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1.
Bioinformatics ; 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31603498

RESUMO

SUMMARY: Cancer hallmarks rely on its specific transcriptional programs, which are dysregulated by multiple mechanisms, including genomic aberrations in the DNA regulatory regions. Genome-wide association studies (GWAS) have shown many variants are found within putative enhancer elements. To provide insights into the regulatory role of enhancer-associated noncoding variants in cancer epigenome, and to facilitate the identification of functional noncoding mutations, we present dbInDel, a database where we have comprehensively analyzed enhancer-associated insertion and deletion variants for both human and murine samples using ChIP-Seq data. Moreover, we provide the identification and visualization of upstream TF binding motifs in InDel-containing enhancers. Downstream target genes are also predicted and analyzed in the context of cancer biology. The dbInDel database promotes the investigation of functional contributions of noncoding variants in cancer epigenome. AVAILABILITY: The database, dbInDel, can be accessed from http://enhancer-indel.cam-su.org/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

2.
ACS Appl Mater Interfaces ; 11(35): 32261-32268, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31394900

RESUMO

Multicolored photonic crystal carbon fiber (CF) yarns and fabrics with mechanical robustness in a full spectrum are reported. By facilely controlling the thickness of the periodic layer, a series of photonic CF yarns and fabrics with vivid structural colors ranging from purple, green, yellow, orange, to red are obtained. Interestingly, the prepared multicolored CF yarns show anisotropic optical reflection properties because of their unique axisymmetric geometry, while the plain-woven fabrics exhibit vivid colors even under ambient scattering light. Most importantly, they can withstand cyclical mechanical rubbing, laundering, and accelerated light aging, indicating great potential for practical uses. Finally, considering such impressive characteristics as well as reflection in the visible and near-infrared regions, the above photonic crystal microstructure is further used as a new material for the application of outdoor reflective cooling of the textile surface, demonstrating a superior temperature reduction up to ∼12 °C with respect to the control sample.

3.
Int Urol Nephrol ; 51(10): 1873-1881, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31332701

RESUMO

BACKGROUND: Administration of ulinastatin was proved to protect many organs from ischemia/reperfusion (I/R) induced injury, yet its protective effects on renal I/R injury under cold condition and mechanism still remain unclear. AIMS: In the present study, the protective effects of ulinastatin on renal cold I/R injury as well as its mechanism were investigated. METHODS AND RESULTS: Renal cold I/R model was constructed via cross-clamping of left renal artery and vein at 4 °C. The ulinastatin was administrated and multi-methods were performed to evaluate the protective effects. The results showed that ulinastatin could mitigate the renal cold I/R injury. In addition, the attenuated kidney cold I/R injury by ulinastatin was also accompanied with its regulating capability of the microenvironment, such as decreased acute inflammatory response, oxidative stress damage and apoptosis, as well as attenuation of vasculature levels decrease, as evidence by reduced TNF-α, IL-6 mRNA expression, MDA levels and apoptosis, higher levels of SOD activity and CD31/α-SMA expression. CONCLUSION: The present study suggested that ulinastatin might be clinically useful in reducing preservation injury induced by cold I/R during renal transplantation surgery.

4.
Brain Res Bull ; 152: 257-264, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31351159

RESUMO

Recently, the insular cortex (IC) was identified as part of the neuronal circuit responsible for the reward expectations in cue-triggered behaviours. Moreover, there are evidences that connections between the IC and the ventral striatum, particularly with the nucleus accumbens (NAc), may mediate the retrieval and performance of actions based on incentive memory. However, the precise role of the IC-NAc connections in cue-related drug-seeking behaviour remains unclear. We used the morphine-induced conditioned place preference (CPP) paradigm to assess the formation and relapse of cue-related drug-seeking. cFos immunostaining was used to determine the activation of the brain regions. Chemogenetic and optogenetic methods were used to manipulate the activity of IC-to-NAc projection neurons. The result showed that neurons in IC and NAc core but not NAc shell were activated following cue-induced morphine-seeking behaviour. Negligible effect of inhibition of IC-to-NAc core projection (IC→NAc core) on morphine CPP expression, whereas chemogenetic inactivation of this projection potently blocked the reinstatement of expressed morphine CPP. Furthermore, optogenetic inhibition of glutamatergic IC→NAc core inputs significant suppressed the CPP reinstatement without significant effect on CPP expression. We demonstrated here, for the first time, that IC→NAc core glutamatergic projection is required for the reinstatement of cue-associated drug seeking behaviour in mice. The present study provide insights into modulations of relapse of cue-associated drug-seeking behaviour following repeated overexposure to opioids in humans.

5.
Nat Commun ; 10(1): 2417, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160569

RESUMO

Accumulating evidence from genome wide association studies (GWAS) suggests an abundance of shared genetic influences among complex human traits and disorders, such as mental disorders. Here we introduce a statistical tool, MiXeR, which quantifies polygenic overlap irrespective of genetic correlation, using GWAS summary statistics. MiXeR results are presented as a Venn diagram of unique and shared polygenic components across traits. At 90% of SNP-heritability explained for each phenotype, MiXeR estimates that 8.3 K variants causally influence schizophrenia and 6.4 K influence bipolar disorder. Among these variants, 6.2 K are shared between the disorders, which have a high genetic correlation. Further, MiXeR uncovers polygenic overlap between schizophrenia and educational attainment. Despite a genetic correlation close to zero, the phenotypes share 8.3 K causal variants, while 2.5 K additional variants influence only educational attainment. By considering the polygenicity, discoverability and heritability of complex phenotypes, MiXeR analysis may improve our understanding of cross-trait genetic architectures.


Assuntos
Transtorno Bipolar/genética , Modelos Genéticos , Modelos Estatísticos , Herança Multifatorial , Esquizofrenia/genética , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação
6.
J Neurosci Res ; 97(9): 1051-1065, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31081159

RESUMO

Repeated opioids abuse may produce long-lasting and complicated cognitive deficits in individuals. Naloxone is a typical mu-opioid receptor antagonist widely used in clinical treatment for opioid overdose and opioid abuse. However, it remains unclear whether naloxone affects morphine-induced cognitive deficits. Using the 5-choice serial reaction time task (5-CSRTT), the present study investigated cognitive profiles including attention, impulsivity, compulsivity, and processing speed in repeated morphine-treated mice. Repeated morphine administration (10 mg/kg, i.p.) induced complex cognitive changes including decreased attention and increased impulsivity, compulsivity, processing speed. Systemic naloxone administration (5 mg/kg, i.p.) reversed these cognitive changes under the heavy perceptual load in 5-CSRTT. Using the novel object recognition (NOR), Y-maze and open-field test (OFT), the present study investigated the memory ability and locomotor activity. Naloxone reversed the effect of morphine on recognition memory and locomotion but had no effect on working memory. In addition, repeated morphine administration decreased the expression of postsynaptic density protein 95 (PSD95) and cAMP response element binding protein (CREB) phosphorylation in the prefrontal cortex (PFC) and hippocampus (HIP), and these effects were significantly reversed by naloxone in PFC. Our study suggests that repeated exposure to morphine affects multiple cognitive aspects and impairs synaptic functions. Systemic naloxone treatment reverses the mu-opioids-induced cognitive changes, especially under the heavy perceptual load, possibly by restoring the synaptic dysfunctions.

7.
Nat Genet ; 51(5): 793-803, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043756

RESUMO

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.


Assuntos
Transtorno Bipolar/genética , Loci Gênicos , Transtorno Bipolar/classificação , Estudos de Casos e Controles , Transtorno Depressivo Maior/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Transtornos Psicóticos/genética , Esquizofrenia/genética , Biologia de Sistemas
8.
Artigo em Inglês | MEDLINE | ID: mdl-31079161

RESUMO

RATIONALE: The basolateral amygdala (BLA) plays important roles in the cognitive control in human and non-human animals. However, inconsistent findings between species have been observed and there have been relatively few detailed investigations of the cognitive properties of BLA, especially in mice. OBJECTIVE: Our aim was to determine the role of BLA in cognition by using optogenetic manipulations. METHODS: Male C57BL/six mice were trained and tested on the five-choice serial reaction time task (5-CSRTT), open-field test (OFT), elevated plus maze (EPM), Y-maze, and novel object recognition (NOR) test during optogenetic stimulation and inhibition of the BLA. RESULTS: Optogenetic activation of the BLA decreased the impulsivity and increased the compulsivity of mice, whereas optogenetic inhibition of BLA had the opposite effect. Similarly, anxiety-like behaviours and spatial working memory were increased in BLA activation mice, whereas BLA inhibition decreased these behaviours. However, both BLA activation and inhibition decreased the motivation of the mice. CONCLUSIONS: These data demonstrate that the BLA regulates impulsive action and spatial working memory, and plays a critical role in anxiety-like behaviours.

9.
Nano Lett ; 19(6): 3387-3395, 2019 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-31090428

RESUMO

There has been increasing demand for materials with functional thermal properties, but traditional experiments and simulations are high-cost and time-consuming. The emerging discipline, materials informatics, is an effective approach that can accelerate materials development by combining material science and big data techniques. Recently, materials informatics has been successfully applied to designing thermal materials, such as thermal interface materials for heat-dissipation, thermoelectric materials for power generation, and so forth. This Mini Review summarizes the research progress associated with studies regarding the prediction and discovery of materials with desirable thermal transport properties by using materials informatics. On the basis of the review of past research, perspectives are discussed and future directions for studying functional thermal materials by materials informatics are given.

10.
ACS Appl Mater Interfaces ; 11(17): 15804-15812, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30964633

RESUMO

Self-powered photodetectors (SPPDs) have attracted lots of attention due to their various advantages including no external power sources, high-sensitivity, fast response speed, and so on. This study reports the fabrication and characterization results of CsPbBr3 microcrystals (MCs) grown by chemical vapor deposition (CVD) method, and the SPPDs have been fabricated on the basis of the CsPbBr3 MCs layer with the sandwich structure of GaN/CsPbBr3 MCs/ZnO. Such designed SPPD shows the detectivity ( D*) of 1014 Jones, on/off ratio of up to 105, peak responsivity ( R) of 89.5 mA/W, and enhanced stability at the incident wavelength of 540 nm. The photodetector enables the fast photoresponse speed of 100 µs rise time and 140 µs decay time. The performances of the SPPD are comparable to the best ones ever reported for CsPbBr3 based PDs but do not need external power supplies, which mainly benefit from the low trap density, long carrier diffusion of high quality CsPbBr3MCs film, and the built-in electric fields in the sandwich structure of GaN/CsPbBr3/ZnO layers.

11.
J Affect Disord ; 252: 350-357, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30999091

RESUMO

BACKGROUND: Post-traumatic stress disorder (PTSD) is a complex psychiatric disorder that occurs with relatively high frequency after deployment to warzones (∼10%). While twin studies have estimated the heritability to be up to 40%, thus indicating a considerable genetic component in the etiology, the biological mechanisms underlying risk and development of PTSD remain unknown. METHODS: Here, we conduct a genome-wide association study (GWAS; N = 2,481) to identify genome regions that associate with PTSD in a highly homogenous, trauma-exposed sample of Danish soldiers deployed to war and conflict zones. We perform integrated analyses of our results with gene-expression and chromatin-contact datasets to prioritized genes. We also leverage on other large GWAS (N>300,000) to investigate genetic correlations between PTSD and other psychiatric disorders and traits. RESULTS: We discover, but do not replicate, one region, 4q31, close to the IL15 gene, which is genome-wide significantly associated with PTSD. We demonstrate that gene-set enrichment, polygenic risk score and genetic correlation analyses show consistent and significant genetic correlations between PTSD and depression, insomnia and schizophrenia. LIMITATIONS: The limited sample size, the lack of replication, and the PTSD case definition by questionnaire are limitations to the study. CONCLUSIONS: Our results suggest that genetic perturbations of inflammatory response may contribute to the risk of PTSD. In addition, shared genetic components contribute to observed correlations between PTSD and depression, insomnia and schizophrenia.

12.
Int J Mol Sci ; 20(6)2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30875808

RESUMO

A novel rice lesion mimic mutant (LMM) was isolated from the mutant population of Japonica rice cultivar Hitomebore generated by ethyl methane sulfonate (EMS) treatment. Compared with the wild-type (WT), the mutant, tentatively designated E40, developed necrotic lesions over the whole growth period along with detectable changes in several important agronomic traits including lower height, fewer tillers, lower yield, and premature death. To understand the molecular mechanism of mutation-induced phenotypic differences in E40, a proteomics-based approach was used to identify differentially accumulated proteins between E40 and WT. Proteomic data from isobaric tags for relative and absolute quantitation (iTRAQ) showed that 233 proteins were significantly up- or down-regulated in E40 compared with WT. These proteins are involved in diverse biological processes, but phenylpropanoid biosynthesis was the only up-regulated pathway. Differential expression of the genes encoding some candidate proteins with significant up- or down-regulation in E40 were further verified by qPCR. Consistent with the proteomic results, substance and energy flow in E40 shifted from basic metabolism to secondary metabolism, mainly phenylpropanoid biosynthesis, which is likely involved in the formation of leaf spots.


Assuntos
Metanossulfonato de Etila/efeitos adversos , Redes Reguladoras de Genes , Oryza/crescimento & desenvolvimento , Proteômica/métodos , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Oryza/efeitos dos fármacos , Oryza/genética , Fenótipo , Doenças das Plantas/induzido quimicamente , Doenças das Plantas/genética , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/genética , Folhas de Planta/crescimento & desenvolvimento , Proteínas de Plantas/metabolismo , Metabolismo Secundário
13.
Molecules ; 24(5)2019 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-30832434

RESUMO

The quality and safety of food are important guarantees for the health and legal rights of consumers. As an important special fruitcrop, there are frequently shoddy practices in the kiwifruit (Actinidia chinensis) market, which harms the interests of consumers. However, there is lack of rapid and accurate identification methods for commercial kiwifruit varieties. Here, twelve common commercial varieties of kiwifruit were morphologically discriminated. DNA barcodes of chloroplast regions psbA-trnH, rbcL, matK, rpoB, rpoC1, ycf1b, trnL and rpl32_trnL(UAG), the nuclear region At103 and intergenic region ITS2 were amplified. Divergences and phylogenetic trees were used to analyze the phylogenetic relationship of these twelve commercial kiwifruit varieties. The results showed that matK, ITS2 and rpl32_trnL(UAG) can be utilized as molecular markers to identify CuiYu, JinYan, HuangJinGuo, ChuanHuangJin, HuaYou, YaTe, XuXiang and HongYang. This provides experimental and practical basis to scientifically resolve kiwifruit-related judicial disputes and legal trials.


Assuntos
Actinidia/genética , Frutas/genética , Proteínas de Plantas/genética , Actinidia/anatomia & histologia , Cloroplastos/genética , Código de Barras de DNA Taxonômico , Inocuidade dos Alimentos , Frutas/anatomia & histologia , Humanos
14.
Accid Anal Prev ; 125: 275-289, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30802778

RESUMO

An increasing number of vehicles travel on freeways result not only in traffic congestions but also accidents. Rear-end crashes in freeways can be collectively attributed to drivers, vehicles, and road infrastructure, but driving behavior plays a key role in influencing car-following safety. This study aims to investigate the impact of heterogeneity of driving behavior on rear-end crash risk. Driving behavior depends on perceived risk levels, acceleration and deceleration habits, and driver reaction characteristics. Thus, the influencing factors of rear-end crash risk were initially analyzed by using the desired safety margin (DSM) model. Subsequently, five driving behavior parameters, including upper and lower limits of DSM, sensitivity coefficients of acceleration and deceleration, and response time, were calibrated by using the vehicle trajectories from the Next Generation Simulation I-80 datasets. Simulation experiments were designed to evaluate the impact of heterogeneity of car-following behavior on rear-end crash risk. Results showed that decreasing the lower (or upper) limit of the DSM, increasing the response time, increasing the sensitivity coefficient for acceleration, or decreasing the sensitivity coefficient for deceleration can increase rear-end crash risk. In addition, if stable and unstable driving styles coexist, then their proportions have important influences on rear-end crash risk. These results imply that two critical factors affect shock waves, namely, driving behavior characteristics and proportion of different driving styles. Thus, a potential strategy for the adjustment of the proportions of unstable driving styles can attenuate shock waves and reduce rear-end crash risk to a certain extent. Moreover, a wide extent of driving behavior heterogeneity can attenuate shock waves and subsequently reduce rear-end crash risk. Overall, driving behavior heterogeneity has an important impact on rear-end crash risk. Exploring the effect of each driving behavior parameter on rear-end crash probability is useful for urban road traffic control, and it can provide improved understanding of abnormal driving behavior characteristics to minimize rear-end crash risks.


Assuntos
Aceleração , Acidentes de Trânsito/prevenção & controle , Condução de Veículo/psicologia , Desaceleração , Simulação por Computador , Humanos , Modelos Logísticos , Tempo de Reação , Medição de Risco
15.
Nat Genet ; 51(3): 404-413, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30617256

RESUMO

Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Locos de Características Quantitativas/genética , Adulto , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Risco , Adulto Jovem
16.
Int J Neuropsychopharmacol ; 22(4): 303-316, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649326

RESUMO

BACKGROUND: Adolescent methamphetamine exposure causes a broad range of neurobiological deficits in adulthood. Glycogen synthase kinase-3ß is involved in various cognitive and behavioral processes associated with methamphetamine exposure. This study aims to investigate the protective effects of the glycogen synthase kinase-3ß inhibitor lithium chloride on adolescent methamphetamine exposure-induced long-term alterations in emotion, cognition, behavior, and molecule and hippocampal ultrastructure in adulthood. METHODS: A behavioral test battery was used to investigate the protective effects of lithium chloride on adolescent methamphetamine exposure-induced long-term emotional, cognitive, and behavioral impairments in mice. Western blotting and immunohistochemistry were used to detect glycogen synthase kinase-3ß activity levels in the medial prefrontal cortex and dorsal hippocampus. Electron microscopy was used to analyze changes in synaptic ultrastructure in the dorsal hippocampus. Locomotor sensitization with a methamphetamine (1 mg/kg) challenge was examined 80 days after adolescent methamphetamine exposure. RESULTS: Adolescent methamphetamine exposure induced long-term alterations in locomotor activity, novel spatial exploration, and social recognition memory; increases in glycogen synthase kinase-3ß activity in dorsal hippocampus; and decreases in excitatory synapse density and postsynaptic density thickness in CA1. These changes were ameliorated by lithium chloride pretreatment. Adolescent methamphetamine exposure-induced working memory deficits in Y-maze spontaneous alternation test and anxiety-like behavior in elevated-plus maze test spontaneously recovered after long-term methamphetamine abstinence. No significant locomotor sensitization was observed after long-term methamphetamine abstinence. CONCLUSIONS: Hyperactive glycogen synthase kinase-3ß contributes to adolescent chronic methamphetamine exposure-induced behavioral and hippocampal impairments in adulthood. Our results suggest glycogen synthase kinase-3ß may be a potential target for the treatment of deficits in adulthood associated with adolescent methamphetamine abuse.

17.
Plant Physiol Biochem ; 135: 87-98, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30529171

RESUMO

Salt stress is one of the environmental factors that evidently limit plant growth and yield. Despite the fact that understanding plant response to salt stress is important to agricultural practice, the molecular mechanisms underlying salt tolerance in garlic remain unclear. In this study, garlic seedlings were exposed to 200 mM NaCl stress for 0, 1, 4, and 12 h, respectively. RNA-seq was applied to analyze the transcriptional response under salinity conditions. A total of 13,114 out of 25,530 differentially expressed unigenes were identified to have pathway annotation, which were mainly involved in purine metabolism, starch and sucrose metabolism, plant hormone signal transduction, flavone and flavonol biosynthesis, isoflavonoid biosynthesis, MAPK signaling pathway, and circadian rhythm. In addition, 272 and 295 differentially expressed genes were identified to be cell wall and hormone signaling-related, respectively, and their interactions under salinity stress were extensively discussed. The results from the current work would provide new resources for the breeding aimed at improving salt tolerance in garlic.


Assuntos
Parede Celular/fisiologia , Alho/fisiologia , Reguladores de Crescimento de Planta/fisiologia , Alho/genética , Regulação da Expressão Gênica de Plantas/fisiologia , Ontologia Genética , Genes de Plantas/genética , Genes de Plantas/fisiologia , Reação em Cadeia da Polimerase em Tempo Real , Estresse Salino , Plântula/fisiologia , Análise de Sequência de RNA , Transdução de Sinais/fisiologia , Transcriptoma
18.
Sci Rep ; 8(1): 18088, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30591712

RESUMO

A large fraction of genetic risk factors for Alzheimer's Disease (AD) is still not identified, limiting the understanding of AD pathology and study of therapeutic targets. We conducted a genome-wide association study (GWAS) of AD cases and controls of European descent from the multi-center DemGene network across Norway and two independent European cohorts. In a two-stage process, we first performed a meta-analysis using GWAS results from 2,893 AD cases and 6,858 cognitively normal controls from Norway and 25,580 cases and 48,466 controls from the International Genomics of Alzheimer's Project (IGAP), denoted the discovery sample. Second, we selected the top hits (p < 1 × 10-6) from the discovery analysis for replication in an Icelandic cohort consisting of 5,341 cases and 110,008 controls. We identified a novel genomic region with genome-wide significant association with AD on chromosome 4 (combined analysis OR = 1.07, p = 2.48 x 10-8). This finding implicated HS3ST1, a gene expressed throughout the brain particularly in the cerebellar cortex. In addition, we identified IGHV1-68 in the discovery sample, previously not associated with AD. We also associated USP6NL/ECHDC3 and BZRAP1-AS1 to AD, confirming findings from a follow-up transethnic study. These new gene loci provide further evidence for AD as a polygenic disorder, and suggest new mechanistic pathways that warrant further investigation.

19.
Sci Transl Med ; 10(472)2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30545964

RESUMO

Schizophrenia and bipolar disorder are complex psychiatric diseases with risks contributed by multiple genes. Dysregulation of gene expression has been implicated in these disorders, but little is known about such dysregulation in the human brain. We analyzed three transcriptome datasets from 394 postmortem brain tissue samples from patients with schizophrenia or bipolar disorder or from healthy control individuals without a known history of psychiatric disease. We built genome-wide coexpression networks that included microRNAs (miRNAs). We identified a coexpression network module that was differentially expressed in the brain tissue from patients compared to healthy control individuals. This module contained genes that were principally involved in glial and neural cell genesis and glial cell differentiation, and included schizophrenia risk genes carrying rare variants. This module included five miRNAs and 545 mRNAs, with six transcription factors serving as hub genes in this module. We found that the most connected transcription factor gene POU3F2, also identified on a genome-wide association study for bipolar disorder, could regulate the miRNA hsa-miR-320e and other putative target mRNAs. These regulatory relationships were replicated using PsychENCODE/BrainGVEX datasets and validated by knockdown and overexpression experiments in SH-SY5Y cells and human neural progenitor cells in vitro. Thus, we identified a brain gene expression module that was enriched for rare coding variants in genes associated with schizophrenia and that contained the putative bipolar disorder risk gene POU3F2 The transcription factor POU3F2 may be a key regulator of gene expression in this disease-associated gene coexpression module.

20.
Mol Plant ; 11(12): 1492-1508, 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30448535

RESUMO

N6-Methyladenine (6mA) DNA methylation has recently been implicated as a potential new epigenetic marker in eukaryotes, including the dicot model Arabidopsis thaliana. However, the conservation and divergence of 6mA distribution patterns and functions in plants remain elusive. Here we report high-quality 6mA methylomes at single-nucleotide resolution in rice based on substantially improved genome sequences of two rice cultivars, Nipponbare (Nip; Japonica) and 93-11 (Indica). Analysis of 6mA genomic distribution and its association with transcription suggest that 6mA distribution and function is rather conserved between rice and Arabidopsis. We found that 6mA levels are positively correlated with the expression of key stress-related genes, which may be responsible for the difference in stress tolerance between Nip and 93-11. Moreover, we showed that mutations in DDM1 cause defects in plant growth and decreased 6mA level. Our results reveal that 6mA is a conserved DNA modification that is positively associated with gene expression and contributes to key agronomic traits in plants.

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