Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression.

How tumor cells genetically lose antigenicity and evade immune checkpoints remains largely elusive. We report that tissue-specific expression of the human long noncoding RNA LINK-A in mouse mammary glands initiates metastatic mammary gland tumors, which phenotypically resemble human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate and inhibitory G-protein-coupled receptor (GPCR) pathways, attenuating protein kinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48-polyubiquitination-mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb and p53, and sensitized mammary gland tumors to immune checkpoint blockers. Patients with programmed ccll death protein-1(PD-1) blockade-resistant TNBC exhibited elevated LINK-A levels and downregulated PLC components. Hence we demonstrate lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which provides the basis for developing combinational immunotherapy treatment regimens and early TNBC prevention.

Metal-Organic Framework Based Sensors for Benzene Vapor.

Sensing of benzene vapor is a hot spot due to the volatile drastic carcinogen even at trace concentration. However, achieving convenient and rapid detection is still a challenge. As a sort of functional porous material, metal-organic frameworks (MOFs) have been developed as detection sensors by adsorbing benzene vapor and converting it into other signals (fluorescence intensity/wavelength, chemiresistive, weight or color, etc.). Supramolecular interaction between benzene molecules and the host framework, aperture size/shape and structural flexibility are influential factors in the performance of MOF-based sensors. Therefore, enhancing the host-guest interactions between the host framework and benzene molecules, or regulating the diffusion rate of benzene molecules by changing the aperture size/shape and flexibility of the host framework to enhance the detection signal are effective strategies for constructing MOF-based sensors. This concept highlights several types of MOF-based sensors for the detection of benzene vapor.

Engineering a Z-Scheme Heterostructure on ZnIn2S4@NH2-MIL-125 Composites for Boosting the Photocatalytic Performance.

Constructing a Z-scheme heterostructure on a metal-organic framework (MOF) composite with an explicit charge transfer mechanism at the interface is considered to be an effective strategy for improving the photocatalytic performance of MOFs. Herein, an internal electric field (IEF)-induced Z-scheme heterostructure on the ZnIn2S4@NH2-MIL-125 composite is designed and fabricated by a facile electrostatic self-assembly process. Systematic investigations reveal that close interfacial contact and difference in work function between NH2-MIL-125 and ZnIn2S4 enable the formation of the IEF, which drives the Z-scheme charge transfer as revealed by the in situ irradiated X-ray photoelectron spectroscopy (ISI-XPS), photoirradiated Kelvin probe force microscope (KPFM) measurement, electron paramagnetic resonance (EPR) radical trapping experiment, as well as density functional theory (DFT) calculation; meanwhile, directions of the interfacial IEFs are determined. Benefiting from the unique merit of IEF-induced Z-scheme charge transfer, the optimized ZnIn2S4@NH2-MIL-125 composite exhibits significantly enhanced photocatalytic activity for the photoreduction of 4-nitroaniline (4-NA) to p-phenylenediamine (PPD) under visible light irradiation. This work not only provides in-depth insights for charge transfer in the IEF-induced Z scheme heterostructure but also affords useful inspirations on designing the Z-scheme MOF composite to boost the photocatalytic performance.

Genetic regulatory and biological implications of the 10q24.32 schizophrenia risk locus.

Genome-wide association studies have identified 10q24.32 as a robust schizophrenia risk locus. Here we identify a regulatory variant (rs10786700) that disrupts binding of transcription factors at 10q24.32. We independently confirmed the association between rs10786700 and schizophrenia in a large Chinese cohort (n = 11 547) and uncovered the biological mechanism underlying this association. We found that rs10786700 resides in a super-enhancer element that exhibits dynamic activity change during the development process and that the risk allele (C) of rs10786700 conferred significant lower enhancer activity through enhancing binding affinity to repressor element-1 silencing transcription factor (REST). CRISPR-Cas9-mediated genome editing identified SUFU as a potential target gene by which rs10786700 might exert its risk effect on schizophrenia, as deletion of rs10786700 downregulated SUFU expression. We further investigated the role of Sufu in neurodevelopment and found that Sufu knockdown inhibited proliferation of neural stem cells and neurogenesis, affected molecular pathways (including neurodevelopment-related pathways, PI3K-Akt and ECM-receptor interaction signalling pathways) associated with schizophrenia and altered the density of dendritic spines. These results reveal that the functional risk single nucleotide polymorphism rs10786700 at 10q24.32 interacts with REST synergistically to regulate expression of SUFU, a novel schizophrenia risk gene which is involved in schizophrenia pathogenesis by affecting neurodevelopment and spine morphogenesis.

Effects of selenium-enriched yeast dietary supplementation on egg quality, gut morphology and caecal microflora of laying hens.

Selenium (Se) is an essential micronutrient for humans and animals and is a powerful antioxidant that can promote reproductive and immune functions. The purpose of this study was to evaluate the effects of supplemental dietary selenium-enriched yeast (SeY) on egg quality, gut morphology and microflora in laying hens. In total, 100 HY-Line Brown laying hens (45-week old) were randomly allocated to two groups with 10 replicates and fed either a basal diet (without Se supplementation) or a basal diet containing 0.2 mg/kg Se in the form of SeY for 8 weeks. The Se supplementation did not have a significant effect on egg quality and intestinal morphology of laying hens. Based on the 16S rRNA sequencing, SeY dietary supplementation effectively modulated the cecal microbiota structure. An alpha diversity analysis demonstrated that birds fed 100 mg/kg SeY had a higher cecal bacterial diversity. SeY dietary addition elevated Erysipelotrichia (class), Lachnospiraceae (family), Erysipelotrichaceae (family) and Ruminococcus_torques_group (genus; p < .05). Analysis of microbial community-level phenotypes revealed that SeY supplementation decreased the microorganism abundance of facultatively anaerobic and potentially pathogenic phenotypes. Overall, SeY supplementation cannot significantly improve intestinal morphology; however, it modulated the composition of cecal microbiota toward a healthier gut.

Proteome-wide association studies have predicted that the protein abundance of LSM6, GMPPB, ICA1L, and CISD2 is associated with attention-deficit/hyperactivity disorder.

Identification of changes in protein abundance for attention-deficit/hyperactivity disorder (ADHD) is important for potential disease mechanisms and therapeutic study for ADHD. In order to identify candidate proteins that confer risk for ADHD, a proteome-wide association study (PWAS) for ADHD was conducted by integrating two human brain proteome datasets and the ADHD genome-wide association study (GWAS) summary statistics released by the Psychiatric Genomics Consortium (PGC). A total of 11 risk proteins were identified as significant candidates that passed the bonferroni corrected proteome-wide significant (PWS) level. The predicted protein abundance level of LSM6, GMPPB, ICA1L and CISD2 are shown significantly associated with ADHD in both proteome datasets, highlighting their potential role in ADHD pathogenesis. A transcriptome-wide association study (TWAS) of ADHD was also conducted, and 13 genes with predicted expression changes related to ADHD were identified. GMPPB, ICA1L and NAT6 were supported by both TWAS and PWASs analysis. This study uncovers the predicted protein abundance changes that confer risk for ADHD and pinpoints a number of high-confidence protein candidates (e.g. LSM6, GMPPB, ICA1L, CISD2) for further functional exploration studies and drug development targeting these proteins.

Stable Pyrene-Based Metal-Organic Framework for Cyclization of Propargylic Amines with CO2 and Detection of Antibiotics in Water.

A pyrene-based metal-organic framework, Cd2(PTTB)(H2O)2 (WYU-11), was synthesized from the tetracarboxylic pyrene ligand H4PTTB (H4PTTB = 1,3,6,8-tetrakis(3-carboxyphenyl)pyrene) and Cd(NO3)2·4H2O. Powder X-ray diffraction analysis discloses that the framework is stable in acid, base, and various organic solvent environments. WYU-11 shows excellent catalytic performance on the cyclization reaction of propargylic amines with CO2 into 2-oxazolidinones under mild conditions (60 °C, atmospheric CO2). 1H NMR studies unveiled that WYU-11 and 1,1,3,3-tetramethylguanidine (TMG) can synergistically activate the propargylic amine substrate and promote the reaction. Importantly, WYU-11 represents a rare example of noble metal-free heterogeneous catalyst that can catalyze the cyclization of CO2 with propargylic amines. In addition, by virtue of the excellent water stability and luminescence properties, WYU-11 shows excellent detection performance for sulfathiazole (STZ) and ornidazole (ODZ) in water. Investigation reveals that the coexistence of photoinduced electron transfer and internal filtering effect could reasonably explain the luminescence quenching of WYU-11 by the antibiotics.

Regulatory variants at 2q33.1 confer schizophrenia risk by modulating distal gene TYW5 expression.

Genome-wide association studies have shown that genetic variants at 2q33.1 are strongly associated with schizophrenia. However, potential causal variants in this locus and their roles in schizophrenia remain unknown. Here, we identified two functional variants (rs796364 and rs281759) that disrupt CTCF, RAD21 and FOXP2 binding at 2q33.1. We systematically investigated the regulatory mechanisms of these two variants with serial experiments, including reporter gene assays and electrophoretic mobility shift assay. Intriguingly, these two single nucleotide polymorphisms physically interacted with TYW5 and showed the most significant associations with TYW5 expression in human brain. Consistently, CRISPR-Cas9-mediated genome editing confirmed the regulatory effect of the two single nucleotide polymorphisms on TYW5 expression. Additionally, expression analysis indicated that TYW5 was significantly upregulated in brains of schizophrenia cases compared with controls, suggesting that rs796364 and rs281759 might confer schizophrenia risk by modulating TYW5 expression. We over-expressed TYW5 in mouse neural stem cells and rat primary neurons to mimic its upregulation in schizophrenia and found significant alterations in the proliferation and differentiation of neural stem cells, as well as dendritic spine density following TYW5 overexpression, indicating its important roles in neurodevelopment and spine morphogenesis. Furthermore, we independently confirmed the association between rs796364 and schizophrenia in a Chinese cohort of 8202 subjects. Finally, transcriptome analysis revealed that TYW5 affected schizophrenia-associated pathways. These lines of evidence consistently revealed that rs796364 and rs281759 might contribute to schizophrenia risk by regulating the expression of TYW5, a gene whose expression dysregulation affects two important schizophrenia pathophysiological processes (i.e. neurodevelopment and dendritic spine formation).

Functional variant rs2270363 on 16p13.3 confers schizophrenia risk by regulating NMRAL1.

Recent genome-wide association studies have reported multiple schizophrenia risk loci, yet the functional variants and their roles in schizophrenia remain to be characterized. Here we identify a functional single nucleotide polymorphism (rs2270363: G>A) at the schizophrenia risk locus 16p13.3. rs2270363 lies in the E-box element of the promoter of NMRAL1 and disrupts binding of the basic helix-loop-helix leucine zipper family proteins, including USF1, MAX and MXI1. We validated the regulatory effects of rs2270363 using reporter gene assays and electrophoretic mobility shift assay. Besides, expression quantitative trait loci analysis showed that the risk allele (A) of rs2270363 was significantly associated with elevated NMRAL1 expression in the human brain. Transcription factors knockdown and CRISPR-Cas9-mediated editing further confirmed the regulatory effects of the genomic region containing rs2270363 on NMRAL1. Intriguingly, NMRAL1 was significantly downregulated in the brain of schizophrenia patients compared with healthy subjects, and knockdown of Nmral1 expression affected proliferation and differentiation of mouse neural stem cells, as well as genes and pathways associated with brain development and synaptic transmission. Of note, Nmral1 knockdown resulted in significant decrease of dendritic spine density, revealing the potential pathophysiological mechanisms of NMRAL1 in schizophrenia. Finally, we independently confirmed the association between rs2270363 and schizophrenia in the Chinese population and found that the risk allele of rs2270363 was the same in European and Chinese populations. These lines of evidence suggest that rs2270363 may confer schizophrenia risk by regulating NMRAL1, a gene whose expression dysregulation might be involved in the pathogenesis of schizophrenia by affecting neurodevelopment and synaptic plasticity.

Relationship between dietary carotenoid intake and sleep duration in American adults: a population-based study.

OBJECTIVE: To investigate the relationship between dietary carotenoid intake and sleep duration. METHODS: Adults enrolled in the National Health and Nutrition Examination Survey (NHANES) 2007-2018 without missing information on dietary carotenoid intake (α-carotene, ß-carotene, ß-cryptoxanthin, lycopene, and lutein + zeaxanthin), sleep duration, and covariates were included. Participants' carotenoid consumption was divided into three groups by quartiles and sleep duration was grouped as short (< 7 h/night), optimal (7-8 h/night), and long (> 8 h/night). Multinominal logistic regression was constructed to examine the association between dietary carotenoid intake and sleep duration. Restricted cubic spline (RCS) regression was further utilized to explore their dose-response relationship. The weighted quantile sum (WQS) model was adopted to calculate the mixed and individual effect of 5 carotenoid sub-types on sleep duration. RESULTS: Multinominal logistic regression presented that people with higher intakes of α-carotene, ß-carotene, ß-cryptoxanthin, lycopene, and lutein + zeaxanthin were less likely to sleep too short or too long. Consistent with the findings from multinominal logistic regression, the RCS models suggested a reverse U-shaped relationship between sleep duration and carotenoid intakes. The mixed effects were also significant, where ß-cryptoxanthin and lutein + zeaxanthin were the top 2 contributors associated with the decreased risks of short sleep duration, while ß-carotene, α-carotene, and ß-cryptoxanthin were the main factors related to the lower risk of long sleep duration. CONCLUSION: Our study revealed that the American adults with optimal sleep duration were associated with more dietary carotenoid intake, in comparison to short or long sleepers.

Evaluation of the repeatability of optical coherence tomography in patients with age-related cataract associated with dry eye.

AIM: To assess the repeatability of a new optical biometer (OA-2000, Tomey, Japan) based on swept-source optical coherence tomography (SS-OCT) and Placido-disk topography in dry eyes with cataracts. METHOD: A cross-sectional study was performed. Two hundred sixteen eyes of 216 cataract patients were enrolled in our hospital from March 2020 to December 2020. According to the subjective symptoms and objective examination of dry eye, the patients were assigned to dry eye group and non-dry eye group. Axial length (AL), keratometry readings (K), lens thickness (LT), anterior chamber depth (ACD), central corneal thickness (CCT) and white-to-white (WTW) distance were measured by one skilled operator. The repeatability of each parameter based on within-subject standard deviation (Sw), repeatability limit of standard deviation (2.77Sw), coefficient of variation (CoV) and intra-class correlation coefficient (ICC) was evaluated. RESULT: There was no significant difference in age and gender between the two groups. NiaBUT and NifBUT in the dry eye group were significantly lower than those in the non-dry eye group (p < 0.05). The ICC mean values of AL, K1, K2, Km, ACD, LT and CCT were all greater than 0.960, except WTW. In the dry eye group, except CCT and WTW, the Sw scores for other biometric parameters were lower than 0.201, 2.77Sw scores were lower than 0.557, CoV(%) was less than 1%, and ICC mean values were greater than 0.964. Among them, the Sw scores for AL, LT and ACD were lower than 0.035, the 2.77Sw scores were lower than 0.097, and the ICC mean values are greater than 0.990. CONCLUSION: The ocular biological parameters measured by SS-OCT have good repeatability for age-related cataract patients with dry eyes, in which the AL, LT and ACD are the highest repeatable. However, more attention should be paid for WTW in clinical application since repeatability influence.

[Zi Huangjing TM Preparation Relieves Cancer-Related Fatigue During Chemotherapy: A Prospective Single-Arm Multicenter Clinical Trial].

Objective: To primarily explore the efficacy of Zi Huangjing TM preparation in patients with cancer-related fatigue (CRF) during chemotherapy. Methods: This study was designed as a prospective, single-arm, multicenter clinical trial. According to the plan of the study, patients with malignant tumors who had received at least one cycle of chemotherapy and had moderate-to-severe CRF (Piper Fatigue Scale score≥4) were enrolled. All the enrolled patients took Zi Huangjing TM preparation (2.1 g, twice a day) every day during the two subsequent cycles of chemotherapy and were followed up. During the period, the enrolled patients independently completed the Piper Fatigue Scale and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) scale, and part of their biochemical and immunological indicators were measured at the baseline, before the second cycle of chemotherapy (day 21), and before the third cycle of chemotherapy (day 42). The primary endpoint was the change in Piper Fatigue Scale scores between the baseline and day 42. Results: Eventually, 47 patients completed the entire study. After treatment, the mean score of the Piper Fatigue Scale assessed before the third cycle of chemotherapy (day 42) was 3.21±1.67, which was significantly lower than that at baseline (5.89±1.36) ( P=0.000), and the patients' CRF was significantly improved. In terms of quality of life, the patient's global quality of life, physical functions, role function, emotional function, cognitive function, and social function were significantly improved. In terms of symptom management, the patient's symptoms, such as fatigue, nausea and vomiting, insomnia, and appetite loss also significantly improved. No severe adverse reactions (grades 3 and 4) occurred during the observation period of this study. After evaluation, the adverse reactions that the patients actually had were considered to be related to chemotherapy, but unrelated to Zi Huangjing TM preparation. Conclusion: According to our preliminary investigation, Zi Huangjing TM preparation is safe and has the potential therapeutic effect of improving CRF in cancer patients during chemotherapy. However, further larger-scale randomized controlled clinical studies are needed to confirm the efficacy of Zi Huangjing TM in improving CRF.

Functional genomics elucidates regulatory mechanisms of Parkinson's disease-associated variants.

BACKGROUND: Genome-wide association studies (GWASs) have identified multiple risk loci for Parkinson's disease (PD). However, identifying the functional (or potential causal) variants in the reported risk loci and elucidating their roles in PD pathogenesis remain major challenges. To identify the potential causal (or functional) variants in the reported PD risk loci and to elucidate their regulatory mechanisms, we report a functional genomics study of PD. METHODS: We first integrated chromatin immunoprecipitation sequencing (ChIP-Seq) (from neuronal cells and human brain tissues) data and GWAS-identified single-nucleotide polymorphisms (SNPs) in PD risk loci. We then conducted a series of experiments and analyses to validate the regulatory effects of these (i.e., functional) SNPs, including reporter gene assays, allele-specific expression (ASE), transcription factor (TF) knockdown, CRISPR-Cas9-mediated genome editing, and expression quantitative trait loci (eQTL) analysis. RESULTS: We identified 44 SNPs (from 11 risk loci) affecting the binding of 12 TFs and we validated the regulatory effects of 15 TF binding-disrupting SNPs. In addition, we also identified the potential target genes regulated by these TF binding-disrupting SNPs through eQTL analysis. Finally, we showed that 4 eQTL genes of these TF binding-disrupting SNPs were dysregulated in PD cases compared with controls. CONCLUSION: Our study systematically reveals the gene regulatory mechanisms of PD risk variants (including widespread disruption of CTCF binding), generates the landscape of potential PD causal variants, and pinpoints promising candidate genes for further functional characterization and drug development.

A missense variant in NDUFA6 confers schizophrenia risk by affecting YY1 binding and NAGA expression.

Genome-wide association studies (GWASs) have revealed that genetic variants at the 22q13.2 risk locus were robustly associated with schizophrenia. However, the causal variants at this risk locus and their roles in schizophrenia remain elusive. Here we identify the risk missense variant rs1801311 (located in the 1st exon of NDUFA6 gene) as likely causal for schizophrenia at 22q13.2 by disrupting binding of YY1, TAF1, and POLR2A. We systematically elucidated the regulatory mechanisms of rs1801311 and validated the regulatory effect of this missense variant. Intriguingly, rs1801311 physically interacted with NAGA (encodes the alpha-N-acetylgalactosaminidase, which is mainly involved in regulating metabolisms of glycoproteins and glycolipids in lysosome) and showed the most significant association with NAGA expression in the human brain, with the risk allele (G) associated with higher NAGA expression. Consistent with eQTL analysis, expression analysis showed that NAGA was significantly upregulated in brains of schizophrenia cases compared with controls, further supporting that rs1801311 may confer schizophrenia risk by regulating NAGA expression. Of note, we found that NAGA regulates important neurodevelopmental processes, including proliferation and differentiation of neural stem cells. Transcriptome analysis corroborated that NAGA regulates pathways associated with neuronal differentiation. Finally, we independently confirmed the association between rs1801311 and schizophrenia in a large Chinese cohort. Our study elucidates the regulatory mechanisms of the missense schizophrenia risk variant rs1801311 and provides mechanistic links between risk variant and schizophrenia etiology. In addition, this study also revealed the novel role of coding variants in gene regulation and schizophrenia risk, i.e., genetic variant in coding region of a specific gene may confer disease risk through regulating distal genes (act as regulatory variant for distal genes).

Comparative study of Curcumin and Lucentis on retinal neovascularization.

Introduction To investigate the effect of Curcumin on retinal neovascularization in mice with oxygen-induced lesions. Methods 7-day-old (P7) C57/BL6J mice were randomly divided into control group, OIR group, DMSO group, 100 mg/kg, 50 mg/kg and 25 mg/kg curcumin group and Lucentis group (15 mice per group). Mice in the experimental group were fed for 5 days in high oxygen partial pressure environment, and then in normal oxygen air environment for another 5 days. Corresponding interventions were given at 12-16 days of age (P12-16). At 17 days of age (P17), the eyeball was removed and the retina was paved with Isolectin GS-IB4 fluorescence staining. Real-time PCR was used to detect VEGF mRNA levels in tissues and cells. The protein expression level of VEGF was detected by Western blot. Results Immunofluorescence showed that curcumin injection could significantly reduce the formation of retinal neovascularization and astrocyte injury in OIR, and 100 mg/kg curcumin group had the best effect. Compared with the control group, mRNA and protein expression of VEGF in retina of mice in OIR and DMSO groups were significantly up-regulated (P<0.05); Compared with OIR group, curcumin group and Lucentis group were down-regulated (P<0.05). The protein expression and mRNA level of VEGF in HRCECs of curcumin group decreased with the increase of curcumin concentration, and the effect of curcumin group at 80µmol/L was similar to that of Lucentis group. In the HRCECs cultured with the same concentration of curcumin, the protein expression and mRNA level of VEGF decreased with the prolongation of drug intervention time. Conclusion Curcumin can down-regulate the expression of VEGF in retinal tissues and cells, thereby inhibiting retinal neovascularization and HRCECs cell proliferation.

Genome-wide association study followed by trans-ancestry meta-analysis identify 17 new risk loci for schizophrenia.

BACKGROUND: Over 200 schizophrenia risk loci have been identified by genome-wide association studies (GWASs). However, the majority of risk loci were identified in populations of European ancestry (EUR), potentially missing important biological insights. It is important to perform 5 GWASs in non-European populations. METHODS: To identify novel schizophrenia risk loci, we conducted a GWAS in Han Chinese population (3493 cases and 4709 controls). We then performed a large-scale meta-analysis (a total of 143,438 subjects) through combining our results with previous GWASs conducted in EAS and EUR. In addition, we also carried out comprehensive post-GWAS analysis, including heritability partitioning, enrichment of schizophrenia associations in tissues and cell types, trancscriptome-wide association study (TWAS), expression quantitative trait loci (eQTL) and differential expression analysis. RESULTS: We identified two new schizophrenia risk loci, including associations in SHISA9 (rs7192086, P = 4.92 × 10-08) and PES1 (rs57016637, P = 2.33 × 10-11) in Han Chinese population. A fixed-effect meta-analysis (a total of 143,438 subjects) with summary statistics from EAS and EUR identifies 15 novel genome-wide significant risk loci. Heritability partitioning with linkage disequilibrium score regression (LDSC) reveals a significant enrichment of schizophrenia heritability in conserved genomic regions, promoters, and enhancers. Tissue and cell-type enrichment analyses show that schizophrenia associations are significantly enriched in human brain tissues and several types of neurons, including cerebellum neurons, telencephalon inhibitory, and excitatory neurons. Polygenic risk score profiling reveals that GWAS summary statistics from trans-ancestry meta-analysis (EAS + EUR) improves prediction performance in predicting the case/control status of our sample. Finally, transcriptome-wide association study (TWAS) identifies risk genes whose cis-regulated expression change may have a role in schizophrenia. CONCLUSIONS: Our study identifies 17 novel schizophrenia risk loci and highlights the importance and necessity of conducting genetic study in different populations. These findings not only provide new insights into genetic etiology of schizophrenia, but also facilitate to delineate the pathophysiology of schizophrenia and develop new therapeutic targets.

Regulatory mechanisms of major depressive disorder risk variants.

Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders and a leading cause of disability worldwide. Though recent genome-wide association studies (GWAS) have identified multiple risk variants for MDD, how these variants confer MDD risk remains largely unknown. Here we systematically characterize the regulatory mechanism of MDD risk variants using a functional genomics approach. By integrating chromatin immunoprecipitation sequencing (ChIP-Seq) (from human brain tissues or neuronal cells) and position weight matrix (PWM) data, we identified 34 MDD risk SNPs that disrupt the binding of 15 transcription factors (TFs). We verified the regulatory effect of the TF binding-disrupting SNPs with reporter gene assays, allelic-specific expression analysis, and CRISPR-Cas9-mediated genome editing. Expression quantitative trait loci (eQTL) analysis identified the target genes that might be regulated by these regulatory risk SNPs. Finally, we found that NEGR1 (regulated by the TF binding-disrupting MDD risk SNP rs3101339) was dysregulated in the brains of MDD cases compared with controls, implying that rs3101339 may confer MDD risk by affecting NEGR1 expression. Our findings reveal how genetic variants contribute to MDD risk by affecting TF binding and gene regulation. More importantly, our study identifies the potential MDD causal variants and their target genes, thus providing pivotal candidates for future mechanistic study and drug development.

Functional variants fine-mapping and gene function characterization provide insights into the role of ZNF323 in schizophrenia pathogenesis.

Schizophrenia is a severe mental disease characterized with positive symptoms, negative symptoms, and cognitive impairments. Although recent genome-wide association studies (GWASs) have identified over 145 risk loci for schizophrenia, pinpointing the causal variants and genes at the reported loci and elucidating their roles in schizophrenia remain major challenges. Here we identify a functional single-nucleotide polymorphism (SNP; rs213237) in ZNF323 promoter by using functional fine-mapping. We found that allelic differences at rs213237 affected the ZNF323 promoter activity significantly. Consistently, expression quantitative trait loci (eQTL) analysis showed that rs213237 was significantly associated with ZNF323 expression in diverse human brain tissues, suggesting that rs213237 may contribute to schizophrenia risk through regulating ZNF323 expression. Interestingly, we found that ZNF323 protein was localized in the nucleus and knockdown of ZNF323 in macaque neural stem cells (mNSCs) significantly impaired proliferation and survival of mNSCs. We further showed that stable knockdown of ZNF323 in SH-SY5Y cells resulted in significant decrease of the tyrosine hydroxylase (TH) protein expression. Finally, transcriptome analysis revealed that ZNF323 may regulate pivotal schizophrenia risk genes (including VIPR2 and NPY) and schizophrenia-associated pathways (including PI3K-AKT and NOTCH signaling pathways), suggesting that ZNF323 may be a major regulator of schizophrenia risk genes. Our study reveals how a genetic variant in ZNF323 promoter contributes to schizophrenia risk through regulating ZNF323 expression. More importantly, our findings demonstrate that ZNF323 may have a pivotal role in schizophrenia pathogenesis through regulating schizophrenia risk genes and schizophrenia-associated biological processes (including neurodevelopment, PI3K-AKT, and NOTCH signaling pathways).

Engineering Porphyrin Metal-Organic Framework Composites as Multifunctional Platforms for CO2 Adsorption and Activation.

As an effective solution toward the establishment of a sustainable society, the reductive transformation of CO2 into value-added products is certainly important and imperative. Herein, we report a porphyrin metal-organic framework composite Au@Ir-PCN-222, which is obtained through the in situ formation of Au nanoparticles in the coordination interspaces of Ir-PCN-222. Catalytic results show that Au@Ir-PCN-222 is highly efficient for CO2 reduction and aminolysis, giving rise to formamides in high yields and selectivities under room temperature and atmospheric pressure. Mechanistic studies disclose that the high efficiency of Au@Ir-PCN-222 is due to the synergistic catalysis of Au NPs and Ir-PCN-222, in which Au NPs can adsorb CO2 molecules on their surfaces and then increase the CO2 concentration in the cavities of the framework, and at the same time, Au NPs transfer electrons to Ir-porphyrin units and therefore increase the interactions with CO2 molecules.

SZDB2.0: an updated comprehensive resource for schizophrenia research.

During the past decade, genetic studies of schizophrenia have become one of the most exciting and fast-moving areas. Hundreds of genes implicated in schizophrenia have been identified by genetic, epigenetic, and gene expression studies. However, how to systematically and efficiently use these published data to pinpoint the causal genes becomes a major challenge in schizophrenia research. Here, we release an updated version of a comprehensive database for schizophrenia research, SZDB2.0 ( www.szdb.org ), which accompanies significant data expansion and feature improvements, as well as functionality optimization. Compared with the first version (SZDB), the current database has the following updates: (1) We added the newly published genome-wide association study (GWAS) of schizophrenia from CLOZUK + PGC, which is the largest GWAS for schizophrenia; (2) We included a polygenic risk score calculator; (3) In the refined "Gene" module of SZDB2.0, we collated genetic, gene expression, methylation, and integrative results of all available schizophrenia studies; (4) In the "CNV (copy number variation)" module, we collated the results of all 77 CNV publications about schizophrenia; (5) We also updated other data, including gene expression quantitative trait loci (eQTL), transcript QTL, methylation QTL, and protein-protein interaction data, based on the information from the latest literatures. We optimized the query interface of SZDB2.0 for a better visualization and data retrieval. The updated SZDB2.0 will advance the research of schizophrenia.