral blood DNA from a Han Chinese cohort composed of 92 SCZ patients, 99 BPD patients and 92 controls (CON). The results showed a decreased S1 methylation level in SCZ, decreased S2 methylation level in BPD and decreased S3 methylation levels in both SCZ and BPD relative to those of the CON. A female-dependent positive correlation of the S3 methylation level with age in CON became non-significant in both SCZ and BPD. These findings demonstrated that LINE-1 methylation varied with development and disease status. The roles of LINE-1 methylation in the pathogenesis of SCZ and BPD remain to be elucidated.