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1.
J Med Genet ; 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501240

RESUMO

BACKGROUND: Male infertility is a prevalent issue worldwide, mostly due to the impaired sperm motility. Multiple morphological abnormalities of the sperm flagella (MMAF) present aberrant spermatozoa with absent, short, coiled, bent and irregular-calibre flagella resulting in severely decreased motility. Previous studies reported several MMAF-associated genes accounting for approximately half of MMAF cases. METHODS AND RESULT: We conducted genetic analysis using whole-exome sequencing in 88 Han Chinese MMAF probands. CFAP65 homozygous mutations were identified in four unrelated consanguineous families, and CFAP65 compound heterozygous mutations were found in two unrelated cases with MMAF. All these CFAP65 mutations were null, including four frameshift mutations (c.1775delC [p.Pro592Leufs*8], c.3072_3079dup [p.Arg1027Profs*41], c.1946delC [p.Pro649Argfs*5] and c.1580delT [p.Leu527Argfs*31]) and three stop-gain mutations (c.4855C>T [p.Arg1619*], c.5270T>A [p.Leu1757*] and c.5341G>T [p.Glu1781*]). Additionally, two homozygous CFAP65 variants likely affecting splicing were identified in two MMAF-affected men of Tunisian and Iranian ancestries, respectively. These biallelic variants of CFAP65 were verified by Sanger sequencing and were absent or very rare in large data sets aggregating sequence information from various human populations. CFAP65, encoding the cilia and flagella associated protein 65, is highly and preferentially expressed in the testis. Here we also generated a frameshift mutation in mouse orthologue Cfap65 using CRISPR-Cas9 technology. Remarkably, the phenotypes of Cfap65-mutated male mice were consistent with human MMAF. CONCLUSIONS: Our experimental observations performed on both human subjects and on Cfap65-mutated mice demonstrate that the presence of biallelic mutations in CFAP65 causes the MMAF phenotype and impairs sperm motility.

2.
Mov Disord ; 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31483537

RESUMO

BACKGROUND: Intronic (TTTCA)n insertions in the SAMD12, TNRC6A, and RAPGEF2 genes have been identified as causes of familial cortical myoclonic tremor with epilepsy. OBJECTIVE: To identify the cause of familial cortical myoclonic tremor with epilepsy pedigrees without (TTTCA)n insertions in SAMD12, TNRC6A, and RAPGEF2. METHODS: Repeat-primed polymerase chain reaction, long-range polymerase chain reaction, and Sanger sequencing were performed to identify the existence of a novel (TTTGA)n insertion. Targeted long-read sequencing was performed to confirm the accurate structure of the (TTTGA)n insertion. RESULTS: We identified a novel expanded intronic (TTTGA)n insertion at the same site as the previously reported (TTTCA)n insertion in SAMD12. This insertion cosegregated with familial cortical myoclonic tremor with epilepsy in 1 Chinese pedigree with no (TTTCA)n insertion. In the targeted long-read sequencing of 2 patients and 1 asymptomatic carrier in this pedigree, with 1 previously reported (TTTCA)n -insertion-carrying patient as a positive control, a respective total of 302, 159, 207, and 50 on-target subreads (predicated accuracy: ≥90%) spanning the target repeat expansion region were generated. These sequencing data revealed the accurate repeat expansion structures as (TTTTA)114-123 (TTTGA)108-116 in the pedigree and (TTTTA)38 (TTTCA)479 in (TTTCA)n -insertion-carrying patient. CONCLUSION: The targeted long-read sequencing helped us to elucidate the accurate structures of the (TTTGA)n and (TTTCA)n insertions. Our finding offers a novel possible cause for familial cortical myoclonic tremor with epilepsy and might shed light on the identification of genetic causes of this disease in pedigrees with no detected (TTTCA)n insertion in the reported causative genes. © 2019 International Parkinson and Movement Disorder Society.

3.
Transl Psychiatry ; 9(1): 233, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534116

RESUMO

Inflammation is a natural defence response of the immune system against environmental insult, stress and injury, but hyper- and hypo-inflammatory responses can trigger diseases. Accumulating evidence suggests that inflammation is involved in multiple psychiatric disorders. Using inflammation-related factors as biomarkers of psychiatric disorders requires the proof of reproducibility and specificity of the changes in different disorders, which remains to be established. We performed a cross-disorder study by systematically evaluating the meta-analysis results of inflammation-related factors in eight major psychiatric disorders, including schizophrenia (SCZ), bipolar disorder (BD), autism spectrum disorder (ASD), major depression disorder (MDD), post-trauma stress disorder (PTSD), sleeping disorder (SD), obsessive-compulsive disorder (OCD) and suicide. A total of 43 meta-analyses involving 704 publications on 44 inflammation-related factors were included in the study. We calculated the effect size and statistical power for every inflammation-related factor in each disorder. Our analyses showed that well-powered case-control studies provided more consistent results than underpowered studies when one factor was meta-analysed by different researchers. After removing underpowered studies, 30 of the 44 inflammation-related factors showed significant alterations in at least one disorder based on well-powered meta-analyses. Eleven of them changed in patients of more than two disorders when compared with the controls. A few inflammation-related factors showed unique changes in specific disorders (e.g., IL-4 increased in BD, decreased in suicide, but had no change in MDD, ASD, PTSD and SCZ). MDD had the largest number of changes while SD has the least. Clustering analysis showed that closely related disorders share similar patterns of inflammatory changes, as genome-wide genetic studies have found. According to the effect size obtained from the meta-analyses, 13 inflammation-related factors would need <50 cases and 50 controls to achieve 80% power to show significant differences (p < 0.0016) between patients and controls. Changes in different states of MDD, SCZ or BD were also observed in various comparisons. Studies comparing first-episode SCZ to controls may have more reproducible findings than those comparing pre- and post-treatment results. Longitudinal, system-wide studies of inflammation regulation that can differentiate trait- and state-specific changes will be needed to establish valuable biomarkers.

4.
Diabetes ; 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506343

RESUMO

Epigenetic changes may contribute substantially to risks of diseases of ageing. Previous studies reported seven methylation variable positions (MVPs) robustly associated with incident type 2 diabetes mellitus (T2DM). However, their causal roles in T2DM are unclear. In an incident T2DM case-cohort study nested within the population-based EPIC-Norfolk cohort, we used whole blood DNA collected at baseline, up to 11 years before T2DM onset to investigate the role of methylation in the aetiology of T2DM. We identified 15 novel MVPs with robust associations with incident T2DM, and robustly confirmed three MVPs identified previously (near to TXNIP, ABCG1 and SREBF1). All 18 MVPs showed directionally consistent associations with incident and prevalent T2DM in independent studies. Further conditional analyses suggested that the identified epigenetic signals appear related to T2DM via glucose and obesity-related pathways acting before the collection of baseline samples. We integrated genome-wide genetic data to identify methylation-associated quantitative trait loci robustly associated with 16 of the 18 MVPs, and found one MVP, cg00574958 at CPT1A, with a possible direct causal role on T2DM. None of the implicated genes was previously highlighted by genetic association studies, suggesting that DNA methylation studies may reveal novel biological mechanisms involved in tissue responses to glycemia.

5.
Transl Psychiatry ; 9(1): 230, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31530798

RESUMO

Schizophrenia, Schizoaffective, and Bipolar disorders share behavioral and phenomenological traits, intermediate phenotypes, and some associated genetic loci with pleiotropic effects. Volumetric abnormalities in brain structures are among the intermediate phenotypes consistently reported associated with these disorders. In order to examine the genetic underpinnings of these structural brain modifications, we performed genome-wide association analyses (GWAS) on 60 quantitative structural brain MRI phenotypes in a sample of 777 subjects (483 cases and 294 controls pooled together). Genotyping was performed with the Illumina PsychChip microarray, followed by imputation to the 1000 genomes multiethnic reference panel. Enlargement of the Temporal Horns of Lateral Ventricles (THLV) is associated with an intronic SNP of the gene NRXN1 (rs12467877, P = 6.76E-10), which accounts for 4.5% of the variance in size. Enlarged THLV is associated with psychosis in this sample, and with reduction of the hippocampus and enlargement of the choroid plexus and caudate. Eight other suggestively significant associations (P < 5.5E-8) were identified with THLV and 5 other brain structures. Although rare deletions of NRXN1 have been previously associated with psychosis, this is the first report of a common SNP variant of NRXN1 associated with enlargement of the THLV in psychosis.

6.
Nat Commun ; 10(1): 4267, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537805

RESUMO

Identifying methylation quantitative trait loci (meQTLs) and integrating them with disease-associated variants from genome-wide association studies (GWAS) may illuminate functional mechanisms underlying genetic variant-disease associations. Here, we perform GWAS of >415 thousand CpG methylation sites in whole blood from 4170 individuals and map 4.7 million cis- and 630 thousand trans-meQTL variants targeting >120 thousand CpGs. Independent replication is performed in 1347 participants from two studies. By linking cis-meQTL variants with GWAS results for cardiovascular disease (CVD) traits, we identify 92 putatively causal CpGs for CVD traits by Mendelian randomization analysis. Further integrating gene expression data reveals evidence of cis CpG-transcript pairs causally linked to CVD. In addition, we identify 22 trans-meQTL hotspots each targeting more than 30 CpGs and find that trans-meQTL hotspots appear to act in cis on expression of nearby transcriptional regulatory genes. Our findings provide a powerful meQTL resource and shed light on DNA methylation involvement in human diseases.

7.
PLoS One ; 14(8): e0219261, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31393881

RESUMO

Emerging evidence suggests microRNAs (miRNAs) may play an important role in explaining variation in stroke risk and recovery in humans, yet there are still few longitudinal studies examining the association between whole blood miRNAs and stroke. Accounting for multiple testing and adjusting for potentially confounding technical and clinical variables, here we show that whole blood miR-574-3p expression was significantly lower in participants with chronic stroke compared to non-cases. To explore the functional relevance of our findings, we analyzed miRNA-mRNA whole blood co-expression, pathway enrichment, and brain tissue gene expression. Results suggest miR-574-3p is involved in neurometabolic and chronic neuronal injury response pathways, including brain gene expression of DBNDD2 and ELOVL1. These results suggest miR-574-3p plays a role in regulating chronic brain and systemic cellular response to stroke and thus may implicate miR-574-3p as a partial mediator of long-term stroke outcomes.

8.
Circulation ; 140(8): 645-657, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31424985

RESUMO

BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts. METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts. RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts. CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

9.
Minerva Urol Nefrol ; 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31287255

RESUMO

BACKGROUND: To report our initial experience using a self-made optical system to visually identify the quality of the chosen access before the operating tract dilation. METHODS: We retrospectively reviewed the data on patients with renal stones treated by percutaneous nephrolithotomy (PCNL) in our hospital. The patients were divided into Groups A and B, according to those who received treatment by visual PCNL and conventional PCNL modalities, respectively. Based on the degree of hydronephrosis, the patients in each group were further divided into two subgroups, the patients with mild hydronephrosis (subgroup 1) and the patients with moderate or severe hydronephrosis (subgroup 2). The demographics and perioperative parameters were analyzed. RESULTS: 124 patients underwent PCNL. 47 patients in Group A (n = 62) were assigned to subgroup 1 and 15 to subgroup 2. 40 patients in Group B (n = 62) were assigned to r subgroup 1 and 22 to subgroup 2. The demographics were not significantly different between Group A and Group B ( P > 0.05 ). The puncture times were shorter in Group A and in subgroups (P <0.01), whereas the access loss rates were not significantly different (P>0.05). The mean decrease in hemoglobin levels, repuncture rates, blood transfusions and hospitalization times in Group A and Group A subgroup 1 were significantly lower than in Group B and Group B subgroup 1 , respectively,(P < 0.05), but no significant differences in subgroup 2( P>0.05 ). When the complications were compared, the collecting system injury rates were significantly different between the two groupsand in subgroup 1(P<0.05). However the rates of fever and urinary sepsis were not statistically different in the two groups and in the subgroups (P >0.05). CONCLUSIONS: We found that visual PCNL was a safe and efficacious treatment for renal stones that may be considered as an alternative to conventional PCNL, especially in patients with mild hydronephrosis. Further prospective randomized controlled trials are needed to confirm the results of this study .

10.
Epigenetics ; : 1-16, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31282290

RESUMO

DNA methylation (DNAm) and microRNAs (miRNAs) have been implicated in a wide-range of human diseases. While often studied in isolation, DNAm and miRNAs are not independent. We analyzed associations of expression of 283 miRNAs with DNAm at >400K CpG sites in whole blood obtained from 3565 individuals and identified 227 CpGs at which differential methylation was associated with the expression of 40 nearby miRNAs (cis-miR-eQTMs) at FDR<0.01, including 91 independent CpG sites at r2 < 0.2. cis-miR-eQTMs were enriched for CpGs in promoter and polycomb-repressed state regions, and 60% were inversely associated with miRNA expression. Bidirectional Mendelian randomization (MR) analysis further identified 58 cis-miR-eQTMCpG-miRNA pairs where DNAm changes appeared to drive miRNA expression changes and opposite directional effects were unlikely. Integration of genetic variants in joint analyses revealed an average partial between cis-miR-eQTM CpGs and miRNAs of 2% after conditioning on site-specific genetic variation, suggesting that DNAm is an important epigenetic regulator of miRNA expression. Finally, two-step MR analysis was performed to identify putatively causal CpGs driving miRNA expression in relation to human complex traits. We found that an imprinted region on 14q32 that was previously identified in relation to age at menarche is enriched with cis-miR-eQTMs. Nine CpGs and three miRNAs at this locus tested causal for age at menarche, reflecting novel epigenetic-driven molecular pathways underlying this complex trait. Our study sheds light on the joint genetic and epigenetic regulation of miRNA expression and provides insights into the relations of miRNAs to their targets and to complex phenotypes.

11.
J Mol Model ; 25(8): 220, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300896

RESUMO

Discovery of novel materials with excellent second-order nonlinear optical (NLO) properties is a very attractive topic in chemistry and materials science. Recently, much more attention has been paid to chiral compounds due to their inherent asymmetric structure and intramolecular charge transfer. Currently, the density functional theory (DFT) has become a powerful methodology to rationalize experimental observations and to design new materials with desirable properties. In this work, on the basis of the reported chiral peropyrene, we designed another five compounds consisting of donor or acceptor moieties and the donor/acceptor combinations. We systematically studied their geometrical/electronic structures and electronic transition/second-order NLO properties. The measured UV-Vis/CD spectra of compound 1 are almost reproduced by our calculations, enabling us to assign its electronic transition property and absolute configuration. For these compounds, the different substituents have great effect on their photophysical properties (i.e., band gap, absorption wavelength, and NLO response). The charge transfer synergy provides some useful information for further performance improvement. Interestingly, compound 6 shows a remarkably large first hyperpolarizability value of 18.14 × 10-30 esu. Our research enables an opportunity for understanding the structure-property relationship of chiral peropyrenes. Graphical abstract The nonlinear optical properties of the studied compounds were studied with the aid of the DFT calculations.

12.
Inorg Chem ; 58(13): 8533-8540, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31188573

RESUMO

The luminescent properties of gold(I)-sulfur compounds have received much attention for their potential applications in the sensing field. The molecular level regulation of luminescence remains a challenge. It is critical to unravel the relationship between the luminescence and the structure. Herein we report a binuclear complex [Au2(dppaptc)2]Cl2 (1, dppaptc = N,N-bis(diphenylphosphanylmethyl)-amino-4-phenyl-thiocarbamide), which exhibits variations at Au-S bond lengths as a function of temperature or solvent. X-ray analysis reveals a linear decrease from 2.900(3) to 2.745(15) Å upon cooling 1·2CHCl3 from 300 to 80 K combined with a linear correlation with its luminescence intensity at 475 nm, which was confirmed by TD-DFT calculations. Compound 1, if solvated with H2O and alcohol, possesses the shorter Au-S bonds and enhanced luminescence. The close relationship between luminescence intensity and Au-S length serves as a complement to existing luminescent gold(I)-sulfur systems and provides some insight into understanding the thermochromism and solvatochromism of the gold(I)-sulfur compounds.

13.
J Med Genet ; 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31048344

RESUMO

BACKGROUND: Male infertility due to multiple morphological abnormalities of the sperm flagella (MMAF) is a genetically heterogeneous disorder. Previous studies revealed several MMAF-associated genes, which account for approximately 60% of human MMAF cases. The pathogenic mechanisms of MMAF remain to be illuminated. METHODS AND RESULTS: We conducted genetic analyses using whole-exome sequencing in 50 Han Chinese probands with MMAF. Two homozygous stop-gain variants (c.910C>T (p.Arg304*) and c.3400delA (p.Ile1134Serfs*13)) of the SPEF2 (sperm flagellar 2) gene were identified in two unrelated consanguineous families. Consistently, an Iranian subject from another cohort also carried a homozygous SPEF2 stop-gain variant (c.3240delT (p.Phe1080Leufs*2)). All these variants affected the long SPEF2 transcripts that are expressed in the testis and encode the IFT20 (intraflagellar transport 20) binding domain, important for sperm tail development. Notably, previous animal studies reported spontaneous mutations of SPEF2 causing sperm tail defects in bulls and pigs. Our further functional studies using immunofluorescence assays showed the absence or a remarkably reduced staining of SPEF2 and of the MMAF-associated CFAP69 protein in the spermatozoa from SPEF2-affected subjects. CONCLUSIONS: We identified SPEF2 as a novel gene for human MMAF across the populations. Functional analyses suggested that the deficiency of SPEF2 in the mutated subjects could alter the localisation of other axonemal proteins.

14.
J Nat Prod ; 82(6): 1527-1534, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31117521

RESUMO

Six new asperane-type sesterterpenoids, asperunguisins A-F (1-6), were isolated from the endolichenic fungus Aspergillus unguis, together with a known analogue, aspergilloxide (7); these are rare asperane-type sesterterpenoids, characterized by a unique hydroxylated 7/6/6/5 tetracyclic system. The structures of asperunguisins A-F (1-6) were elucidated on the basis of spectroscopic methods (NMR and HRESIMS), X-ray single-crystal diffraction analysis, ECD calculations, and biogenetic considerations. Asperunguisin C (3) showed cytotoxicity against the human cancer cell line A549 with an IC50 value of 6.2 µM. Further investigation revealed that the observed cell death was a result of G0/G1 cell cycle arrest via DNA damage followed by cellular apoptosis.

15.
Int Braz J Urol ; 452019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-31038858

RESUMO

PURPOSE: As a rare bladder tumor, paraganglioma of the urinary bladder (PUB) is frequently misdiagnosed as bladder cancer, particularly for the non-functional type. To date, transurethral resection remains a controversial treatment for non-functional PUB. This study aimed to identify the clinical features, pathological characteristics, prognosis, and safe/effective treatment of non-functional PUB using transurethral resection of the bladder tumor (TURBT). MATERIALS AND METHODS: The clinical records, radiological data, pathological characteristics and follow-up times were retrospectively reviewed in 10 patients with clinically and pathologically proven non-functional PUB in our hospital from January 2008 to November 2016. All patients underwent TURBT treatment. RESULTS: The incidence of non-functional PUB in patients with bladder cancer was 0.17%. The mean age at diagnosis was 44.5 ± 13.6 years (range, 29-70 years), and the patient population had a female: male ratio of 3: 2. No patients had excess catecholamine (CA) whilst four patients had painless hematuria. All neoplasms were completely resected via TURBT. The majority of samples were positive for immunohistochemical markers including chromogranin A (CgA) and Synaptophysin (Syn), but were negative for cytokeratins (CKs). Only a single recurrence was observed from the mean follow-up period of 36.4 ± 24.8 months. CONCLUSION: Complete TURBT is a safe and effi cient treatment that serves both diagnostic and therapeutic purposes. Histopathological and immunohistochemistry examinations are mandatory for diagnostic confi rmation. Long-term follow-up is recommended for patients with non-functional PUB.

16.
Int J Biol Macromol ; 132: 1098-1105, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30974136

RESUMO

Wound dressing is of significant importance to promote cutaneous wound healing process. To develop an effective wound dressing, a PVA/DA hydrogel was prepared using a Poly (vinyl alcohol)/Dextran-aldehyde solution blend, followed by crosslinking via freeze-thaw method and freeze-drying. We characterized the hydrogel by infrared spectroscopy, mechanical property tests, swelling behavior test and biocompatibility test. Results showed that the PVA/DA hydrogels had a 3-dimensional, highly porous structure with uniformly distributed pores of 5-10 µm, strong tensile strength of 5.6 MPa, efficient ability to absorb fluid of 6 time its weight and suitable water vapor transmission rate of 2100 g m-2day-1 to keep a moist environment and good biocompatibility shown by very low hemolysis and no cytotoxicity. In wound healing tests using a full-thickness skin wound model, macroscopic observations showed that the wound covered by the PVA/DA hydrogel almost reached complete healing faster by 10 days, while histological analysis indicated a faster regeneration of skin. Thus, the PVA/DA hydrogel was suitable for application as a wound dressing and may have potential for use in various biomedical applications.

17.
Nanoscale ; 11(18): 8776-8784, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31025664

RESUMO

To overcome the intrinsic chemical-reduction-activity of highly p-doped PEDOT:PSS and improve the open-circuit voltage (Voc) of planar inverted perovskite solar cells, a kind of oxidized carbon nanorods (OCNRs) is developed by a ball-milling/chemical-oxidation method and incorporated into PEDOT:PSS hole transport layer (HTL). The incorporation of OCNRs can increase the work function of the PEDOT:PSS layer, which avoids the energy-level mismatch between the PEDOT:PSS HTL and the HOMO level of the CH3NH3PbI3 perovskite layer, leading to a relatively high Voc of 1.01 V (vs. 0.92 V for the PEDOT:PSS device). Moreover, the introduction of OCNRs into the PEDOT:PSS HTL increases the grain size and uniformity of the perovskite layer, accompanied by the improved charge transport ability. As a result, the fill factor of perovskite solar cells is increased from 75.4% to 81.7%, and the best power conversion efficiency of 19.02% is achieved.

18.
Nat Neurosci ; 22(5): 691-699, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30988527

RESUMO

Genome-wide association studies (GWAS) have identified more than 100 schizophrenia (SCZ)-associated loci, but using these findings to illuminate disease biology remains a challenge. Here we present integrative risk gene selector (iRIGS), a Bayesian framework that integrates multi-omics data and gene networks to infer risk genes in GWAS loci. By applying iRIGS to SCZ GWAS data, we predicted a set of high-confidence risk genes, most of which are not the nearest genes to the GWAS index variants. High-confidence risk genes account for a significantly enriched heritability, as estimated by stratified linkage disequilibrium score regression. Moreover, high-confidence risk genes are predominantly expressed in brain tissues, especially prenatally, and are enriched for targets of approved drugs, suggesting opportunities to reposition existing drugs for SCZ. Thus, iRIGS can leverage accumulating functional genomics and GWAS data to advance our understanding of SCZ etiology and potential therapeutics.


Assuntos
Redes Reguladoras de Genes , Predisposição Genética para Doença , Genômica/métodos , Esquizofrenia/genética , Animais , Teorema de Bayes , Modelos Animais de Doenças , Estudo de Associação Genômica Ampla , Humanos , Camundongos , Fatores de Risco
19.
Am J Hum Genet ; 104(4): 738-748, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30929735

RESUMO

Male infertility is a major concern affecting human reproductive health. Asthenoteratospermia can cause male infertility through reduced motility and abnormal morphology of spermatozoa. Several genes, including DNAH1 and some CFAP family members, are involved in multiple morphological abnormalities of the sperm flagella (MMAF). However, these known genes only account for approximately 60% of human MMAF cases. Here, we conducted further genetic analyses by using whole-exome sequencing in a cohort of 65 Han Chinese men with MMAF. Intriguingly, bi-allelic mutations of TTC21A (tetratricopeptide repeat domain 21A) were identified in three (5%) unrelated, MMAF-affected men, including two with homozygous stop-gain mutations and one with compound heterozygous mutations of TTC21A. Notably, these men consistently presented with MMAF and additional abnormalities of sperm head-tail conjunction. Furthermore, a homozygous TTC21A splicing mutation was identified in two Tunisian cases from an independent MMAF cohort. TTC21A is preferentially expressed in the testis and encodes an intraflagellar transport (IFT)-associated protein that possesses several tetratricopeptide repeat domains that perform functions crucial for ciliary function. To further investigate the potential roles of TTC21A in spermatogenesis, we generated Ttc21a mutant mice by using CRISPR-Cas9 technology and revealed sperm structural defects of the flagella and the connecting piece. Our consistent observations across human populations and in the mouse model strongly support the notion that bi-allelic mutations in TTC21A can induce asthenoteratospermia with defects of the sperm flagella and head-tail conjunction.

20.
Diabetes ; 68(5): 1073-1083, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30936141

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate <0.05 (corresponding P = 6.9 × 10-6) with replication at Bonferroni-corrected P < 8.6 × 10-4 Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (P = 2.5 × 10-4). Hypomethylation of the same CpG was also associated with risk for new-onset T2D (P = 0.005). Our study demonstrates that a peripheral blood-derived DNA methylation signature is robustly associated with hepatic fat accumulation. The hepatic fat-associated CpGs may represent attractive biomarkers for T2D. Future studies are warranted to explore mechanisms and to examine DNA methylation signatures of NAFLD across racial/ethnic groups.

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