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1.
Sleep Med Rev ; : 101203, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31494051

RESUMO

Changes in nighttime sleep consolidation and daytime discontinuation have been observed in early life. Yet information about societal or cultural factors remains scant for implementing sleep recommendations. We aimed to provide pooled estimates of subjective sleep duration, number of nightwakings and sleep timing; to describe their age-related trends; and to determine potential cross-cultural disparities between predominantly-Asian (PA) and predominantly-Caucasian (PC) regions during the first three years of life. We performed this review according to the PRISMA guidelines. Overall, 102 studies with 167,886 children aged 0-3 y from 26 different countries were included. Compared to PC regions, PA toddlers had shorter sleep duration and more frequent nightwakings. When PC regions were further divided into Pacific Rim and Europe, differences were much more evident between PA and Pacific Rim for all nighttime sleep parameters. Trends of nighttime sleep duration and bedtime for PC regions showed rapid changes over the first 3-6 mo before stabilizing to a plateau, whereas a different change was found for PA regions. In conclusion, an apparent cross-cultural disparity of the subjective sleep parameters already exists in early childhood. Improved operationalization of sleep parameters and more objective evidence are needed to establish cultural-sensitive recommendations this early in life.

2.
Obes Res Clin Pract ; 13(4): 352-357, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31402168

RESUMO

BACKGROUND: The rs9939609 SNP in fat mass and obesity-associated (FTO) gene influence obesity, whose effects might be mediated by lifestyle factors. However, evidence was lacked in early adolescents. This study aimed to investigate the interactions effects of FTO rs9939609 and lifestyle factors on obesity indices in early adolescence. METHODS: The study included 1149 children aged 10-12 years. Their body mass index (BMI) and body fat percentage (BF%) were measured, and lifestyle factors were surveyed through questionnaires. The rs9939609 SNP in the FTO gene was genotyped. RESULTS: Significant associations were found between FTO rs9939609 and obesity indices after adjusting for confounding factors. An interaction effect between rs9939609 and soft drinks was observed with p=0.019 for BMI after adjustment for confounding factors. The children carrying risk allele A had a significantly higher mean BMI (mean=19.67kg/m2) than those carrying only the wild allele T (mean=17.987kg/m2) when they reported a higher intake of soft drinks (≥3 times/week), but the association was not observed among children with a lower intake of soft drinks. No significant interactions were established between appetite, weekday TV viewing, sleep, exclusive breast feeding in the first four months and FTO rs9939609 on BMI or BF%. Bioinformatics revealed that rs9939609 and its linkage disequilibrium (LD) SNPs are potentially implicated in the regulation of gene expression in blood, pancreatic and brain tissue cells. CONCLUSION: FTO rs9939609 had an obvious and independent effect on obesity-related indices in early adolescents. Soft drinks may exert a modifying effect on the relationship between FTO rs9939609 and BMI.

3.
Carbohydr Polym ; 219: 143-154, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31151511

RESUMO

In recent years, the utilization of polysaccharides as targeted drug carriers has attracted considerable attention. Herein, Angelica sinensis polysaccharide (ASP), a plant polysaccharide with good biocompatibility, excellent aqueous solubility and intrinsic liver-targeted capability, was modified with hydrophobic group (deoxycholic acid) to fabricate amphiphilic conjugate (ASP-DOCA). Self-assembled nanoparticles were successfully developed for hepatoma-targeted delivery of therapeutic drug doxorubicin (DOX). The DOX loaded nanoparticles (DOX/ASP-DOCA NPs) were spherical in shape with a particle size of 228 nm and negatively charged around -17 mV. DOX was released from nanoparticles in a sustainable and pH-dependent manner. In vitro cellular uptake revealed that DOX/ASP-DOCA NPs were internalized into HepG2 cells through asialoglycoprotein receptor (ASGPR)-mediated endocytosis, resulting in a higher anti-proliferation effect than DOX-loaded dextran derivative DOX/DEX-DOCA NPs. Additionally, DOX/ASP-DOCA NPs showed higher inhibition on the growth of HepG2 multicellular spheroids (MCs) than DOX/DEX-DOCA NPs. In vivo imaging demonstrated that ASP-DOCA NPs specifically targeted HepG2 tumors via ASGPR, improving the accumulation of DOX/ASP-DOCA NPs in tumors and generating superior antitumor activity compared with free DOX and DOX/DEX-DOCA NPs. Taken together, ASP-DOCA NPs possess potential applications in drug delivery systems targeting liver cancer.


Assuntos
Angelica sinensis/metabolismo , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Nanoconjugados/uso terapêutico , Nanopartículas/uso terapêutico , Polissacarídeos/uso terapêutico , Animais , Receptor de Asialoglicoproteína/metabolismo , Ácido Desoxicólico/química , Células HeLa , Células Hep G2 , Humanos , Camundongos , Nanopartículas/ultraestrutura , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
4.
Chemistry ; 25(43): 10188-10196, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31192495

RESUMO

The fabrication of carbon dots and their doped forms by top-down chemical cleavage has attracted considerable attention in the efforts to meet the increasing demands for optoelectronic applications ranging from biosensing to electro- and photocatalysis. However, due to strong quantum confinement effects, the size decrease often leads to an increase in the band gap, even in the emission of deep-ultraviolet (DUV) light, which greatly limits their applications. Here, we report a facile hot-tailoring strategy for fabricating carbon nitride nanodots (CNDs) with redshifted intrinsic photoluminescent (PL) emission, compared with the pristine bulk precursor. It has been found that the different leaving abilities of the C,N-containing groups during the pyrolysis stage and the chemical passivation during the liquid-collection stage played vital roles. Due to the redshifted photoluminescence and other attractive features, the as-obtained CNDs were successfully applied in visual double text encryption with higher security and also in bioimaging with photostability superior to traditional dyes. This work highlights the great potential of the hot-tailoring method in modulating carbon-based nanostructures and offsetting band-gap widening as the size decreases.


Assuntos
Nitrilos/química , Pontos Quânticos/química , Sobrevivência Celular/efeitos dos fármacos , Humanos , Células MCF-7 , Microscopia Confocal , Espectroscopia Fotoeletrônica , Pirólise , Pontos Quânticos/toxicidade , Espectrometria de Fluorescência , Raios Ultravioleta
5.
J Am Coll Cardiol ; 73(24): 3118-3131, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31221261

RESUMO

BACKGROUND: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions. OBJECTIVES: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population. METHODS: Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs. RESULTS: Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals. CONCLUSIONS: The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms.

6.
Nanoscale ; 11(19): 9598-9607, 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31063163

RESUMO

Conformal hydrolysis of MOF precursors is a promising strategy to prepare hierarchical metal hydroxide electrode materials on a large scale with low cost and high efficiency. However, a complete transformation is challenging due to the normal "outside-in" conversion process. After studying the hydrolysis of Ni-MOF-74, which has regular 1D channels, we suggest that the transformation to Ni(OH)2 can occur simultaneously outside and within the precursor depending on the treatment temperature. Molecular dynamics simulations reveal that a higher temperature weakens the steric effects of OH- ions and facilitates the diffusion in the regular channels, and therefore, a complete transformation from Ni-MOF-74 to Ni(OH)2 is achieved. It is for the first time demonstrated that the 1D channels of MOFs are utilized for the complete conformal hydrolysis of Ni-MOF-74 to Ni(OH)2 electrode materials. Meanwhile, we also perform pioneering work illustrating that the complete conformal hydrolysis is the key to the improved supercapacitor performances of the MOF-derived Ni(OH)2 electrodes. The prepared Ni(OH)2 electrode under the optimized conditions has a specific capacity of 713.2 C g-1 at a current density of 1 A g-1, which is at least 28% larger than those of the Ni(OH)2 prepared at other temperatures. The detailed analyses based on CV and EIS of the obtained Ni(OH)2 electrodes indicate that the residual MOFs within electrodes due to incomplete hydrolysis significantly influence the diffusion length and diffusion efficiency of OH-, drastically lowering the supercapacitor performances.

7.
Neurosci Lett ; 706: 99-104, 2019 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-31091460

RESUMO

Hearing loss is a common sensory disorder that affects more than 360 million people worldwide, and is primarily caused by the loss of hair cells (HCs). Ototoxic drugs, viral infections, genetic predisposition, aging or noise all damage HCs. 3ß-hydroxysteroid-Δ24 reductase (DHCR24), one enzyme in the cholesterol biosynthetic pathway, is involved in inflammation, oxidative stress and neuroprotection. However, researchers have not determined whether DHCR24 is present in the cochlea and the mechanism by which it exerts its regulatory effect on HC loss. In the present study, we analyzed DHCR24 expression in the postnatal day 1 (P1) rat cochlea and found that DHCR24 was localized in HCs of the organ of Corti. Next, exposure to cisplatin caused HC loss in cochlear organotypic cultures. Then, we inhibited DHCR24 expression with U18666A and observed significantly increased cisplatin-induced damage of cochlear HCs. These findings were consistent with the observed increase in DHCR24 expression in response to cisplatin treatment, and U18666A significantly decreased DHCR24 expression. Finally, DHCR24 inhibition increased the levels of reactive oxygen species and cleaved caspase-3 after cisplatin-induced injury. Collectively, DHCR24 may play a significant role in regulating auditory function and potentially represents a new therapeutic target for the treatment of cisplatin-induced ototoxicity.

8.
ACS Nano ; 13(6): 7024-7030, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31120727

RESUMO

Pseudomorphic conversion of metal-organic frameworks (MOFs) enables the fabrication of nanomaterials with well-defined porosities and morphologies for enhanced performances. However, the commonly reported calcination strategy usually requires high temperature to pyrolyze MOF particles and often results in uncontrolled growth of nanomaterials. Herein, we report the controlled alkaline hydrolysis of MOFs to produce layered double hydroxide (LDH) while maintaining the porosity and morphology of MOF particles. The preformed trinuclear M3(µ3-OH) (M = Ni2+ and Co2+) clusters in MOFs were demonstrated to be critical for the pseudomorphic transformation process. An isotopic tracing experiment revealed that the 18O-labeled M3(µ3-18OH) participated in the structural assembly of LDH, which avoided the leaching of metal cations and the subsequent uncontrolled growth of hydroxides. The resulting LDHs maintain the spherical morphology of MOF templates and possess a hierarchical porous structure with high surface area (BET surface area up to 201 m2·g-1), which is suitable for supercapacitor applications. As supercapacitor electrodes, the optimized LDH with the Ni:Co molar ratio of 7:3 shows a high specific capacitance (1652 F·g-1 at 1 A·g-1) and decent cycling performance, retaining almost 100% after 2000 cycles. Furthermore, the hydrolysis method allows the recycling of organic ligands and large-scale synthesis of LDH materials.

9.
PLoS Genet ; 15(4): e1007739, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30990817

RESUMO

Sleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.


Assuntos
Hexoquinase/genética , Subunidade alfa de Receptor de Interleucina-18/genética , Oxiemoglobinas/metabolismo , Sono/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Moléculas de Adesão Celular Neuronais/genética , Biologia Computacional , Proteínas da Matriz Extracelular/genética , Feminino , Redes Reguladoras de Genes , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Hipóxia/sangue , Hipóxia/genética , Masculino , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas do Tecido Nervoso/genética , Oxigênio/sangue , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Serina Endopeptidases/genética , Síndromes da Apneia do Sono/sangue , Síndromes da Apneia do Sono/genética , Adulto Jovem
10.
Medicine (Baltimore) ; 98(14): e15104, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30946375

RESUMO

To prospectively compare the reproducibility of normal pancreas-normalized apparent diffusion coefficient (ADC) measurements for the normal pancreas and mean normalized ADCs at different pancreas anatomic locations.In total, 22 healthy volunteers underwent pancreatic 3.0-T magnetic resonance (MR) imaging, including axial diffusion-weighted (DW) imaging with 3 b values used (0, 400, and 800 s/mm) and with the respiratory-triggered (RT) technique. The mean ADCs from 3 regions of interest (ROIs) in 5 anatomic locations (head [H], body [B], and tail [T] of pancreas and spleen [S] and erector spinae muscles [M]) were calculated. The pancreas-normalized ADC was defined as the ratio of the ADC for the pancreas to the ADC for the spleen or erector spinae muscle. Reproducibility of ADCs and normalized ADCs was assessed by the Bland-Altman method. The ADC and normalized ADC data were analyzed by repeated-measures ANOVA.Mean ADC and normalized ADC values did not differ (P >.05) with repeated measurements at the different pancreas anatomic locations. Reproducibility of pancreas-normalized ADC measurements in each of the 3 pancreatic anatomic locations was better with the erector spinae muscle rather than the spleen used as a reference. Mean ADC and normalized ADC values significantly differed between the 3 pancreatic segments (H: 1.36 × 10 mm/s, B: 1.38 × 10 mm/s, T: 1.25 × 10 mm/s, P = .022; H/S: 1.75, B/S: 1.78, T/S: 1.59, P = .009; H/M: 0.91, B/M: 0.95, T/M: 0.85, P = .008). Mean ADC values and normalized ADC values showed a trend to decrease from the pancreatic head to tail.Our preliminary results suggest that normalized ADC measurements for the pancreas show good intra- and interobserver reproducibility, the erector spinae muscle is a better choice than the spleen for calculating normalized ADC values for the pancreas, and the normalized ADC values are lower for the pancreatic tail than other pancreatic segments.


Assuntos
Imagem de Difusão por Ressonância Magnética/métodos , Interpretação de Imagem Assistida por Computador/métodos , Pâncreas/anatomia & histologia , Pâncreas/diagnóstico por imagem , Adulto , Análise de Variância , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Estudos Prospectivos , Melhoria de Qualidade , Valores de Referência , Reprodutibilidade dos Testes , Baço/anatomia & histologia , Baço/diagnóstico por imagem
11.
Anal Chem ; 91(9): 5489-5493, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-30968689

RESUMO

Methionine sulfoxide reductases (Msrs) play essential roles in maintaining mitochondrial function and are recognized as potential therapeutic targets. However, current probes for Msrs fail to target mitochondria and exhibit a relatively slow response and limited sensitivity. Here we develop a novel turn-on fluorescence probe that facilitates imaging of mitochondrial Msrs in living cells. The probe is constructed by conjugating a methyl phenyl sulfoxide, a mimic Msrs substrate, to an electron-withdrawing hydrophobic cation, methylpyridinium. The probe of acceptor-acceptor structure is initially nonemissive. Msrs catalyzed reduction of sulfoxide to sulfide generated a fluorophore of distinct donor-acceptor structure. The probe is demonstrated to exhibit high sensitivity, fast response, and high selectivity toward MsrA in vitro. Furthermore, the probe is successfully introduced to detect and image Msrs in living cells with excellent mitochondrial-targeting capability. Moreover, the probe also reveals decreased Msrs activity in a cellular Parkinson's disease model. Our probe affords a powerful tool for detecting and visualizing mitochondrial Msrs in living cells.

12.
Chem Commun (Camb) ; 55(30): 4387-4390, 2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30916085

RESUMO

A novel and versatile platform for single-step amplified fluorescence detection of antibodies via specific proximity-induced hybridization chain assembly is developed.


Assuntos
Anticorpos/sangue , Técnicas Biossensoriais/métodos , DNA/química , DNA/genética , Técnicas de Amplificação de Ácido Nucleico , Anticorpos/metabolismo , DNA/metabolismo , Humanos , Limite de Detecção , Espectrometria de Fluorescência
13.
Anal Chem ; 91(4): 2610-2614, 2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30701962

RESUMO

DNA hydrogels are biocompatible and are suitable for many biomedical applications. However, to be useful imaging probes or drug carriers, the ordinary bulk size of DNA hydrogels must be overcome. Here we put forward a new strategy for fabricating a novel and simple protein-scaffolded DNA nanohydrogel, constructed through a direct DNA self-assembly using three types of streptavidin (SA)-based DNA tetrad for the activation of imaging and targeting therapy of cancer cells. The DNA nanohydrogels are easily prepared, and we show that by varying the initial concentration of DNA tetrad, it is possible to finely control their size within nanoscale range, which are favorable as carriers for intracellular imaging and transport. By further incorporating therapeutic agents and tumor-targeting MUC1 aptamer, these multifunctionalized SA-scaffolded DNA nanohydrogels (SDH) can specifically target cancer cells and selectively release the preloaded therapeutic agents via a structure switching when in an ATP-rich intracellular environment, leading to the activation of the fluorescence and efficient treatment of cancer cells. With the advantages of facile modular design and assembly, effective cellular uptake, and excellent biocompatibility, the method reported here has the potential for the development of new tunable DNA nanohydrogels with multiple synergistic functionalities for biological and biomedical applications.

14.
Eur J Hum Genet ; 27(6): 952-962, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30679814

RESUMO

Genome-wide association studies (GWAS) of quantitative electrocardiographic (ECG) traits in large consortia have identified more than 130 loci associated with QT interval, QRS duration, PR interval, and heart rate (RR interval). In the current study, we meta-analyzed genome-wide association results from 30,000 mostly Dutch samples on four ECG traits: PR interval, QRS duration, QT interval, and RR interval. SNP genotype data was imputed using the Genome of the Netherlands reference panel encompassing 19 million SNPs, including millions of rare SNPs (minor allele frequency < 5%). In addition to many known loci, we identified seven novel locus-trait associations: KCND3, NR3C1, and PLN for PR interval, KCNE1, SGIP1, and NFKB1 for QT interval, and ATP2A2 for QRS duration, of which six were successfully replicated. At these seven loci, we performed conditional analyses and annotated significant SNPs (in exons and regulatory regions), demonstrating involvement of cardiac-related pathways and regulation of nearby genes.

15.
Int Urol Nephrol ; 51(2): 359-367, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30536192

RESUMO

PURPOSE: To assess the role of serum pigment epithelium-derived factor (PEDF) in the occurrence and development of proteinuria and renal dysfunction and determine its relevant signaling pathway. METHODS: We analyzed serum PEDF, creatinine, the urinary albumin-to-creatinine ratio, and renal morphology of normal or streptozotocin (STZ)-induced diabetic mice, before and after treatment with PEDF. In vitro, podocytes were stimulated with PEDF under normal or high-glucose conditions; permeability was measured by the transwell assay with fluorescein isothiocyanate (FITC)-dextran; and F-actin cytoskeleton was analyzed by phalloidin staining. Apoptosis was assessed by flow cytometry. RhoA activity and ROCK1, ZO-1, nephrin, and podocin levels were detected by Western blotting. RESULTS: Diabetic mice exhibited a high serum PEDF level. In vivo, elevated serum PEDF led to proteinuria, increased serum creatinine, and podocyte foot process fusion in normal or diabetic mice. In vitro, both high-glucose and PEDF stimulation activated the RhoA/ROCK1 pathway in podocytes and promoted cell permeability, F-actin rearrangement, and apoptosis. Inhibition of RhoA/ROCK1 alleviated the damage from these effects. CONCLUSIONS: Elevated serum PEDF aggravates the development of proteinuria and renal dysfunction by inducing F-actin arrangement, foot process fusion, and apoptosis of podocytes in both normal and diabetic mice, and this effect may be mediated by activation of the RhoA/ROCK1 pathway.


Assuntos
Actinas/metabolismo , Nefropatias Diabéticas/metabolismo , Proteínas do Olho/sangue , Rim , Fatores de Crescimento Neural/sangue , Podócitos/metabolismo , Proteinúria , Serpinas/sangue , Proteínas rho de Ligação ao GTP/metabolismo , Quinases Associadas a rho/metabolismo , Animais , Apoptose , Diabetes Mellitus Experimental , Nefropatias Diabéticas/etiologia , Rim/metabolismo , Rim/fisiopatologia , Testes de Função Renal , Camundongos , Proteinúria/diagnóstico , Proteinúria/metabolismo , Transdução de Sinais
16.
Hum Mol Genet ; 2018 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-30403821

RESUMO

Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Its prevalence and severity vary across ancestral background. Although OSA traits are heritable, few genetic associations have been identified. To identify genetic regions associated with OSA and improve statistical power, we applied admixture mapping on three primary OSA traits (the apnea hypopnea index [AHI], overnight average oxyhemoglobin saturation [SaO2] and percentage time SaO2<90%) and a secondary trait (respiratory event duration) in a Hispanic/Latino American population study of 11,575 individuals with significant variation in ancestral background. Linear mixed models were performed using previously inferred African, European and Amerindian local genetic ancestry markers. Global African ancestry was associated with a lower AHI, higher oxyhemoglobin saturation and shorter event duration. Admixture mapping analysis of the primary OSA traits identified local African ancestry at the chromosomal region 2q37 as genome-wide significantly associated with AHI (P<5.7×10-5), and European and Amerindian ancestries at 18q21 suggestively associated with both AHI and percentage time SaO2<90% (P<10-3). Follow-up joint ancestry-SNP association analyses identified novel variants in ferrochelatase (FECH), significantly associated with AHI and percentage time SaO2<90% after adjusting for multiple tests (P<8×10-6). These signals contributed to the admixture mapping associations and were replicated in independent cohorts. In this first admixture mapping study of OSA, novel associations with variants in the iron/heme metabolism pathway suggest a role for iron in influencing respiratory traits underlying OSA.

17.
Drug Des Devel Ther ; 12: 3301-3309, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30323562

RESUMO

Background: Gliomas are one of the most common types of primary brain tumors. It is usually evaluated by gadolinium(III)-based contrast agents by magnetic resonance imaging (MRI) in the clinic. Methotrexate (MTX), as a type of folate analog that inhibits the enzyme dihydrofolate reductase, is widely used as a chemotherapeutic agent to treat gliomas in the experiment. Purpose: In this study, a novel theranostic agent MTX-DOTA-Gd (MTX-Gd) was synthesized, which integrates magnetic resonance imaging (MRI) with anticancer treatment. Methods: MTX-Gd was synthesized by connecting MTX and Gd through 1,4,7,10-tetraazacy-clododecane-1,4,7,10-tetraacetic acid (DOTA). The characterization of MTX-Gd was detected by ultraviolet (UV) and infrared spectroscopy (IR). To confirm the antitumor effect of MTX-Gd, the cytotoxicity of MTX-Gd was examined by the MTT assay. The contrast enhancement of the MTX-Gd was measured through MRI in vitro. Then, nude mice bearing C6 tumor xenografts were used to study in vivo imaging capabilities. Results: The ultraviolet-visible-near infrared radiation (UV-NIR) absorption curve indicated that MTX-Gd had a broad absorption in the region of 500-700 nm. The formation of MTX-Gd was confirmed from the characteristic bands of MTX-DOTA-Gd in the 1413 cm-1 (C-N), 1577 cm-1 (-NH2), and 3429 cm-1 (N-H), in the fourier-transform infrared (FTIR) spectra. MTX-Gd showed little difference in the cell viability compared with MTX, except for the highest concentration (270 µM). In vitro, the imaging of MTX-Gd was significantly brighter than Gd-DOTA at the same concentration, and the brightness and signal intensity of MRI were increased followed by the increased concentration of MTX-Gd. And it also showed that MTX was not visualized on MRI. The other images revealed that the concentration of 4 mM MTX-Gd had the same imaging effect with the concentration of 10 mM Gd-DOTA. Then, MTX-Gd was injected in nude mice bearing C6 tumor xenografts through the tail vein. Significant contrast enhancement was observed at the tumor site from 0.5 h to 3 h. The signal of tumor area was strongest at 3 h due to accumulation by size effect of macromolecules. Conclusion: A novel stable and unique theranostic agent (MTX-Gd) was successfully synthe-sized, and it has good stability, strong anticancer ability and excellent magnetic capacity. The methotrexate component of MTX-Gd, as a chemotherapeutic agent, played an important role in targeted therapies of cancer. The DOTA-Gd component of MTX-Gd performed as the MRI contrast agent. The superior MRI imaging performance and synergetic chemical antineoplastic ability of MTX-Gd was revealed, and it has great potential in the diagnosis and treatment of glioma and potentially other cancers, with prospects of clinical application in the near future.

18.
EBioMedicine ; 37: 221-235, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30327268

RESUMO

BACKGROUND: Cardiac remodeling is a pathophysiological process that involves various changes in heart, including cardiac hypertrophy and fibrosis. Cardiac remodeling following pathological stimuli is common trigger leading to cardiac maladaptation and onset of heart failure, and their pathogenesis remains unclear. METHODS: Heart specimens of tetralogy of Fallot (TOF) patients, myocardial infarction (MI) and transverse aortic constriction (TAC) mouse models were collected to determine changes of microtubule associated protein 4 (MAP4) phosphorylation. MAP4 (S667A, S737E and S760E) knock in (MAP4 KI) mouse and cultured neonatal mouse cardiomyocytes or fibroblasts were used to investigate changes of cardiac phenotypes and possible mechanisms with a variety of approaches, including functional, histocytological and pathological observations. FINDINGS: Elevated cardiac phosphorylation of MAP4 (S737 and S760) was observed in TOF patients, MI and TAC mouse models. In MAP4 KI mice, age-dependent cardiac phenotypes, including cardiac hypertrophy, fibrosis, diastolic and systolic dysfunction were observed. In addition, increased cardiomyocyte apoptosis together with microtubule disassembly and mitochondrial translocation of phosphorylated MAP4 was detected prior to the onset of cardiac remodeling, and p38/MAPK was demonstrated to be the possible signaling pathway that mediated MAP4 (S737 and S760) phosphorylation. INTERPRETATION: Our data reveal for the first time that MAP4 drives pathological cardiac remodeling through its phosphorylation. These findings bear the therapeutic potential to ameliorate pathological cardiac remodeling by attenuating MAP4 phosphorylation. FUND: This work was supported by the Key Program of National Natural Science Foundation of China (No.81430042) and National Natural Science Foundation of China (No.81671913).

19.
Anal Chem ; 90(21): 12951-12958, 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30303006

RESUMO

Spherical nucleic acid (SNA) constructs are promising new single entity materials, which possess significant advantages in biological applications. Current SNA-based drug delivery system typically employed single-layered ss- or ds-DNA as the drug carriers, resulting in limited drug payload capacity and disease treatment. To advance corresponding applications, we developed a novel DNA-programmed polymeric SNA, a long concatamer DNA polymer that is uniformly distributed on gold nanoparticles (AuNPs), by self-assembling from two short alternating DNA building blocks upon initiation of immobilized capture probes on AuNPs, through a supersandwich hybridization reaction. The long DNA concatamer of polymeric SNA enables to allow high-capacity loading of bioimaging and therapeutics agents. We demonstrated that both of the fluorescence signals and therapeutic efficacy were effectively inhibited in resultant polymeric SNA. By further modifying with the nucleolin-targeting aptamer AS1411, this polymeric SNA could be specifically internalized into the tumor cells through nucleolin-mediated endocytosis and then interact with endogenous ATP to cause the release of therapeutics agents from long DNA concatamer via a structure switching, leading to the activation of the fluorescence and selective synergistic chemotherapy and photodynamic therapy. This nanostructure can afford a promising targeted drug transport platform for activatable cancer theranostics.

20.
Inorg Chem ; 57(17): 10953-10960, 2018 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-30137967

RESUMO

Supercapacitors are regarded to be highly probable candidates for next-generation energy storage devices. Herein, a bimetallic Co/Ni MOF is used as a sacrificial template through an alkaline hydrolysis and selective oxidation process to prepare an accordion-like ternary NiCo2O4/ß-Ni xCo1- x(OH)2/α-Ni xCo1- x(OH)2 composite, which is composed of Co/Ni(OH)2 nanosheets with large specific surface as the frame and NiCo2O4 nanoparticles with high conductivity as the insertion, for supercapacitor application. This material exhibits both high specific capacitance (1315 F·g-1 at 5 A·g-1) and excellent cycle performance (retained 90.7% after 10 000 cycles). This hydrolysis-oxidation process, alkali hydrolysis followed by oxidation with H2O2, offers a novel approach to fabricate the Ni/Co-based electrode materials with enhanced supercapacitor performance.

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