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1.
Hum Mutat ; 2021 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-34882887

RESUMO

Approximately 10% of von Willebrand factor (VWF) gene variants are suspected to disrupt mRNA processing, the number of which might be underestimated due to the lack of transcript assays. In present study, we provided a detailed strategy to evaluate the effects of nine putative splice site variants (PSSVs) of VWF on mRNA processing as well as protein properties and establish their genotype-phenotype relationships. Eight of nine PSSVs affected VWF splicing: c.322A>T, c.1534-13_1551delinsCA and c.8116-2del caused exon skipping; c.221-2A>C, c.323+1G>T and c.2547-13T>A resulted in the activation of cryptic splice sites; c.2684A>G led to exon skipping and activation of a cryptic splice site; c.2968-14A>G created a new splice site. The remaining c.5171-9del was likely benign. The efficiency of nonsense mediated mRNA decay (NMD) was much higher in platelets compared to leukocytes, impairing the identification of aberrant transcripts in 4 of 8 PSSVs. The nonsense variant c.322A>T partially impaired mRNA processing, leaking a small amount of correct transcripts with c.322T (p.Arg108*), while the missense variant c.2684A>G totally disrupted normal splicing of VWF, rather than produced mutant protein with the substitution of Gln895Arg. The results of this study would certainly added novel insights into the molecular events behind von Willebrand disease. This article is protected by copyright. All rights reserved.

2.
Mater Horiz ; 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34586118

RESUMO

Recent advances in wearable and implantable electronics have increased the demand for biocompatible integrated energy storage systems. Conducting polymers, such as polyaniline (PANi), have been suggested as promising electrode materials for flexible biocompatible energy storage systems, based on their intrinsic structural flexibility and potential polymer chain compatibility with biological interfaces. However, due to structural disorder triggering insufficient electronic conductivity and moderate electrochemical stability, PANi still cannot fully satisfy the requirements for flexible and biocompatible energy storage systems. Herein, we report a biocompatible physiological electrolyte activated flexible supercapacitor encompassing crystalline tetra-aniline (c-TANi) as the active electrode material, which significantly enhances the specific capacitance and electrochemical cycling stability with chloride electrochemical interactions. The crystallization of TANi endows it with sufficient electronic conductivity (8.37 S cm-1) and a unique Cl- dominated redox charge storage mechanism. Notably, a fully self-healable and biocompatible supercapacitor has been assembled by incorporating polyethylene glycol (PEG) with c-TANi as a self-healable electrode and a ferric-ion cross-linked sodium polyacrylate (Fe3+-PANa)/0.9 wt% NaCl as a gel electrolyte. The as-prepared device exhibits a remarkable capacitance retention even after multiple cut/healing cycles. With these attractive features, the c-TANi electrode presents a promising approach to meeting the power requirements for wearable or implantable electronics.

3.
Cancer Cell Int ; 21(1): 294, 2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34092242

RESUMO

BACKGROUND: Lung adenocarcinoma (LUAD) is one of the most common types in the world with a high mortality rate. Despite advances in treatment strategies, the overall survival (OS) remains short. Our study aims to establish a reliable prognostic signature closely related to the survival of LUAD patients that can better predict prognosis and possibly help with individual monitoring of LUAD patients. METHODS: Raw RNA-sequencing data were obtained from Fudan University and used as a training group. Differentially expressed genes (DEGs) for the training group were screened. The univariate, least absolute shrinkage and selection operator (LASSO), and multivariate cox regression analysis were conducted to identify the candidate prognostic genes and construct the risk score model. Kaplan-Meier analysis, time-dependent receiver operating characteristic (ROC) curve were used to evaluate the prognostic power and performance of the signature. Moreover, The Cancer Genome Atlas (TCGA-LUAD) dataset was further used to validate the predictive ability of prognostic signature. RESULTS: A prognostic signature consisting of seven prognostic-related genes was constructed using the training group. The 7-gene prognostic signature significantly grouped patients in high and low-risk groups in terms of overall survival in the training cohort [hazard ratio, HR = 8.94, 95% confidence interval (95% CI)] [2.041-39.2]; P = 0.0004), and in the validation cohort (HR = 2.41, 95% CI [1.779-3.276]; P < 0.0001). Cox regression analysis (univariate and multivariate) demonstrated that the seven-gene signature is an independent prognostic biomarker for predicting the survival of LUAD patients. ROC curves revealed that the 7-gene prognostic signature achieved a good performance in training and validation groups (AUC = 0.91, AUC = 0.7 respectively) in predicting OS for LUAD patients. Furthermore, the stratified analysis of the signature showed another classification to predict the prognosis. CONCLUSION: Our study suggested a new and reliable prognostic signature that has a significant implication in predicting overall survival for LUAD patients and may help with early diagnosis and making effective clinical decisions regarding potential individual treatment.

4.
ACS Nano ; 15(4): 7821-7832, 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33834770

RESUMO

MXenes are an emerging class of highly conductive two-dimensional (2D) materials with electrochemical storage features. Oriented macroscopic Ti3C2Tx fibers can be fabricated from a colloidal 2D nematic phase dispersion. The layered conductive Ti3C2Tx fibers are ideal candidates for constructing high-speed ionic transport channels to enhance the electrochemical capacitive charge storage performance. In this work, we assemble Ti3C2Tx fibers with a high degree of flake orientation by a wet spinning process with controlled spinning speeds and morphology of the spinneret. In addition to the effects of cross-linking of magnesium ions between Ti3C2Tx flakes, the electronic conductivity and mechanical strength of the as-prepared fibers have been improved to 7200 S cm-1 and 118 MPa, respectively. The oriented Ti3C2Tx fibers present a volumetric capacitive charge storage capability of up to 1360 F cm-3 even in a Mg-ion based neutral electrolyte, with contributions from both nanofluidic ion transport and Mg-ion intercalation pseudocapacitance. The oriented 2D Ti3C2Tx driven nanofluidic channels with great electronic conductivity and mechanical strength endows the MXene fibers with attributes for serving as conductive ionic cables and active materials for fiber-type capacitive electrochemical energy storage, biosensors, and potentially biocompatible fibrillar tissues.

5.
Vet Immunol Immunopathol ; 233: 110183, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33476923

RESUMO

Mannose-binding lectin (MBL) glycoproteins in blood can selectively recognise lectins on the surface of bacteria, and play an important role in natural immunity. Micro RNAs (miRNAs) are key molecules that regulate gene expression at the post-transcriptional level in vivo, and their pathways are specific and effective. Previous studies indicate that small RNAs such as miRNAs perform regulatory roles in immunology. Herein, we investigated differential expression of miRNAs during MBL protein immunotherapy in sheep following treatment with different MBL genotypes (resistant and susceptible), and identified miRNAs linked to different target genes and pathways. RNA was extracted from liver tissue of resistant and susceptible sheep, miRNAs were identified by high-throughput sequencing, and differentially expressed miRNAs were analysed by SOAP to predict target genes and biological pathways. Results: Some miRNAs (oar-mir-143, oar-mir-10b, oar-mir-382, oar-mir-432 and oar-mir-379) were up-regulated, while others were down-regulated. GPATCH3 and DNAJC5 were predicted target genes of oar-mir-379, DMRT1 and GATA4 were linked to oar-mir-382, and oar-mir-432 was associated with STAT2, DMRT1 and ATG16L1. Identification of miRNAs differentially expressed in resistant and susceptible sheep may expand our understanding of miRNAs in immune regulation, and the role of MBL in innate immunity.


Assuntos
Lectinas de Ligação a Manose/genética , MicroRNAs/fisiologia , Pneumonia por Mycoplasma/veterinária , Doenças dos Ovinos/genética , Animais , Resistência à Doença/genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/veterinária , MicroRNAs/genética , MicroRNAs/metabolismo , Pneumonia por Mycoplasma/genética , Pneumonia por Mycoplasma/imunologia , Fator de Transcrição STAT2/metabolismo , Ovinos , Doenças dos Ovinos/imunologia
6.
Gene ; 768: 145319, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33246031

RESUMO

Myogenesis is a complex, regulated process that involves myoblast proliferation, migration, adhesion, and fusion into myotubes. To investigate early development of embryonic muscles and the expression of regulatory genes during myogenesis in chicken, quail and their hybrids, meat-breeding cocks and egg-breeding cocks were selected as male parents, quails were used as female parents. Their offspring were meat and egg hybrids via Artificial insemination. We measured expression of MUSTN1, IGF-1, and PDK4 using qRT-PCR. We examined muscle fiber diameter using scanning electron microscopy. The results showed that muscle development was two days slower in chicken, egg hybrid, and meat hybrid than in quail. Muscle fiber spacing was the largest in chicken, followed by meat hybrid, egg hybrid, and quail. A similar trend was obtained for muscle fiber diameter. Additionally, muscle fiber diameter increased with embryogenesis. The sarcomere was present on day 17 of incubation in quail, but not in the other species. MUSTN1 could up-regulated IGF-1 by activating PI3K/Akt. IGF-1 expression was consistent with myoblast proliferation and myotube fusion. PDK4 was expressed from E7 to E17. The first peak was reached on E10, egg hybrid and meat hybrid reached their peak at E15. PDK4 is involved in the early proliferation and differentiation of muscle, thereby affecting muscle growth and development. Our findings demonstrated that MUSTN1, IGF-1 and PDK4 genes are expressed to varying levels in breast muscle of chicken, quail, egg hybrid and meat hybrid during the embryonic period. Interestingly, with increasing embryonic age, muscle development was approximately 48 h faster in quail than in other species. We speculated that MUSTN1, IGF-1 and PDK4 genes may be the main candidate genes that cause differences in poultry muscle traits, but the molecular regulation mechanisms need to be further studied. Our findings shed some light on the avian embryo muscle formation and molecular breeding of poultry muscle traits, which provide theoretical basis for poultry breeding.


Assuntos
Quimera/embriologia , Fator de Crescimento Insulin-Like I/genética , Músculo Esquelético/crescimento & desenvolvimento , Proteínas Nucleares/genética , Piruvato Desidrogenase Quinase de Transferência de Acetil/genética , Animais , Cruzamento , Galinhas , Quimera/genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Microscopia de Força Atômica , Desenvolvimento Muscular , Músculo Esquelético/metabolismo , Codorniz
7.
Cancer Genet ; 240: 59-65, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31786363

RESUMO

PURPOSE: Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia and its progressive genomic basis over time remains unclear. We aimed to investigate the longitudinal genomic evolution of MPAL from diagnosis to relapse. METHODS: We performed whole genome sequencing (WGS) on bone marrow (BM) samples obtained at the four stages of this disease in a male patient with Philadelphia chromosome positive (Ph+) MPAL, including primary, complete cytogenetic remission (CCR), complete molecular remission (CMR), and relapse stage during the 3 year follow-up period. RESULTS: 156 single-nucleotide variants (SNVs) and indels were detected, which exhibited distinctive evolutionary behaviors. Seventeen mutations disappeared quickly upon DCTER treatment and never came back. Seven mutations, although disappeared initially, reoccurred with the withdrawal of TKI treatment. Notably, ten mutations emerged in spite of the active DCTER chemotherapy. Moreover, copy number loss played critical roles in monitoring MPAL progression, displaying 7, 0, 0, and 383 losses at the stages of primary, CCR, CMR, and relapse respectively. CONCLUSION: This longitudinal genomic investigation of the Ph+ MPAL patient established one MPAL evolution model in which the primary tumor acquired additional variations leading to tumor relapse. Moreover, the event of copy number loss remained a valuable hallmark in the progression of MPAL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Evolução Clonal , Variações do Número de Cópias de DNA , Leucemia Aguda Bifenotípica/genética , Recidiva Local de Neoplasia/genética , Adulto , Análise Mutacional de DNA , Progressão da Doença , Humanos , Leucemia Aguda Bifenotípica/tratamento farmacológico , Leucemia Aguda Bifenotípica/patologia , Estudos Longitudinais , Masculino , Recidiva Local de Neoplasia/patologia , Cromossomo Filadélfia , Sequenciamento Completo do Genoma
8.
Blood ; 134(20): 1745-1754, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31558466

RESUMO

Combined factor V (FV) and FVIII deficiency (F5F8D) is a rare autosomal-recessive bleeding disorder caused by mutations in lectin mannose binding-1 (LMAN1) and multiple coagulation factor deficiency-2 (MCFD2). Six causative homozygous mutations (5 in LMAN1 and 1 in MCFD2) were identified in 6 patients with F5F8D. A thrombin-generation assay, triggered with tissue factor (1 pM) in F5F8D plasma, paradoxically exhibited enhanced thrombin generation compared with normal plasma. Significantly lower free tissue factor pathway inhibitor (fTFPI) was found in F5F8D patients compared with healthy controls (P < .01). Normalizing tissue factor pathway inhibitor α (TFPIα) in F5F8D plasma greatly delayed and reduced thrombin generation. Increasing FV concentrations by adding plasma FV to F5F8D plasma only caused a gradual decrease in thrombin generation, suggesting that low levels of TFPIα and FV cocontributed to the elevated thrombin generation by reducing anticoagulant effects. On the contrary, thrombin generation in F5F8D platelet-rich plasma (PRP) was significantly lower than in normal controls (P < .05); however, it was fully corrected by normalizing FVIII or after 1-deamino-8-d-arginine vasopressin (DDAVP) infusion, indicating that the hypocoagulable state of F5F8D patients is associated with low FVIII levels. In addition, plasma and platelet FV in F5F8D PRP were sufficient to support normal thrombin generation, and low TFPIα may have no effect on thrombin generation. DDAVP infusion induced a complete response in 5 F5F8D patients and a partial response in the remaining patient. Based on our findings, we suggest that DDAVP may be considered a potential substitute for FVIII concentrates, and fresh-frozen plasma (FFP) infusion may not be necessary for F5F8D patients with minor bleeding challenges.


Assuntos
Deficiência do Fator V/sangue , Fator V/análise , Hemofilia A/sangue , Hemorragia/sangue , Adulto , Deficiência do Fator V/complicações , Feminino , Hemofilia A/complicações , Hemorragia/etiologia , Hemostasia , Humanos , Masculino , Pessoa de Meia-Idade , Trombina/análise , Adulto Jovem
9.
Cancer Med ; 8(12): 5673-5686, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31369215

RESUMO

INTRODUCTION: Targeted therapies are based on specific gene alterations. Various specimen types have been used to determine gene alterations, however, no systemic comparisons have yet been made. Herein, we assessed alterations in selected cancer-associated genes across varying sample sites in lung cancer patients. MATERIALS AND METHODS: Targeted deep sequencing for 48 tumor-related genes was applied to 153 samples from 55 lung cancer patients obtained from six sources: Formalin-fixed paraffin-embedded (FFPE) tumor tissues, pleural effusion supernatant (PES) and pleural effusion cell sediments (PEC), white blood cells (WBCs), oral epithelial cells (OECs), and plasma. RESULTS: Mutations were detected in 96% (53/55) of the patients and in 83% (40/48) of the selected genes. Each sample type exhibited a characteristic mutational pattern. As anticipated, TP53 was the most affected sequence (54.5% patients), however this was followed by NOTCH1 (36%, across all sample types). EGFR was altered in patient samples at a frequency of 32.7% and KRAS 10.9%. This high EGFR/ low KRAS frequency is in accordance with other TCGA cohorts of Asian origin but differs from the Caucasian population where KRAS is the more dominant mutation. Additionally, 66% (31/47) of PEC samples had copy number variants (CNVs) in at least one gene. Unlike the concurrent loss and gain in most genes, herein NOTCH1 loss was identified in 21% patients, with no gain observed. Based on the relative prevalence of mutations and CNVs, we divided lung cancer patients into SNV-dominated, CNV-dominated, and codominated groups. CONCLUSIONS: Our results confirm previous reports that EGFR mutations are more prevalent than KRAS in Chinese lung cancer patients. NOTCH1 gene alterations are more common than previously reported and reveals a role of NOTCH1 modifications in tumor metastasis. Furthermore, genetic material from malignant pleural effusion cell sediments may be a noninvasive manner to identify CNV and participate in treatment decisions.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Pulmonares/genética , Receptor Notch1/genética , Variações do Número de Cópias de DNA , Humanos , Mutação , Taxa de Mutação , Metástase Neoplásica , Análise de Sequência de DNA
10.
Sci Rep ; 9(1): 8063, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31147592

RESUMO

The overland flow erosion is common and became more serious because of the climate warming inducing more runoff in the Tibet Plateau. The purposes of this study were to evaluate the effects of flow rate, slope gradient, shear stress, stream power, unit stream power and unit energy of water-carrying section on the soil detachment capacity for the soil in the Tibet Plateau of China due to the information is limited. To achieve this aim, laboratory experiments were performed under six flow rates (5, 10, 15, 20, 25 and 30 L min-1) and six slope gradients (8.74%, 17.63%, 26.79%, 36.40%, 46.63 and 57.73%) by using a slope-adjustable steel hydraulic flume (4 m length, 0.4 m width, 0.2 m depth). The results indicated that soil detachment capacity ranged from 0.173 to 6.325 kg m-2 s-1 with 1.972 kg m-2 s-1 on average. The soil detachment capacity increased with power function as the flow rate and the slope gradient augmented (R2 = 0.965, NRMSE = 0.177 and NSE = 0.954). The soil detachment capacity was more influenced by flow rate than by slope gradient in this study. The relation between soil detachment capacity and shear stress, stream power, unit stream power and unit energy of water-carrying section can be described by using the linear function and power function, the power function relationship performed better than the linear function in generally. The stream power exhibits the best performance in describing the soil detachment capacity among shear stress, stream power, unit stream power and unit energy of water-carrying section in this study. The erodibility value in this study was larger than and the critical shear stress was less than those for soil in the eastern China. There has a huge potential for the soil in the Tibet Plateau eroded by the water erosion when enough runoff exiting. More attention should be payed to the water erosion process and mechanism in the Tibet Plateau area in the future.

11.
BMC Bioinformatics ; 20(1): 236, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077131

RESUMO

BACKGROUND: With the widespread use of multiple amplicon-sequencing (MAS) in genetic variation detection, an efficient tool is required to remove primer sequences from short reads to ensure the reliability of downstream analysis. Although some tools are currently available, their efficiency and accuracy require improvement in trimming large scale of primers in high throughput target genome sequencing. This issue is becoming more urgent considering the potential clinical implementation of MAS for processing patient samples. We here developed pTrimmer that could handle thousands of primers simultaneously with greatly improved accuracy and performance. RESULT: pTrimmer combines the two algorithms of k-mers and Needleman-Wunsch algorithm, which ensures its accuracy even with the presence of sequencing errors. pTrimmer has an improvement of 28.59% sensitivity and 11.87% accuracy compared to the similar tools. The simulation showed pTrimmer has an ultra-high sensitivity rate of 99.96% and accuracy of 97.38% compared to cutPrimers (70.85% sensitivity rate and 58.73% accuracy). And the performance of pTrimmer is notably higher. It is about 370 times faster than cutPrimers and even 17,000 times faster than cutadapt per threads. Trimming 2158 pairs of primers from 11 million reads (Illumina PE 150 bp) takes only 37 s and no more than 100 MB of memory consumption. CONCLUSIONS: pTrimmer is designed to trim primer sequence from multiplex amplicon sequencing and target sequencing. It is highly sensitive and specific compared to other three similar tools, which could help users to get more reliable mutational information for downstream analysis.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos , Algoritmos , Humanos
12.
Int J Cancer ; 145(9): 2547-2557, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30919951

RESUMO

The liquid biopsy is being integrated into cancer diagnostics and surveillance. However, critical questions still remain, such as how to precisely evaluate cancer mutation burden and interpret the corresponding clinical implications. Herein, we evaluated the role of peripheral blood cell-free DNA (cfDNA) in characterizing the dynamic mutation alterations of 48 cancer driver genes from cervical cancer patients. We performed targeted deep sequencing on 93 plasma cfDNA from 57 cervical cancer patients and from this developed an algorithm, allele fraction deviation (AFD), to monitor in an unbiased manner the dynamic changes of genomic aberrations. Differing treatments, including chemotherapy (n = 22), radiotherapy (n = 14) and surgery (n = 15), led to a significant decrease in AFD values (Wilcoxon, p = 0.029). The decrease of cfDNA AFD values was accompanied by shrinkage in the size of the tumor in most patients. However, in a subgroup of patients where cfDNA AFD values did not reflect a reduction in tumor size, there was a detection of progressive disease (metastasis). Furthermore, a low AFD value at diagnosis followed a later increase of AFD value also successfully predicted relapse. These results show that plasma cfDNA, together with targeted deep sequencing, may help predict treatment response and disease development in cervical cancer.


Assuntos
Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Alelos , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Quimiorradioterapia/métodos , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Feminino , Genoma/genética , Genômica/métodos , Humanos , Pessoa de Meia-Idade , Mutação/genética , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/radioterapia
13.
Angew Chem Int Ed Engl ; 58(3): 811-815, 2019 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-30417513

RESUMO

Nanostructured-alloy-type anodes have received great interest for high-performance lithium-ion batteries (LIBs). However, these anodes experience huge volume fluctuations during repeated lithiation/delithiation and are easily pulverized and subsequently form aggregates. Herein, an efficient method to stabilize alloy-type anodes by creating defects on the surface of the metal oxide support is proposed. As a demonstration, PPy-encapsulated SnS2 nanosheets supported on defect-rich TiO2 nanotubes were produced and investigated as an anode material for LIBs. Both experimental results and theoretical calculations demonstrate that defect-rich TiO2 provides more chemical adhesions to SnS2 and discharge products, compared to defect-poor TiO2 , and then effectively stabilizes the electrode structure. As a result, the composite exhibits an unprecedented cycle stability. This work paves the way to designing durable and active nanostructured-alloy-type anodes on oxide supports.

14.
Blood Cells Mol Dis ; 73: 47-54, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30249384

RESUMO

The development of a novel coagulation factor VIII (FVIII) expression cassette with an enhanced activity for gene therapy of hemophilia A (HA) is essential. The biological properties of several non-human FVIII sequences, such as porcine and canine, have been evaluated. Here, we compared the activity level of rat FVIII (rFVIII) and human FVIII (hFVIII) by using single-chain and dual-chain strategies in 293 T cells and the HA mice. In both in vitro and hydrodynamic injection studies, the activity of rFVIII detected by the activated partial thromboplastin time assay was higher than that of hFVIII both by single-chain (~2.96-fold and ~1.72-fold, respectively) and dual-chain (~7.69-fold and ~2.35-fold, respectively). Moreover, the dual chain exerted a potentially higher delivery efficacy compared with the single chain (~4.96-fold and ~2.99-fold, respectively). The blood loss of HA mice administrated with rFVIII was less than those with hFVIII. AAV-delivered rFVIII and hFVIII also exerted long-term therapeutic effects on HA mice and caused a transient ALT elevation. These data might help to the development of novel, optimized FVIII expression cassettes based on the amino acid difference between rFVIII and hFVIII. These data indicate that the dual-chain strategy would likely enhance the delivery efficiency of the AAV-mediated FVIII gene therapy.


Assuntos
Fator VIII/administração & dosagem , Terapia Genética/métodos , Hemofilia A/tratamento farmacológico , Adenoviridae/genética , Animais , Fator VIII/genética , Vetores Genéticos , Células HEK293 , Humanos , Tempo de Tromboplastina Parcial , Ratos , Transfecção
15.
Genetics ; 210(2): 547-558, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30076202

RESUMO

Investigation of spontaneous mutations by next-generation sequencing technology has attracted extensive attention lately due to the fundamental roles of spontaneous mutations in evolution and pathological processes. However, these studies only focused on the mutations accumulated through many generations during long-term (possibly be years of) culturing, but not the freshly generated mutations that occur at very low frequencies. In this study, we established a molecularly barcoded deep sequencing strategy to detect low abundant spontaneous mutations in genomes of bacteria cell cultures. Genome-wide spontaneous mutations in 15 Escherichia coli cell culture samples were defined with a high confidence (P < 0.01). We also developed a hotspot-calling approach based on the run-length encoding algorithm to find the genomic regions that are vulnerable to the spontaneous mutations. The hotspots for the mutations appeared to be highly conserved across the bacteria samples. Further biological annotation of these regions indicated that most of the spontaneous mutations were located at the repeat domains or nonfunctional domains of the genomes, suggesting the existence of mechanisms that could somehow prevent the occurrence of mutations in crucial genic areas. This study provides a more faithful picture of mutation occurrence and spectra in a single expansion process without long-term culturing.


Assuntos
Escherichia coli/genética , Genoma Bacteriano , Taxa de Mutação , Loci Gênicos , Modelos Genéticos , Análise de Sequência de DNA/métodos
16.
Opt Express ; 26(13): 16292-16302, 2018 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-30119462

RESUMO

Mach-Zehnder interferometer is a common device in quantum phase estimation and the photon losses in it are an important issue for achieving a high phase accuracy. Here we thoroughly discuss the precision limit of the phase in the Mach-Zehnder interferometer with a coherent state and a superposition of coherent states as input states. By providing a general analytical expression of quantum Fisher information, the phase-matching condition and optimal initial parity are given. Especially, in the photon loss scenario, the sensitivity behaviors are analyzed and specific strategies are provided to restore the phase accuracies for symmetric and asymmetric losses.

17.
Artigo em Inglês | MEDLINE | ID: mdl-27738446

RESUMO

Objective. To investigate the absorption property of the representative hydrolyzable tannin, namely corilagin, and its hydrolysates gallic acid (GA) and ellagic acid (EA) from the Fructus Phyllanthi tannin fraction (PTF) in vitro. Methods. Caco-2 cells monolayer model was established. Influences of PTF on Caco-2 cells viability were detected with MTT assay. The transport across monolayers was examined for different time points, concentrations, and secretory directions. The inhibitors of P-glycoprotein (P-gp), multidrug resistance proteins (MRPs), organic anion transporting polypeptide (OATP) and sodium/glucose cotransporter 1 (SGLT1), and tight junction modulators were used to study the transport mechanism. LC-MS method was employed to quantify the absorption concentration. Results. The apparent permeability coefficient (Papp) values of the three compounds were below 1.0 × 10-6 cm/s. The absorption of corilagin and GA were much lower than their efflux, and the uptake of both compounds was increased in the presence of inhibitors of P-gp and MRPs. The absorption of EA was decreased in the company of OATP and SGLT1 inhibitors. Moreover, the transport of corilagin, GA, and EA was enhanced by tight junction modulators. Conclusion. These observations indicated that the three compounds in PTF were transported via passive diffusion combined with protein mediated transport. P-gp and MRPs might get involved in the transport of corilagin and GA. The absorption of EA could be attributed to OATP and SGLT1 protein.

18.
Artigo em Inglês | MEDLINE | ID: mdl-27200104

RESUMO

The plants of the genus Phyllanthus (Euphorbiaceae) have been used as traditional medicinal materials for a long time in China, India, Brazil, and the Southeast Asian countries. They can be used for the treatment of digestive disease, jaundice, and renal calculus. This review discusses the ethnopharmacological, phytochemical, and pharmacological studies of Phyllanthus over the past few decades. More than 510 compounds have been isolated, the majority of which are lignins, triterpenoids, flavonoids, and tannins. The researches of their remarkable antiviral, antioxidant, antidiabetic, and anticancer activities have become hot topics. More pharmacological screenings and phytochemical investigations are required to support the traditional uses and develop leading compounds.

19.
Molecules ; 21(5)2016 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-27213329

RESUMO

Ganoderma triterpenes (GTs) are the major secondary metabolites of Ganoderma lucidum, which is a popularly used traditional Chinese medicine for complementary cancer therapy. In the present study, systematic isolation, and in silico pharmacological prediction are implemented to discover potential anti-cancer active GTs from G. lucidum. Nineteen GTs, three steroids, one cerebroside, and one thymidine were isolated from G. lucidum. Six GTs were first isolated from the fruiting bodies of G. lucidum, including 3ß,7ß,15ß-trihydroxy-11,23-dioxo-lanost-8,16-dien-26-oic acid methyl ester (1), 3ß,7ß,15ß-trihydroxy-11,23-dioxo-lanost-8,16-dien-26-oic acid (2), 3ß,7ß,15α,28-tetrahydroxy-11,23-dioxo-lanost-8,16-dien-26-oic acid (3), ganotropic acid (4), 26-nor-11,23-dioxo-5α-lanost-8-en-3ß,7ß,15α,25-tetrol (5) and (3ß,7α)-dihydroxy-lanosta-8,24-dien- 11-one (6). (4E,8E)-N-d-2'-hydroxypalmitoyl-l-O-ß-d-glucopyranosyl-9-methyl-4,8-spingodienine (7), and stigmasta-7,22-dien-3ß,5α,6α-triol (8) were first reported from the genus Ganodema. By using reverse pharmacophoric profiling of the six GTs, thirty potential anti-cancer therapeutic targets were identified and utilized to construct their ingredient-target interaction network. Then nineteen high frequency targets of GTs were selected from thirty potential targets to construct a protein interaction network (PIN). In order to cluster the pharmacological activity of GTs, twelve function modules were identified by molecular complex detection (MCODE) and gene ontology (GO) enrichment analysis. The results indicated that anti-cancer effect of GTs might be related to histone acetylation and interphase of mitotic cell cycle by regulating general control non-derepressible 5 (GCN5) and cyclin-dependent kinase-2 (CDK2), respectively. This research mode of extraction, isolation, pharmacological prediction, and PIN analysis might be beneficial to rapidly predict and discover pharmacological activities of novel compounds.


Assuntos
Antineoplásicos/química , Neoplasias/tratamento farmacológico , Reishi/química , Triterpenos/química , Acetilação , Antineoplásicos/uso terapêutico , Divisão Celular/efeitos dos fármacos , Quinases Ciclina-Dependentes/antagonistas & inibidores , Humanos , Medicina Tradicional Chinesa , Estrutura Molecular , Mapas de Interação de Proteínas/efeitos dos fármacos , Relação Estrutura-Atividade , Triterpenos/uso terapêutico
20.
Blood Cells Mol Dis ; 58: 29-34, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27067486

RESUMO

Congenital factor XI (FXI) deficiency is a rare bleeding disorder with unpredictable bleeding tendency. Few studies in a large cohort have been reported regarding associations between FXI activity (FXI:C) or genotypes and bleeding symptoms currently. This study characterized clinical manifestations and mutation spectrum of 57 subjects with FXI deficiency in China. Clinical data were collected and mutations were identified by direct sequencing and determined by mRNA analysis. The result revealed bleeding symptoms were only found in 12 patients (12/57, 21.1%) with severely reduced FXI:C, and prolonged bleeding post injury/surgery as well as easy bruising were the commonest bleeding manifestations presented in respective 5 cases (5/12, 41.7%). A total number of 37 mutations were identified including 19 missense mutations, 9 nonsense mutations, 6 splice site mutations and 3 small deletions. Among them, 4 missense mutations, 5 splice mutations, 3 small deletions and a nonsense mutation were newly detected. W228*, G400V, Q263* and c.1136-4delGTTG with a total frequency of 48.3% were the most four common mutations in Chinese patients. RT-PCR analysis was carried out and confirmed that both c.596-8T>A and c.1136-4delGTTG were pathogenic due to frameshift resulting in respective truncated proteins. Our findings suggested clinical manifestations had little to do with FXI:C or genotypes, which required further study. This study, the largest investigation of FXI deficiency in China revealed that the F11 mutation spectrum of Chinese population was distinct from those of other populations earlier established.


Assuntos
Deficiência do Fator XI/genética , Fator XI/genética , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , China/epidemiologia , Deficiência do Fator XI/complicações , Deficiência do Fator XI/epidemiologia , Feminino , Genótipo , Hemorragia/epidemiologia , Hemorragia/genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Linhagem , RNA Mensageiro/genética , Adulto Jovem
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