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1.
Eur J Pharm Sci ; 141: 105134, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31678425

RESUMO

Neuromuscular blockers (NMBs) selectively block neuromuscular transmission at the N2-nicotinic receptor on motor neurons to paralyze skeletal muscles, and are mainly used to facilitate tracheal intubation and surgical procedures. Rapid reversal is necessary in clinical practice to avoid profound block and reduce recovery time. Adamgammadex sodium is a modified γ-cyclodextrin derivative consisting of a lipophilic core and a hydrophilic outer end that forms an inactive tight inclusion complex with free molecules of rocuronium and vecuronium. In preclinical study, adamgammadex produced a concentration-dependent reversion effect of neuromuscular blockade induced by rocuronium in beagle dogs. Furthermore, adamgammadex had a less potential side effects than sugammadex and other clinical used neuromuscular block antagonists. In this study, the objective was to assess the safety, tolerability, and pharmacokinetics of single intravenous injection of adamgammadex in healthy volunteers. Approved by the China Food and Drug Administration, 52 healthy volunteers (half male and half female) were enrolled in this single-center, randomized, double-blind placebo-controlled study. No serious adverse effects were happened in this study. The overall frequency of adverse effects in adamgammadex was similar for that in placebo, and there was no specific adverse effect in adamgammadex. All of the volunteers bearing the adverse effects were recovered to normal without any treatment or intervention. In pharmacokinetic study, the value of half-time, Tmax, and clearance were not changed significantly, and the Cmax and AUC0-∞ increased with a similar ratio of the escalating doses. For dose proportionality analysis of adamgammadex, the estimate of slope was close to 1, and it was not significantly different from 1 after doses (AUC0-∞, 0.9965 [90%CI, 0.9468, 1.046]; Cmax, 0.9462 [90%CI, 0.8800, 1.012]). Therefore, adamgammadex exposure in plasma increased in a dose- proportional manner. The urinary route is a significant excretory pathway for adamgammadex, and it is mostly completed at 8 h. All the results in this study showed that adamgammadex may be a novel safe neuromuscular blockade reversal agent .

2.
Dev Comp Immunol ; 103: 103526, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31655126

RESUMO

Inhibitory protein IκBα plays a crucial role in the inflammatory process and immune response by regulating the activity of transcription factor NF-κB. In teleost, great progress has been achieved regarding NF-κB signaling for innate immunity, but whether this pathway modulates adaptive immunity, and how, remains largely unclear. In this study, after characterizing the sequence, structure, and phylogeny of Nile tilapia Oreochromis niloticus IκBα (defined as On-IκBα), we investigated the association between IκBα-regulated NF-κB activation and the lymphocyte-mediated adaptive immune response in Nile tilapia. We found that On-IκBα was evolutionarily conserved, and its mRNA was expressed widely in various tissues, with most abundance in the trunk kidney. mRNA expression of On-IκBα was significantly upregulated in spleen at both innate and adaptive immune stages after Aeromonas hydrophila infection. Moreover, phosphorylation of On-IκBα and the downstream On-NF-κB p65 was obviously elevated in spleen leukocytes at 3, 5, or 8 days after A. hydrophila infection, indicating the activation of NF-κB signaling. Correlating with the augmented protein phosphorylation, leukocyte proliferation was enhanced during the same immune stage, suggesting the potential association of IκBα and IκBα-regulated NF-κB signaling in the primary adaptive immune response. Although lymphocyte activation by the T cell-specific mitogen PHA did not alter On-IκBα mRNA expression significantly, lymphocyte activation by the agonist PMA obviously elevated On-IκBα and OnNF-κB p65 phosphorylation in spleen leukocytes. Together, the results suggest that IκBα phosphorylation and its regulated NF-κB activation are essential events associated with lymphocyte activation, proliferation, and anti-bacterial adaptive immune response in Nile tilapia. Our study aids to understand the regulatory mechanism of adaptive immunity in teleost.

3.
J Pharm Biomed Anal ; 177: 112808, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31585328

RESUMO

Consulting the national pharmacopoeia, no official quality standard was found for estimation of related substances and assay of atosiban acetate injection, of which main active component is atosiban. To solve this problem, herein, a novel high performance liquid chromatographic (HPLC) method was developed and validated in this study. A chromatographic system comprising an Inertsil ODS-2 analytical column, mobile phase-A of water (pH adjusted to 3.2 with trifluoroacetic acid)-acetonitrile-methanol (77:14:9, v/v/v), mobile phase-B of acetonitrile-methanol (65:35, v/v), a flow rate of 1.0 mL min-1 and a UV detector set at 220 nm with column temperature at 35 °C has shown simple, reproducible and specific determination for atosiban and its five related substances. Also, we combined with mass spectrometry to characterize the molecular weight and tentative structure of the impurities. Using HPLC verified methodology, results of the validation study showed that the precision, specificity and accuracy of the five impurities, good linear equation R squared was greater than 0.9993, and as such, the limit of detection and the limit of quantification have been determined. The proposed method in this study, which, to the best of our knowledge, is the most comprehensive HPLC determination applied to the routine analysis in quality control of this injection.

4.
Nanotechnology ; 31(4): 045202, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31557740

RESUMO

Spin transfer nano-oscillators (STNOs) are a new type of radio frequency (RF) oscillators that utilize the current-induced magnetization precession in a magnetic tunnel junction device to generate high frequency microwave signal. Since both the frequency and the amplitude of STNOs can be tuned by changing the current, they are potentially used for amplitude shift keying and frequency shift keying modulation without the need for an RF mixer, which leads to compact RF components. In this letter, a novel strategy is proposed to modulate the frequency and the amplitude by memristor-controlled spin nano-oscillators, whereby the STNO is responsible for microwave emitting and memristor serves as a current regulator which further modulates the frequency and amplitude. In addition, the I-V curves show that a multilevel resistance behavior can also be achieved in the same architecture.

5.
J Endocrinol ; 244(1): 163-175, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31600720

RESUMO

Changes in zebrafish testicular gene expression induced by follicle-stimulating hormone (Fsh) or anti-Mullerian hormone (Amh) suggested that Amh inhibition and Fsh stimulation of spermatogenesis involved up and downregulation, respectively, of prostaglandin (PG) signaling. We found that Sertoli cells contacting type A undifferentiated (Aund) and differentiating (Adiff) spermatogonia expressed a key enzyme of PG production (Ptgs2); previous work showed that Sertoli cells contacting Adiff and B spermatogonia and spermatocytes showed ptges3b expression, an enzyme catalyzing PGE2 production. In primary testis tissue cultures, PGE2, but not PGD2 or PGF2α, reduced the mitotic activity of Adiff and their development into B spermatogonia. Vice versa, inhibiting PG production increased the mitotic activity of Adiff and B spermatogonia. Studies with pharmacological PG receptor antagonists suggest that an Ep4 receptor mediates the inhibitory effects on the development of spermatogonia, and cell-sorting experiments indicated this receptor is expressed mainly by testicular somatic cells. Combined inhibition of PG and steroid production moreover reduced the mitotic activity of Aund spermatogonia and led to their partial depletion, suggesting that androgens (and/or other testicular steroids), supported by PGE2, otherwise prevent depletion of Aund. Androgens also decreased testicular PGE2 production, increased the transcript levels of the enzyme-catabolizing PGs and decreased PGE2 receptor ptger4b transcript levels. Also Fsh potentially reduced, independent of androgens, PGE2 production by decreasing ptges3b transcript levels. Taken together, our results indicate that PGE2, via Ep4 receptors, favors self-renewal in conjunction with androgens and, independent of Fsh and androgens, inhibits differentiating divisions of spermatogonia.

6.
IEEE Trans Vis Comput Graph ; 26(1): 1022-1032, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31545731

RESUMO

We propose BarcodeTree (BCT), a novel visualization technique for comparing topological structures and node attribute values of multiple trees. BCT can provide an overview of one hundred shallow and stable trees simultaneously, without aggregating individual nodes. Each BCT is shown within a single row using a style similar to a barcode, allowing trees to be stacked vertically with matching nodes aligned horizontally to ease comparison and maintain space efficiency. We design several visual cues and interactive techniques to help users understand the topological structure and compare trees. In an experiment comparing two variants of BCT with icicle plots, the results suggest that BCTs make it easier to visually compare trees by reducing the vertical distance between different trees. We also present two case studies involving a dataset of hundreds of trees to demonstrate BCT's utility.

7.
J Cell Biochem ; 121(1): 49-62, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31571264

RESUMO

Acute coronary syndrome (ACS) is characterized by atherosclerotic plaque rupture with a high incidence of recurrent ischemic events. Several microRNAs are found to be aberrantly expressed in atherosclerotic plaques. This study aims to investigate the effects of microRNA-9 (miR-9) on vulnerable atherosclerotic plaque and vascular remodeling in ACS and underlying mechanisms. Microarray-based gene expression profiling was used to identify differentially expressed genes related to ACS and regulatory miRNAs. Oxidized low-density lipoprotein (lectin-like) receptor 1 (OLR1) was identified to be aberrantly activated in ACS and regulated by miR-9. OLR1 was verified as a target gene of miR-9 by bioinformatics prediction and dual luciferase reporter gene assay. The atherosclerotic models were induced in ApoE-/- mice, in which the agomir or antagomir of miR-9, or small interfering RNA (siRNA) against OLR1 were separately introduced. Serum lipid levels and expression of vascular remodeling and inflammatory response-related factors were determined, respectively. On the basis of the obtained results, in the atherosclerosis mice treated with the agomir of miR-9 and siRNA against OLR1, the p38-mitogen-activated protein kinase (p38MAPK) pathway was inhibited; levels of triglyceride, total cholesterol, low-density lipoprotein cholesterol, tumor necrosis factor-α, interleukin-6, and vascular endothelial growth factor were reduced, but the high-density lipoprotein cholesterol level was increased, along with decreased vulnerable atherosclerotic plaque area and enhanced vascular remodeling. Taken together, these findings suggested an inhibitory role miR-9 acts in the formation of vulnerable atherosclerotic plaques in ACS mice, along with a promoted vascular remodeling, via a negative feedback regulation of OLR1-mediated p38MAPK pathway.

8.
Carbohydr Polym ; 228: 115387, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31635736

RESUMO

A type of cellulose solvent, i.e., aqueous N-methylmorpholine- N-O xide (NMMO) solutions, was used to modify cellulose nanocrystal (CNC) photonic films. CNC films can be swollen by NMMO, resulting in red-shifted reflected colors. The swelling effect is supposed to come from NMMO permeation into the crystalline regions of individual CNCs and intercalating in between CNC particles. When NMMO was removed, the reflected colors of CNC films blue shifted because of the reduced helical pitches. NMMO-treated CNC films display reversible responsive colors to humidity changes in several minutes. Increasing NMMO content allows CNC films to enlarge the responsive color range. Aqueous NMMO can be used as an ink to depict responsive photonic patterns on CNC films. This post-treatment approach to producing responsive colors and photonic patterns in CNC films may be applied to the areas of sensor, anti-counterfeiting, and decoration.

9.
PLoS Comput Biol ; 15(11): e1007399, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31682602

RESUMO

Genome segmentation approaches allow us to characterize regulatory states in a given cell type using combinatorial patterns of histone modifications and other regulatory signals. In order to analyze regulatory state differences across cell types, current genome segmentation approaches typically require that the same regulatory genomics assays have been performed in all analyzed cell types. This necessarily limits both the numbers of cell types that can be analyzed and the complexity of the resulting regulatory states, as only a small number of histone modifications have been profiled across many cell types. Data imputation approaches that aim to estimate missing regulatory signals have been applied before genome segmentation. However, this approach is computationally costly and propagates any errors in imputation to produce incorrect genome segmentation results downstream. We present an extension to the IDEAS genome segmentation platform which can perform genome segmentation on incomplete regulatory genomics dataset collections without using imputation. Instead of relying on imputed data, we use an expectation-maximization approach to estimate marginal density functions within each regulatory state. We demonstrate that our genome segmentation results compare favorably with approaches based on imputation or other strategies for handling missing data. We further show that our approach can accurately impute missing data after genome segmentation, reversing the typical order of imputation/genome segmentation pipelines. Finally, we present a new 2D genome segmentation analysis of 127 human cell types studied by the Roadmap Epigenomics Consortium. By using an expanded set of chromatin marks that have been profiled in subsets of these cell types, our new segmentation results capture a more complex picture of combinatorial regulatory patterns that appear on the human genome.

10.
Acta Pharmacol Sin ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31685975

RESUMO

Proximal renal tubular damage is a critical process underlying diabetic kidney disease (DKD). Our previous study shows that prostaglandin E1 (PGE1) reduces the apoptosis of renal tubular cells in DKD rats. But its underlying mechanisms remain unclear. In this study we investigated the protective effects of PGE1 in DKD rats and high glucose (HG, 30 mM)-treated HK-2 proximal tubular cells. Four weeks after uninephrectomized streptozotocin-induced diabetic rats were established, the DKD rats were administered PGE1 (10 µg· kg-1· d-1, iv.) for 10 consecutive days. We showed that PGE1 administration did not change blood glucose levels, but alleviated diabetic kidney injury in the DKD rats, evidenced by markedly reduced proteinuria and renal tubular apoptosis. In the in vitro experiments, PGE1 (0.1-100 µM) significantly enhanced HG-reduced HK-2 cell viability. In HG-treated HK-2 cells, PGE1 (10 µM) significantly suppressed the c-Jun N-terminal kinase (JNK) and the mitochondrial apoptosis-related protein expressions such as Bim, Bax, caspase-3 and cleaved caspase-3; similar changes were also observed in the kidney of PGE1-treated DKD rats. By using two pharmacological tools-JNK activator anisomycin (AM) and JNK inhibitor SP600125, we revealed that PGE1 blocked HG-triggered activation of JNK/Bim pathway in HK-2 cells; JNK was an upstream regulator of Bim. In conclusion, our results demonstrate that the nephroprotective effects of PGE1 against apoptosis of proximal renal tubule in DKD rats via suppressing JNK-related Bim signaling pathway.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31714218

RESUMO

Surgical resection is the main clinical method for the treatment of bone tumors. A critical procedure for bone tumor resection is to plan a set of cut planes that enable resecting the bone tumor with a safe margin while preserving the maximum amount of healthy bone. Currently, the surgeons rely on manual methods to plan the cut planes, which highly depend on the surgeons' experiences and have been demonstrated to be error-prone, and in turn, increase the recurrence rate or resect much healthy bone. This study targets on improving the precision of cut plane planning for the image guided pelvis tumor resection surgeries. A semi-automatic approach to cut plane planning was proposed via a coarse-to-fine strategy. It can efficiently identify a dangerous region in the 3D space, which contains the bone tumor and its surrounding normal tissue with a safe margin. By projecting the dangerous region into an appropriate 2D space, a segmented boundary-constrained linear regression method was leveraged to plan a set of 3D cut planes that ensure the minimum area of the resected specimen in the 2D space while having the dangerous region cleared. Further, a coarse-to-fine 3D cut plane planning method was developed by incorporating a 3D cut plane refinement scheme with our 2D planning method. Extensive experiments, on the surgical data from nine previous pelvis tumor resection surgeries, demonstrated that our proposed approach substantially improved the localization precision of cut planes (p<0.001) and decreased the amount of resected specimen (p<0.05), as compared to the manual method.

12.
J Agric Food Chem ; 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31725276

RESUMO

With the ultimate goal of addressing pest-related constraints on global agricultural production, we used combination principles to design and synthesize 2,4-diphenyl-1,3-oxazolines containing a sulfonate moiety at the para-position of the 4-phenyl group. The target compounds, which have strong affinity for lipids and can be expected to traverse cell membranes, were characterized by 1H and 13C NMR spectroscopy and high-resolution mass spectrometry. Their activities against the larvae and eggs of carmine spider mites (Tetranychus cinnabarinus) were determined by a leaf-dipping method and compared with the activity of the commercial acaricide etoxazole. Most of the test compounds displayed good ovicidal and larvicidal activities. In particular, a tert-butylphenyl-substituent compound possessed better larvicidal activity (LC50 = 0.022 ± 0.009 mg/L) and ovicidal activity (0.044 ± 0.020 mg/L) than etoxazole (0.091 ± 0.051 and 0.095 ± 0.059 mg/L, respectively). Given its outstanding bioactivities, this compound deserves further attention as a pesticide candidate.

13.
Dent Mater ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31727444

RESUMO

OBJECTIVES: The rapidly increasing use of zirconia-based CAD/CAM multi-layer structures in dentistry calls for a thorough evaluation of their mechanical integrity. This work examines the effect of the multi-layering architecture as well as variations in composition and inclusion of pigments among the layers on the flexural strength of multi-layer zirconias. METHODS: A modified 4-point bending test, aided by a Finite Element Analysis (FEA), was used to probe the interfacial strength of 3 classes of yttria-partially-stabilized zirconia: Ultra Translucent Multi-Layer (UTML-5Y-PSZ), Super Translucent Multi-Layer (STML-4Y-PSZ), Multi-Layer (ML-3Y-PSZ). In accord with the size limitation (22-mm height) of CAD/CAM pucks, test samples were prepared in the form of "long" (25×2×3mm) and "short" (17.8×1.5×2mm) beams. Homogeneous beams (both long and short) were produced from either the Enamel (the lightest shade) or Dentin (the darkest shade) layer, whereas multi-layer beams (short beam only) were obtained by cutting the pucks along their thickness direction, where the material components of various shades were stacked. RESULTS: The Enamel and Dentin layers exhibited similar flexural strength for a given material class, with ML amassing the highest strength (800-900MPa) followed by STML (560-650MPa) and UTML (470-500MPa). The 3 classes of multi-layer zirconia showed a trade-off between strength and translucency, reflecting different yttria contents in these materials. The failure stress of the cross-sectional multi-layer beams was, however, ∼30% lower than that of their Enamel or Dentin layer counterparts, regardless of material tested. SIGNIFICANCE: The weakness of interfaces is a drawback in these materials. Additionally, when measuring strength using short beam flexure, friction between the specimen and supporting pins and accuracy in determining loading span distances may lead to major errors.

14.
J Cell Mol Med ; 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729180

RESUMO

Generating universal human umbilical mesenchymal stem cells (UMSCs) without immune rejection is desirable for clinical application. Here we developed an innovative strategy using CRISPR/Cas9 to generate B2M- UMSCs in which human leucocyte antigen (HLA) light chain ß2-microglobulin (B2M) was deleted. The therapeutic potential of B2M- UMSCs was examined in a mouse ischaemic hindlimb model. We show that B2M- UMSCs facilitated perfusion recovery and enhanced running capability, without inducing immune rejection. The beneficial effect was mediated by exosomes. Mechanistically, microRNA (miR) sequencing identified miR-24 as a major component of the exosomes originating from B2M- UMSCs. We identified Bim as a potential target of miR-24 through bioinformatics analysis, which was further confirmed by loss-of-function and gain-of-function approaches. Taken together, our data revealed that knockout of B2M is a convenient and efficient strategy to prevent UMSCs-induced immune rejection, and it provides a universal clinical-scale cell source for tissue repair and regeneration without the need for HLA matching in the future.

15.
Sci Rep ; 9(1): 15774, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31673051

RESUMO

Imrecoxib is a registered treatment for osteoarthritis pain symptoms in China. This study aims to assess the effect of imrecoxib on the pharmacodynamics and pharmacokinetics of warfarin. 12 healthy male volunteers with CYP2C9*3 AA and VKORC1 AA genotypes took a 5 mg dose of warfarin both alone and concomitantly with steady-state imrecoxib. Both warfarin alone and concomitantly with imrecoxib have safey and good tolerance across the trial. Following warfarin and imrecoxib co-administration, neither Cmax, AUC0-t and t1/2 of warfarin enantiomers nor AUC of international normalized ratio (INR) were markedly different from those of warfarin alone. The geometric mean ratios (GMRs) (warfarin + imrecoxib: warfarin alone) of INR(AUC) was 1 (0.99, 1.01). The GMRs of warfarin AUC0-∞ (90% confidence interval, CIs) for warfarin + imrecoxib: warfarin alone were 1.12 (1.08, 1.16) for R-warfarin and 1.13 (1.07, 1.18) for S- warfarin. The 90% CIs of the GMRs of AUC0-∞, Cmax and INR (AUC) were all within a 0.8-1.25 interval. The combination of warfarin and imrecoxib did not impact the pharmacodynamics and pharmacokinetics of single-dose warfarin; therefore, when treating a patient with imrecoxib and warfarin, it is not required to adjust the dosage of warfarin.

16.
Acta Biomater ; 2019 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-31722254

RESUMO

Correct selection of alloying elements is important for developing novel biodegradable magnesium alloys with superior mechanical and biological performances. In contrast to various reports on nutrient elements (Ca, Zn, Sr, etc.) as alloying elements of biomedical magnesium alloys, there is limited information about how to choose the right rare earth elements (REEs) as alloying elements of magnesium. In this work, 16 kinds of REEs were individually added into Mg, including Sc, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Du, Ho, Er, Tm, Yb and Lu, to fabricate binary Mg-RE model alloys with different composition points. Under the same working history, comparative studies were undertaken and the impact of each kind of rare earth element on the microstructure, mechanical property, corrosion behavior and biocompatibility of Mg were investigated. The corresponding influence level for the 16 kinds of REEs were ranked. The results showed that the second phases were detected in some Mg-RE alloys, which were mainly composed of Mg12RE. By adding different REEs into Mg with proper contents, the mechanical properties of resulting Mg-RE binary alloys could be adjusted in wide range. The corrosion resistance of Mg-light REE alloys was generally better than Mg-heavy REE alloys. As for biocompatibility, Mg-RE model alloys showed no cytotoxic effect on MC3T3-E1 cells. The hemolysis rates of all experimental Mg-RE model alloys were lower than 5% except for Mg-Lu alloy model. In general, the addition of different REEs into Mg could improve its performance from different aspects. This work provides a better understanding on suitable REEs as alloying elements for magnesium, and the future R&D direction on biomedical Mg-RE alloys was proposed. Statement of Significance In contrast to various reports on nutrient elements (Ca, Zn, Sr, etc.) as alloying elements of biomedical magnesium alloys, until now there is limited information about how to choose the right rare earth elements (REEs) as alloying elements of magnesium. In this work, comparative studies were undertaken by individually adding 16 kinds of REEs, including Sc, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Du, Ho, Er, Tm, Yb and Lu, into Mg to fabricate binary Mg-RE model alloys, with different composition points, then the impact of each kind of rare earth element on the microstructure, mechanical property, corrosion behavior and biocompatibility of Mg under the same working history were investigated, and the corresponding influence level for the 16 kinds of REEs were ranked. This work provides a better understanding on suitable REEs as alloying elements for magnesium, and the future R&D direction on biomedical Mg-RE alloys was proposed.

17.
Clin Genet ; 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31674007

RESUMO

The genotype-first approach has been successfully applied and has elucidated several subtypes of autism spectrum disorder (ASD). However, it requires very large cohorts because of the extensive genetic heterogeneity. We investigate the alternate possibility of whether phenotype-specific genes can be identified from a small group of patients with specific phenotype(s). To identify novel genes associated with ASD and abnormal head circumference using a phenotype-to-genotype approach, we performed whole-exome sequencing on 67 families with ASD and abnormal head circumference. Clinically relevant pathogenic or likely pathogenic variants account for 23.9% of patients with microcephaly or macrocephaly, and 81.25% of those variants or genes are head-size associated. Significantly, recurrent pathogenic mutations were identified in two macrocephaly genes (PTEN, CHD8) in this small cohort. De novo mutations in several candidate genes (UBN2, BIRC6, SYNE1, and KCNMA1) were detected, as well as one new candidate gene (TNPO3) implicated in ASD and related neurodevelopmental disorders. We identify genotype-phenotype correlations for head-size-associated ASD genes and novel candidate genes for further investigation. Our results also suggest a phenotype-to-genotype strategy would accelerate the elucidation of genotype-phenotype relationships for ASD by using phenotype-restricted cohorts.

18.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(5): 589-594, 2019 Oct 30.
Artigo em Chinês | MEDLINE | ID: mdl-31699187

RESUMO

Objective To investigate the effect of microRNA-133b(miR-133b)on cardiac fibrosis and its mechanism.Methods Human cardiac fibroblasts(CFs)were harvested.The proliferation of CFs was detected by CCK8 during the overexpression and knock-down of miR-133b.The expressions of connective tissue growth factor(CTGF),α-smooth muscle actin(α-SMA),collagen Ⅰ,and collagen Ⅲ were detected with qRT-PCR and Western blot analysis after miR-133b overexpression or downexpression.Target genes of miR-133b were predicted by bioinformatics software.Dual-luciferase activity assay were used to verify a target gene of miR-133b.Results qRT-PCR showed that the expression level of miR-133b in the miR-133b mimic group was significantly higher than that in the negative control group(t=26.219,P=0.000).The expression level of miR-133b in the miR-133b inhibitor group was significantly lower than that in the negative control group(t=6.738,P=0.003).After 21,45,69,93,and 117 hours of transfection,the proliferation ability of CFs significantly decreased in the miR-133b mimic group but significantly increased in the miR-133b group(all P<0.05,compared with the negative control group).After overexpression of miR-133b,the mRNA and protein levels of CTGF(t=9.213,P=0.001;t=8.195,P=0.001),α-SMA(t=6.511,P =0.003;t=4.434,P=0.011),collagenⅠ(t=3.172,P=0.034;t=4.053,P=0.015)and collagen Ⅲ(t=6.404,P=0.003;t=5.319,P=0.006)were significantly down-regulated.After the expression of miR-133b was knocked down,the mRNA and protein levels of CTGF(t=9.439,P=0.001;t=14.100,P=0.000),α-SMA(t=4.519,P=0.011;t=4.377,P=0.012),collagen Ⅰ(t=5.966,P=0.004;t=5.514,P=0.005)and collagen Ⅲ(t=4.622,P=0.010;t=4.996,P=0.008)were significantly increased.The relative luciferase activity of the cells co-transfected with miR-133b mimic and WT 3'UTR expression vector was significantly lower than that of the cells co-transfected with mimic control and WT 3'UTR expression vectors(t=5.654,P=0.005);however,there was no significant difference in relative luciferase activity between cells co-transfected with miR-133b mimic and MUT 3'UTR expression vectors and cells co-transfected with mimic control and MUT 3'UTR expression vectors(t=0.380,P=0.724).Conclusion miR-133b may affect the activation and proliferation of CFs by targeting CTGF and thus improve cardiac fibrosis.


Assuntos
Fibroblastos/citologia , MicroRNAs/genética , Miocárdio/patologia , Actinas/metabolismo , Proliferação de Células , Células Cultivadas , Colágeno/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Fibrose , Humanos
19.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(5): 709-713, 2019 Oct 30.
Artigo em Chinês | MEDLINE | ID: mdl-31699205

RESUMO

Renal cell carcinoma(RCC)is one of the most common malignant tumors in the urinary system.Many patients have already been in the advanced stage at the first medical consultation and the prognosis is dismal.Metabonomics searches for differential metabolomes through high-throughput analysis of endogenous metabolites showing high potential in the early diagnosis of RCC and the investigations on its pathophysiological mechanisms.Metabonomics techniques are also useful for identifying tumor markers,which will help to enable early diagnosis and improve clinical prognosis of RCC.


Assuntos
Carcinoma de Células Renais/diagnóstico , Neoplasias Renais/diagnóstico , Metaboloma , Biomarcadores Tumorais , Detecção Precoce de Câncer , Humanos , Prognóstico
20.
Dalton Trans ; 48(45): 16861-16868, 2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31710076

RESUMO

The efficiency of photosensitizers in tumor photodynamic therapy (PDT) often compromises their poor water solubility, low extinction coefficients, photobleaching, and dissatisfactory reactive oxygen species (ROS) generation efficiency. Herein, a nanoscale 2D metal-organic framework, Sm-H2TCPP nanosheets, was first synthesized by Sm3+-driven coordination with a porphyrin derivative (tetrakis(4-carboxyphenyl)porphyrin (H2TCPP)) for highly effective PDT of breast cancer. The prepared Sm-H2TCPP possessed nanoplate morphology with ultrathin thickness at the sub-10 nm level and an ultrasmall plane size at the sub-100 nm level. Compared with free H2TCPP, the prominent ROS generation capacity of the well-defined Sm-H2TCPP nanosheets is mainly attributed to their improved physicochemical properties and the enhanced intersystem crossing caused by heavy Sm nodes. The significantly improved PDT efficacy of the Sm-H2TCPP nanosheets was further investigated in vitro and in vivo based on the MCF-7 breast cancer model. It is envisaged that the Sm-H2TCPP nanosheets will offer a new avenue for the development of a new class of potential PDT agents.

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