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1.
Kidney Blood Press Res ; : 1-12, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31734665

RESUMO

BACKGROUND: Depression is prevalent in patients with all stages of CKD and is associated with adverse outcome. Abnormally elevated GFR, or hyperfiltration, may play a crucial role in the initiation and progression of CKD. However, the association between depression and hyperfiltration is not known. The aim of this study is to investigate the relationship between depression and hyperfiltration. METHODS: This was an observational cross-sectional study. A total of 3,716 volunteers (1,303 males and 2,413 females) aged 40-75 years without CKD from a community in China were included for the study. Depressive symptoms and the presence of a minor or major depressive episode were assessed with the 9-item Patient Health Questionnaire (PHQ-9) and Diagnostic and Statistical Manual of Mental Disorders (4th edition)-based structured interview, respectively. RESULTS: The mean age of the participants in the present study was 53.8 ± 9.0 years. 115 participants had clinically relevant depression, and 122 participants had a minor or major depressive episode. In a multivariable logistic regression analysis adjusted for potential confounders, the association between clinically relevant depression and renal hyperfiltration remained significant in men but not in women. As compared with men without depression (PHQ <5) or depressive episodes, those with clinically relevant depression (PHQ ≥10) had a significantly higher risk of renal hyperfiltration. The fully adjusted OR (95% CI) was 4.81 (1.62-14.30, p = 0.005), those with a major depressive episode had a higher risk of renal hyperfiltration (OR 7.45; 95% CI 2.04-27.21, p = 0.002). CONCLUSION: Depressive symptoms and major depressive episodes are associated with renal hyperfiltration in middle-aged and elderly Chinese men without CKD. Future studies are needed to verify and clarify the role of depression in the development of abnormally high eGFR and CKD.

2.
BMC Plant Biol ; 19(1): 523, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31775649

RESUMO

BACKGROUND: The homeobox transcription factor has a diversity of functions during plant growth and development process. Previous transcriptome analyses of seed development in grape hybrids suggested that specific homeodomain transcription factors are involved in seed development in seedless cultivars. However, the molecular mechanism of homeobox gene regulating seed development in grape is rarely reported. RESULTS: Here, we report that the grapevine VvHB58 gene, encoding a homeodomain-leucine zipper (HD-Zip I) transcription factor, participates in regulating fruit size and seed number. The VvHB58 gene was differentially expressed during seed development between seedless and seeded cultivars. Subcellular localization assays revealed that the VvHB58 protein was located in the nucleus. Transgenic expression of VvHB58 in tomato led to loss of apical dominance, a reduction in fruit pericarp expansion, reduced fruit size and seed number, and larger endosperm cells. Analysis of the cytosine methylation levels within the VvHB58 promoter indicated that the differential expression during seed development between seedless and seeded grapes may be caused by different transcriptional regulatory mechanisms rather than promoter DNA methylation. Measurements of five classic endogenous hormones and expression analysis of hormone-related genes between VvHB58 transgenic and nontransgenic control plants showed that expression of VvHB58 resulted in significant changes in auxin, gibberellin and ethylene signaling pathways. Additionally, several DNA methylation-related genes were expressed differentially during seed development stages in seedless and seeded grapes, suggesting changes in methylation levels during seed development may be associated with seed abortion. CONCLUSION: VvHB58 has a potential function in regulating fruit and seed development by impacting multiple hormonal pathways. These results expand understanding of homeodomain transcription factors and potential regulatory mechanism of seed development in grapevine, and provided insights into molecular breeding for grapes.

3.
Opt Express ; 27(20): 27807-27819, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31684542

RESUMO

Light influenced by the turbulent ocean can be fully characterized with the help of the power spectrum of the water's refractive index fluctuations, resulting from the combined effect of two scalars, temperature and salinity concentration advected by the velocity field. The Nikishovs' model [ Fluid Mech. Res.27, 8298 (2000)] frequently used in the analysis of light evolution through the turbulent ocean channels is the linear combination of the temperature spectrum, the salinity spectrum and their co-spectrum, each being described by an approximate expression developed by Hill [ J. Fluid Mech.88, 541562 (1978)] in the first of his four suggested models. The fourth of the Hill's models provides much more precise power spectrum than the first one expressed via a non-linear differential equation that does not have a closed-form solution. We develop an accurate analytic approximation to the fourth Hill's model valid for Prandtl/Schmidt numbers in the interval [3, 3000] and use it for the development of a more precise oceanic power spectrum. To illustrate the advantage of our model, we include numerical examples relating to the spherical wave scintillation index evolving in the underwater turbulent channels with different average temperatures, and, hence, different Prandtl numbers for temperature and different Schmidt numbers for salinity. Since our model is valid for a large range of Prandtl number (or/and Schmidt number), it can be readily adjusted to oceanic waters with seasonal or extreme average temperature and/or salinity or any other turbulent fluid with one or several advected quantities.

4.
Cancer Med ; 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31663692

RESUMO

Previous studies have shown that single-nucleotide polymorphisms (SNPs) of a disintegrin and metalloproteinase with thrombospondin type 1 motif 4 (ADAMTS4) may involve in the pathogenesis of some diseases. However, it is not clear whether they are associated with hepatocellular carcinoma (HCC). A hospital-based case-control study, including 862 cases with HCC and 1120 controls, was conducted to assess the effects of 258 SNPs in the coding regions of ADAMTS4 on HCC risk and prognosis. We found that six SNPs in ADAMTS4 were differential distribution between cases and controls via the primary screening analyses; however, only rs538321148 and rs1014509103 polymorphisms were further identified to modify the risk of HCC (odds ratio: 2.73 and 2.95; 95% confidence interval, 2.28-3.29 and 2.43-3.58; P-value, 5.73 × 10-27 and 1.36 × 10-27 , respectively). Significant interaction between these two SNPs and two known causes of hepatitis B virus and aflatoxin B1 were also observed. Furthermore, rs538321148 and rs1014509103 polymorphisms were associated not only with clinicopathological features of tumor such as tumor stage and grade, microvessel density, and vessel metastasis, but with poor overall survival. Additionally, these SNPs significantly downregulated ADATMS4 expression in tumor tissues. These data suggest that SNPs in the coding region of ADAMTS4, such as rs538321148 and rs1014509103, may be potential biomarkers for predicting HCC risk and prognosis.

5.
Int J Mol Sci ; 20(18)2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31540007

RESUMO

Members of the plant-specific B3-domain transcription factor family have important and varied functions, especially with respect to vegetative and reproductive growth. Although B3 genes have been studied in many other plants, there is limited information on the genomic organization and expression of B3 genes in grapevine (Vitis vinifera L.). In this study, we identified 50 B3 genes in the grapevine genome and analyzed these genes in terms of chromosomal location and syntenic relationships, intron-exon organization, and promoter cis-element content. We also analyzed the presumed proteins in terms of domain structure and phylogenetic relationships. Based on the results, we classified these genes into five subfamilies. The syntenic relationships suggest that approximately half of the genes resulted from genome duplication, contributing to the expansion of the B3 family in grapevine. The analysis of cis-element composition suggested that most of these genes may function in response to hormones, light, and stress. We also analyzed expression of members of the B3 family in various structures of grapevine plants, including the seed during seed development. Many B3 genes were expressed preferentially in one or more structures of the developed plant, suggesting specific roles in growth and development. Furthermore, several of the genes were expressed differentially in early developing seeds from representative seeded and seedless cultivars, suggesting a role in seed development or abortion. The results of this study provide a foundation for functional analysis of B3 genes and new resources for future molecular breeding of grapevine.

6.
Free Radic Biol Med ; 143: 387-396, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31446056

RESUMO

Activation of the NF-E2-related factor 2 (Nrf2) cascade can offer significant protection against oxidative stress in retinal pigment epithelium (RPE) cells. Here, we identified a novel kelch-like ECH-associated protein 1 (Keap1)-targeting microRNA, microRNA-626 (miR-626) that activates Nrf2 signaling. In ARPE-19 cells and primary human RPE cells, ectopic overexpression of miR-626 targeting the 3'-UTR (3'-untranslated region) of Keap1 downregulated its expression, promoting Nrf2 protein stabilization and nuclear translocation, leading to expression of ARE-dependent genes (HO1, NOQ1 and GCLC). Functional studies showed that miR-626 protected RPE cells from hydrogen peroxide (H2O2)-induced oxidative injury. Conversely, miR-626 inhibition induced Keap1 upregulation and Nrf2 cascade inhibition, exacerbating oxidative injury in RPE cells. Further studies demonstrated that miR-626 was ineffective in Keap1-knockout or Nrf2-knockout RPE cells. Importantly, miR-626 also activated Keap1-Nrf2 signaling cascade in human lens epithelial cells (HLECs) and primary human retinal ganglion cells (RGCs), providing protection from H2O2. At last, we show that plasma miR-626 levels are significantly downregulated in age-related macular degeneration (AMD) patients than those in the healthy donors. We conclude that targeting Keap1 by miR-626 protects RPE cells and other ophthalmic cells from oxidative injury via activation of Nrf2 signaling cascade.

7.
Cornea ; 38(11): 1443-1449, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31436645

RESUMO

PURPOSE: To identify differentially expressed circular RNAs (circRNAs) in corneal neovascularization. METHODS: We established an alkali burn-induced corneal neovascularization model and performed circRNA expression profiling to identify differentially expressed circRNAs between avascular corneas and vascularized corneas. Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes analyses of the host genes of dysregulated circRNAs were performed to determine the related biological modules and pathological pathways. Real-time polymerase chain reactions were performed to detect the expression pattern of circRNAs in the clinical samples. In vitro experiments were performed to determine the role of circRNAs in vascular endothelial angiogenic effects. RESULTS: Two hundred twenty-nine circRNAs were differentially expressed between avascular corneas and vascularized corneas. The host genes of dysregulated circRNAs were targeted to cell cycle (biologic process), cytoplasm (cellular component), and protein binding (molecular function). Rap1 signaling was identified as the most enriched signaling pathway. Clinical studies showed that the human ortholog of cZFP609 and cKifap3 was dysregulated in the vascularized human corneas. cKifap3 silencing facilitated vascular endothelial angiogenic effects by regulating endothelial cell proliferation, migration, and tube formation. CONCLUSIONS: This study suggests that circRNAs are involved in the pathogenesis of corneal neovascularization. cZFP609 and cKifap3 may serve as promising targets for the treatment of corneal neovascularization.

8.
J Cell Biochem ; 120(11): 19202-19214, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31270856

RESUMO

Uveal melanoma (UVM) is an adult intraocular malignancy which is the most frequent and has a high tendency for metastasis. This study aims to develop significant differential gene subnetwork between primary and metastatic UVM to identify potential prognostic biomarkers. Differentially expressed genes (DEGs) among three chip datasets were downloaded from Gene Expression Omnibus and identified according to standardization annotation information. Genetic enrichment analyses were utilized to describe biologic functions. The protein-protein interaction network of DEGs was developed and the module analysis was constructed by STRING and Cytoscape. Kaplan-Meier method of the integrated expression score was applied to analyze survival outcomes. Functional annotation was assessed to perform GO and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. In addition, ClueGO and gene set enrichment analysis were analyzed to detect underlying significant genes and involved signaling pathways. A total of 103 DEGs with function enrichment were recognized and might be considered as candidate prognostic biomarkers between primary and metastatic UVM. Furthermore, Kaplan-Meier method suggested that SCD5, SPTBN1, FABP5, SQLE, PTPLA (HACD1), and CDC25B were independent prognostic factors in UVM. Functional annotations indicated that the most involved significant pathways including interferon-gamma response, IL-6 JAK STAT3 signaling, TNFA signaling via NFKB and inflammatory response. Significant DEGs between primary and metastatic UVM tissue were identified and might have involved in the metastasis of UVM. SCD5, SPTBN1, FABP5, SQLE, PTPLA (HACD1), and CDC25B transcription levels were of high prognostic value, which might assist us to understand the underlying carcinogenesis or advancement of UVM better.

9.
J Clin Pathol ; 72(11): 748-754, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31262952

RESUMO

AIMS: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a newly recognised entity in the WHO 2016 classification defined as the germline mutation of FH gene. Fumaratehydratase-deficient renal cell carcinoma (FH-deficient RCC) is recommended for tumours with FH deficiency but lacking of genetic evidences of FH germline mutation. In this study, we described the clinicopathological and molecular changes of 13 FH-deficient RCCs. METHODS AND RESULTS: Histology features, clinicopathological data, radiology performance and outcomes were collected for each patient. Next-generation sequencing and DNA sequencing of FH gene were performed to examine FH mutations. The patient group included five females and eight males. Different morphological patterns of papillary, nested, adenoid, foam adenoid, cribriform, tubular, tubulocystic, cystic and loose oedema stroma were observed. Except typical big nuclei with or without eosinophilic nucleoli and perinucleolar halos, raisin-like, hobnail-like and even low-grade nuclei were also observed in these tumours. Eleven cases with high-grade nuclei showed disease progression or death, but no disease progression was detected in two cases with low-grade nuclei and eosinophilic cytoplasm. FH expression was absent in tumour cells except for case 11. Next-generation sequencing and DNA sequencing verified seven FH germline mutations and four somatic mutations out of 13 cases. CONCLUSIONS: FH-deficient RCC is a rare renal tumour and has a wide morphological spectrum. Most of the tumours had high-grade nuclei and were aggressive. However, we observed a morphological subtype of FH-deficient RCC with low-grade nuclei and eosinophilic cytoplasm, which might mainly occur in young women and show a relatively good prognosis.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Fumarato Hidratase/genética , Mutação em Linhagem Germinativa , Neoplasias Renais/genética , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/deficiência , Biópsia , Carcinoma de Células Renais/enzimologia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Núcleo Celular/patologia , Citoplasma/patologia , Análise Mutacional de DNA/métodos , Feminino , Fumarato Hidratase/deficiência , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Neoplasias Renais/enzimologia , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Fenótipo
11.
J Pak Med Assoc ; 69(6): 828-833, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31189290

RESUMO

OBJECTIVE: To examine receptors for advanced glycation end-products Gly82Ser polymorphism in patients of type 2 diabetes with comorbid depression. METHODS: The case-control study was conducted at Fujian Provincial Hospital, Fuzhou, China, between December 2011 and December 2012, and comprised unrelated Chinese Han patients of type 2 diabetes, and diabetics with diagnosed clinical depression. Gly82Ser polymorphism polymorphism was determined using polymerase chain reaction amplification-high resolution melting curve protocol. Serum levels of endogenous secretory receptor for advanced glycation end products were measured using enzyme-linked immunosorbent assay. SPSS 16 was used for data analysis. RESULTS: Of the 114 subjects, 72(63.15%) were clinically depressed. Lower levels of endogenous secretory receptor were found in the depression group compared with the other group (p=0.049). No difference in genotypes or allele frequencies existed between the two groups (p>0.05). Gly82Ser carriers had significantly higher Hamilton Rating Scale scores (p<0.001) and lower serum endogenous secretory receptor (p=0.012) among the depressed diabetics. There were also significant differences in body mass index (p=0.005), abdominal circumference (p=0.038), carotid intima-media thickness (p=0.037) and high-sensitivity C-reactive protein (p=0.005) concentration between the different genotypes.. CONCLUSIONS: Receptors for advanced glycation end-products-ligands system may be involved in type 2 diabetes with comorbid depression at the genetic level.

12.
Endocr Pract ; 25(4): 299-305, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30995429

RESUMO

Objective: To assess the association between famine exposure in early life and osteoporosis in adulthood. Methods: A total of 2,292 participants born between 1955 and 1965 in Fujian Province were selected; after 3 years, 1,378 participants attended a follow-up research visit. Calcaneus bone mineral density and bone quality were measured by quantitative ultrasound. The T-score was used to assess bone mineral density, and the parameters quantitative ultrasound index (QUI), speed of sound (SOS), and broadband ultrasonic attenuation (BUA) were used to assess bone quality. A T-score threshold of -1.8 was defined as osteoporosis, and a possible vertebral fracture was considered as a prospective height loss of 0.8 inches or more. Results: Compared with the nonexposed cohort, risks of osteoporosis for fetal-, early childhood, and mid-childhood famine-exposed cohorts in postmenopausal women were adjusted odds ratio (OR), 3.741 (95% confidence interval [CI], 1.233, 11.44) versus OR 2.894 (95% CI, 0.997, 8.571) versus OR 4.699 (95% CI, 1.622, 13.612) by logistic regression but not significant in men. Moreover, the fetal-exposed cohort had a weak negative relation with QUI (ß, -5.07 [-10.226, 0.127]) and BUA (ß, -4.321 [-0.88, 0.238]). The early- and mid-childhood-exposed cohorts had significantly lower QUI (ß, -7.085 [-11.799, -2.372] versus ß, -10.845 [-15.68, -6.01]) and BUA (ß, -6.381 [-10.515, -2.246] versus ß, -8.573 [-12.815, -4.331]) than the nonexposed cohort by linear regression. None of the famine-exposed cohorts had a significant relationship with SOS. Conclusion: Famine exposure during early life is associated with higher risk of osteoporosis in adulthood, which is most obvious in postmenopausal women. Furthermore, famine exposure in early life has adverse effects on bone quality. Abbreviations: BMD = bone mineral density; BUA = broadband ultrasonic attenuation; CI = confidence interval; OR = odds ratio; QUI = quantitative ultrasound index; QUS = quantitative ultrasound; SOS = speed of sound.


Assuntos
Osteoporose , Absorciometria de Fóton , Densidade Óssea , Feminino , Humanos , Masculino , Estudos Prospectivos , Inanição
13.
Eur J Radiol ; 113: 110-115, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30927934

RESUMO

OBJECTIVE: To investigate the MDCT features of primary adrenal lymphoma (PAL) and correlate the results with clinicopathological findings. MATERIALS AND METHODS: Twenty eight patients (17 men, 11 women; median age, 61.5years) with pathologically confirmed PAL were included in this study. MDCT features of the lesions were retrospectively reviewed and correlated with clinicopathological findings. RESULTS: All of the 28 cases were non-Hodgkin's lymphoma (NHL), in which 25 cases were diffuse large B-cell lymphoma and 3 cases T-cell lymphoma. 21 (75%) patients had bilateral tumors with maximum diameter of 3.9-17.7 cm (median, 9.18 cm), and 7 (25%) patients had unilateral tumors with maximum diameter of 4.3-14.9 cm (median, 8.6 cm). The sign of infiltrating adjacent organs and encasing adjacent vessels were appeared in 10 and 15 patients respectively, in which 9 patients had both signs. 20 (71.4%) patients had the appearance of adeniform, and 3 (10.7%) patients showed infiltrating and embedding the adrenal gland. Among all the patients, 27 (96.4%) and 26 (92.9%) patients had mild enhancement on arterial and parenchymal phase, respectively; and 12 (42.8%) were homogenous, 14 (50%) slightly inhomogeneous and 2 (7.1%) heterogeneous on both phase. In addition, adrenal insufficiency was found in 33.3% (7/21) of the patients with bilateral lesions, and none in unilateral lesions. CONCLUSION: Large adrenal soft tissue mass with maintenance of adreniform shape, encasing vessels, homogenous or slightly inhomogeneous density with no calcification, and mild enhancement on both arterial and parenchymal phase could be seen as the main MDCT features of PAL. In addition, infiltrating and embedding the adrenal gland may be specific imaging characteristics of PAL.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Linfoma não Hodgkin/diagnóstico por imagem , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Calcinose/diagnóstico por imagem , Calcinose/patologia , Feminino , Humanos , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada Multidetectores , Estudos Retrospectivos
14.
Cell Death Dis ; 10(4): 293, 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30926772

RESUMO

Hydrogen sulfide (H2S) serves as a gasotransmitter in the regulation of organ development and maintenance of homeostasis in tissues. Its abnormal levels are associated with multiple human diseases, such as neurodegenerative disease, myocardial injury, and ophthalmic diseases. Excessive exposure to H2S could lead to cellular toxicity, orchestrate pathological process, and increase the risk of various diseases. Interestingly, under physiological status, H2S plays a critical role in maintaining cellular physiology and limiting damages to tissues. In mammalian species, the generation of H2S is catalyzed by cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CSE), 3-mercapto-methylthio pyruvate aminotransferase (3MST) and cysteine aminotransferase (CAT). These enzymes are found inside the mammalian eyeballs at different locations. Their aberrant expression and the accumulation of substrates and intermediates can change the level of H2S by orders of magnitude, causing abnormal structures or functions in the eyes. Detailed investigations have demonstrated that H2S donors' administration could regulate intraocular pressure, protect retinal cells, inhibit oxidative stress and alleviate inflammation by modulating the function of intra or extracellular proteins in ocular tissues. Thus, several slow-releasing H2S donors have been shown to be promising drugs for treating multiple diseases. In this review, we discuss the biological function of H2S metabolism and its application in ophthalmic diseases.

15.
Sci Rep ; 9(1): 4393, 2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30867530

RESUMO

Flexible thermoelectric generators (TEGs) can provide uninterrupted, green energy from body-heat, overcoming bulky battery configurations that limit the wearable-technologies market today. High-throughput production of flexible TEGs is currently dominated by printing techniques, limiting material choices and performance. This work investigates the compatibility of physical vapour deposition (PVD) techniques with a flexible commercial process, roll-to-roll (R2R), for thermoelectric applications. We demonstrate, on a flexible polyimide substrate, a sputtered Bi2Te3/GeTe TEG with Seebeck coefficient (S) of 140 µV/K per pair and output power (P) of 0.4 nW per pair for a 20 °C temperature difference. For the first time, thermoelectric properties of R2R sputtered Bi2Te3 films are reported and we demonstrate the ability to tune the power factor by lowering run times, lending itself to a high-speed low-cost process. To further illustrate this high-rate PVD/R2R compatibility, we fabricate a TEG using Virtual Cathode Deposition (VCD), a novel high deposition rate PVD tool, for the first time. This Bi2Te3/Bi0.5Sb1.5Te3 TEG exhibits S = 250 µV/K per pair and P = 0.2 nW per pair for a 20 °C temperature difference.

16.
Proc Natl Acad Sci U S A ; 116(15): 7455-7464, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30914462

RESUMO

The crosstalk between vascular pericytes and endothelial cells (ECs) is critical for microvascular stabilization and remodeling; however, the crosstalk is often disrupted by diabetes, leading to severe and even lethal vascular damage. Circular RNAs are a class of endogenous RNAs that regulate several important physiological and pathological processes. Here we show that diabetes-related stress up-regulates cPWWP2A expression in pericytes but not in ECs. In vitro studies show that cPWWP2A directly regulates pericyte biology but indirectly regulates EC biology via exosomes carrying cPWWP2A. cPWWP2A acts as an endogenous miR-579 sponge to sequester and inhibit miR-579 activity, leading to increased expression of angiopoietin 1, occludin, and SIRT1. In vivo studies show that cPWWP2A overexpression or miR-579 inhibition alleviates diabetes mellitus-induced retinal vascular dysfunction. By contrast, inhibition of cPWWP2A-mediated signaling by silencing cPWWP2A or overexpressing miR-579 aggravates retinal vascular dysfunction. Collectively, this study unveils a mechanism by which pericytes and ECs communicate. Intervention of cPWWP2A or miR-579 expression may offer opportunities for treating diabetic microvascular complications.


Assuntos
Comunicação Celular , Retinopatia Diabética/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , MicroRNAs/biossíntese , Pericitos/metabolismo , Transdução de Sinais , Regulação para Cima , Animais , Retinopatia Diabética/patologia , Exossomos/metabolismo , Exossomos/patologia , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Masculino , Camundongos , MicroRNAs/genética , Pericitos/patologia , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia
17.
BMC Bioinformatics ; 20(1): 69, 2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30736745

RESUMO

BACKGROUND: Determining which target to pursue is a challenging and error-prone first step in developing a therapeutic treatment for a disease, where missteps are potentially very costly given the long-time frames and high expenses of drug development. With current informatics technology and machine learning algorithms, it is now possible to computationally discover therapeutic hypotheses by predicting clinically promising drug targets based on the evidence associating drug targets with disease indications. We have collected this evidence from Open Targets and additional databases that covers 17 sources of evidence for target-indication association and represented the data as a tensor of 21,437 × 2211 × 17. RESULTS: As a proof-of-concept, we identified examples of successes and failures of target-indication pairs in clinical trials across 875 targets and 574 disease indications to build a gold-standard data set of 6140 known clinical outcomes. We designed and executed three benchmarking strategies to examine the performance of multiple machine learning models: Logistic Regression, LASSO, Random Forest, Tensor Factorization and Gradient Boosting Machine. With 10-fold cross-validation, tensor factorization achieved AUROC = 0.82 ± 0.02 and AUPRC = 0.71 ± 0.03. Across multiple validation schemes, this was comparable or better than other methods. CONCLUSION: In this work, we benchmarked a machine learning technique called tensor factorization for the problem of predicting clinical outcomes of therapeutic hypotheses. Results have shown that this method can achieve equal or better prediction performance compared with a variety of baseline models. We demonstrate one application of the method to predict outcomes of trials on novel indications of approved drug targets. This work can be expanded to targets and indications that have never been clinically tested and proposing novel target-indication hypotheses. Our proposed biologically-motivated cross-validation schemes provide insight into the robustness of the prediction performance. This has significant implications for all future methods that try to address this seminal problem in drug discovery.


Assuntos
Algoritmos , Descoberta de Drogas , Modelos Teóricos , Teorema de Bayes , Benchmarking , Ensaios Clínicos como Assunto , Sistemas de Liberação de Medicamentos/métodos , Humanos , Modelos Logísticos
18.
Adv Mater ; 31(14): e1807083, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30773719

RESUMO

A variety of alternative plasmonic and dielectric material platforms-among them nitrides, semiconductors, and conductive oxides-have come to prominence in recent years as means to address the shortcomings of noble metals (including Joule losses, cost, and passive character) in certain nanophotonic and optical-frequency metamaterial applications. Here, it is shown that chalcogenide semiconductor alloys offer a uniquely broad pallet of optical properties, complementary to those of existing material platforms, which can be controlled by stoichiometric design. Using combinatorial high-throughput techniques, the extraordinary epsilon-near-zero, plasmonic, and low/high-index characteristics of Bi:Sb:Te alloys are explored. Depending upon composition they can, for example, have plasmonic figures of merit higher than conductive oxides and nitrides across the entire UV-NIR range, and higher than gold below 550 nm; present dielectric figures of merit better than conductive oxides at near-infrared telecommunications wavelengths; and exhibit record-breaking refractive indices as low as 0.7 and as high as 11.5.

19.
Eur Respir J ; 53(4)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30765504

RESUMO

RATIONALE: We aimed to identify differentially methylated regions (DMRs) in cord blood DNA associated with childhood lung function, asthma and chronic obstructive pulmonary disease (COPD) across the life course. METHODS: We meta-analysed epigenome-wide data of 1688 children from five cohorts to identify cord blood DMRs and their annotated genes, in relation to forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC) ratio and forced expiratory flow at 75% of FVC at ages 7-13 years. Identified DMRs were explored for associations with childhood asthma, adult lung function and COPD, gene expression and involvement in biological processes. RESULTS: We identified 59 DMRs associated with childhood lung function, of which 18 were associated with childhood asthma and nine with COPD in adulthood. Genes annotated to the top 10 identified DMRs were HOXA5, PAOX, LINC00602, ABCA7, PER3, CLCA1, VENTX, NUDT12, PTPRN2 and TCL1A. Differential gene expression in blood was observed for 32 DMRs in childhood and 18 in adulthood. Genes related with 16 identified DMRs were associated with respiratory developmental or pathogenic pathways. INTERPRETATION: Our findings suggest that the epigenetic status of the newborn affects respiratory health and disease across the life course.

20.
Biomed Pharmacother ; 111: 548-554, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30597308

RESUMO

Proliferative vitreoretinopathy (PVR) is one of the major challenges in retinal surgery, which occurs in the patient with complex retinal surgery or penetrating eye injury. Circular RNAs (circRNAs) have emerged as important regulators in many biological processes and disease development. However, the characterization and function of circRNAs in PVR remains elusive. In this study, we identified 91 dysregulated circRNAs in the epiretinal membranes (ERMs) of PVR patients. We further investigated the expression pattern of circ_0043144. circ_0043144 was significantly up-regulated in the vitreous samples and the corresponding serum samples of the patients with PVR. circ_0043144 expression was significantly down-regulated after PVR operation. In vitro studies revealed that circ_0043144 was involved in the regulation of the proliferation, migration and secretion ability of ARPE-19 cells, which is critical for ERM formation. Collectively, this study indicates that circRNAs are potential regulators of the pathogenesis of PVR. circ_0043144 is a promising prognostic and diagnostic indicator for PVR diseases.


Assuntos
Perfilação da Expressão Gênica/métodos , RNA/genética , RNA/metabolismo , Vitreorretinopatia Proliferativa/genética , Vitreorretinopatia Proliferativa/metabolismo , Células Cultivadas , Membrana Epirretiniana/genética , Membrana Epirretiniana/metabolismo , Membrana Epirretiniana/patologia , Humanos , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Vitreorretinopatia Proliferativa/patologia
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