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1.
Aging (Albany NY) ; 12(5): 4379-4393, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32139661

RESUMO

Hirschsprung disease (HSCR), the most common enteric neuropathy, stands as a model for complex genetic disorders. It has recently been demonstrated that both ARHGEF3 and CTNNAL1 map to the RET-dependent HSCR susceptibility loci. We therefore sought to explore whether genetic variants within RET, ARHGEF3 and CTNNAL1, and their genetic interaction networks are associated with HSCR. Taking advantage of a strategy that combined the MassArray system and gene-gene interaction analysis with case-control study, we interrogated 38 polymorphisms within RET, ARHGEF3 and CTNNAL1 in 1015 subjects (502 HSCR cases and 513 controls) of Han Chinese origin. There were statistically significant associations between 20 genetic variants in these three genes and HSCR. Haplotype analysis also revealed some significant global P values, i.e. RET_ rs2435357-rs752978-rs74400468-rs2435353-rs2075913-rs17028-rs2435355 (P = 3.79×10-58). Using the MDR and GeneMANIA platforms, we found strong genetic interactions among RET, ARHGEF3, and CTNNAL1 and our previously studied GAL, GAP43, NRSN1, PTCH1, GABRG2 and RELN genes. These results offer the first indication that genetic markers of RET, ARHGEF3 and CTNNAL1 and relevant genetic interaction networks confer the altered risk to HSCR in the Han Chinese population.

3.
J Med Genet ; 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066630

RESUMO

BACKGROUND: Hirschsprung disease (HSCR) is a life-threatening congenital disorder in which the enteric nervous system is completely missing from the distal gut. Recent studies have shown that miR-4516 markedly inhibits cell migration, and as one of its potential targets, MAPK10 functions as a modifier for developing HSCR. We thus aimed to evaluate the role of miR-4516 and MAPK10 in HSCR and how they contribute to the pathogenesis of HSCR. METHODS: We examined 13 genetic variants using the MassArray system in a case-control study (n=1015). We further investigated miR-4516-mediated regulation of MAPK10 in HSCR cases and human neural cells, the effects of cis-acting elements in MAPK10 on miR-4516-mediated modulation and cell migration process. RESULTS: Three positive 3' UTR variants in MAPK10 were associated with altered HSCR susceptibility. We also showed that miR-4516 directly regulates MAPK10 expression, and this regulatory mechanism is significantly affected by the 3' UTR cis-acting elements of MAPK10. In addition, knock-down of MAPK10 rescued the effect of miR-4516 on the migration of human neural cells. CONCLUSION: Our findings indicate a key role of miR-4516 and its direct target MAPK10 in HSCR risk, and highlight the general importance of cis- and posttranscriptional modulation for HSCR pathogenesis.

4.
Nat Commun ; 11(1): 824, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32047159

RESUMO

As natural gas demand surges in China, driven by the coal-to-gas switching policy, widespread attention is focused on its impacts on global gas supply-demand rebalance and greenhouse gas (GHG) emissions. Here, for the first time, we estimate well-to-city-gate GHG emissions of gas supplies for China, based on analyses of field-specific characteristics of 104 fields in 15 countries. Results show GHG intensities of supplies from 104 fields vary from 6.2 to 43.3 g CO2eq MJ-1. Due to the increase of GHG-intensive gas supplies from Russia, Central Asia, and domestic shale gas fields, the supply-energy-weighted average GHG intensity is projected to increase from 21.7 in 2016 to 23.3 CO2eq MJ-1 in 2030, and total well-to-city-gate emissions of gas supplies are estimated to grow by ~3 times. While securing gas supply is a top priority for the Chinese government, decreasing GHG intensity should be considered in meeting its commitment to emission reductions.

5.
Exp Cell Res ; 388(2): 111854, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31954694

RESUMO

The cardiac and skeletal muscle tissues are both striated and contractile but their intrinsic cellular properties are distinct. The minimal cardiomyocyte proliferation and the lack of cardiac stem cells directly leads to poor heart repair in adult mammals. But in skeletal muscle, the robust proliferation of widespread muscle stem cells support efficient muscle regeneration. The endogenous cardiomyocyte and muscle stem cell proliferation has been analyzed in common laboratory animals but not in large mammals including pigs, which are more comparable to human. In this study, we rigorously examined the cell cycle dynamics of porcine cardiomyocytes and muscle stem cells through different developmental stages. Proliferative cardiomyocytes and muscle stem cells were broadly observed in the embryonic heart and limb muscle respectively. Muscle stem cells continue to proliferate postnatally but cardiomyocyte proliferation was drastically reduced after birth. However, robust cardiomyocyte cell cycle activity was detected around postnatal day 20, which could be attributed to the binucleation but not cell division. Increased proliferating cells were detected in maternal heart during early pregnancy but they represent non-cardiomyocyte cell types. The islet1 expressing cells were only identified in the embryonic and new born porcine hearts. Furthermore, the accumulated oxidative DNA damage in the cardiac but not skeletal muscle during development could be responsible for the diminished cardiomyocyte proliferation in adult pig. Similarities and differences in the proliferation of heart and skeletal muscle cells are identified in pigs across different developmental stages. Such cellular proliferative features must be taken into account when using porcine models for cardiovascular and muscular research.

6.
Sci Total Environ ; 711: 134555, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31812396

RESUMO

China is the country with the most carbon emissions and the largest foreign trade volume worldwide. China's carbon footprint, especially the carbon footprint of exports, must be studied to clarify China's responsibility for carbon emissions, avoid "carbon leakage" and develop more reasonable emission reduction policies. By comparing 6 update models, this paper adopts the GRAS, which is a typical entropy optimization method for matrix updating, to construct new time series input-output (IO) tables for China from 2009 to 2016 to analyze the carbon footprint of China's domestic final demand and exports. Then, the changes in the footprints were investigated with a structural decomposition analysis (SDA) to determine the driving factors. The carbon footprint of exports showed an upward trend from 2009 to 2012 and a downward trend from 2012 to 2016. The export share of the total consumption-based carbon footprint also increased from 2009 (17.64%) to 2012 (21.47%) and then decreased to 16.40% in 2016, reflecting a reduction in the CO2 emissions transferred to China after 2013. According to the SDA results, the emission intensity effect (664.20 Mt CO2) and primary input effect (555.21 Mt CO2) played a key role in reducing the carbon footprint, and the total export effect (1083.12 Mt CO2) contributed the most to the increase in the carbon footprint of exports. Based on further SDA, the effects of the primary input, Leontief structure and export structure dramatically varied based on China's industrial structure adjustment and technological change during the subperiod. The analysis framework and data in this paper can be applied to further study China's energy economy and environmental issues.

8.
Nat Commun ; 10(1): 5465, 2019 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-31784535

RESUMO

Liquid-liquid phase separation (LLPS) of intrinsically disordered proteins (IDPs) is involved in both intracellular membraneless organelles and extracellular tissues. Despite growing understanding of LLPS, molecular-level mechanisms behind this process are still not fully established. Here, we use histidine-rich squid beak proteins (HBPs) as model IDPs to shed light on molecular interactions governing LLPS. We show that LLPS of HBPs is mediated though specific modular repeats. The morphology of separated phases (liquid-like versus hydrogels) correlates with the repeats' hydrophobicity. Solution-state NMR indicates that LLPS is a multistep process initiated by deprotonation of histidine residues, followed by transient hydrogen bonding with tyrosine, and eventually by hydrophobic interactions. The microdroplets are stabilized by aromatic clustering of tyrosine residues exhibiting restricted molecular mobility in the nano-to-microsecond timescale according to solid-state NMR experiments. Our findings provide guidelines to rationally design pH-responsive peptides with LLPS ability for various applications, including bioinspired protocells and smart drug-delivery systems.

9.
Sensors (Basel) ; 20(1)2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31878139

RESUMO

Spin-based devices can reduce energy leakage and thus increase energy efficiency. They have been seen as an approach to overcoming the constraints of CMOS downscaling, specifically, the Magnetic Tunnel Junction (MTJ) which has been the focus of much research in recent years. Its nonvolatility, scalability and low power consumption are highly attractive when applied in several components. This paper aims at providing a survey of a selection of MTJ applications such as memory and analog to digital converter, among others.

10.
Molecules ; 25(1)2019 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-31881790

RESUMO

In Chinese medicine, the effect of promoting blood circulation and removing stasis could be enhanced after Chuanxiong Rhizoma is processed by wine. However, the relevant mechanism remains unclear. In this manuscript, a rapid and sensitive quantification method employing ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was established and validated to simultaneously determine butylidenephthalide, ligustilide, senkyunolide A and ferulic acid in rat plasma after oral administration of raw Chuanxiong Rhizoma (RCR) and wine-processed Chuanxiong Rhizoma (WCR) respectively. All analytes were extracted from plasma by proteins precipitation with methanol. Chromatographic separation was carried out on a Hypersil GOLD C18 column by using a gradient mobile phase system of acetonitrile and water with 0.01% formic acid, the flow rate was 0.3 mL/min. For exact mass detecting, quick switching mode was used, positive and negative ions could be detected in one injection. The pharmacokinetic profiles of four components in the two groups were evaluated and compared. The results showed that, compared to the RCR group, the Vd and AUC0→t values of four active compounds were increased and decreased respectively in WCR group, which revealed the effect of wine processing to Chuanxiong Rhizoma: the stronger the effect, the wider the distribution.

11.
Front Oncol ; 9: 1133, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31709191

RESUMO

Background: DNA methyltransferase 3A (DNMT3A) plays a unique role in hematopoiesis and acute myeloid leukemia (AML) pathogenesis. While the influences of DNMT3A mutation subtypes are still under debate. Purpose: Exploration of the clinical and molecular differences between AML patients carrying DNMT3A R882 mutations and DNMT3A frameshift mutations. Methods: Next generation of sequencing (NGS) and clinical data of 118 AML patients in our center were analyzed and compared. NGS, mRNA and miRNA profiling and clinical data from 12 patients in TCGA database were integrative analyzed. Results: Among all patients enrolled, 113 patients were positive for the variants of interest. Overall, a total of 295 variants were discovered, among which 24 DNMT3A mutations were detected, including 1 non-sense, 20 missense, 3 frameshift mutations. And 7 DNMT3A R882 mutations (3 R882H, 2 R882C, and 2 R882P) were found. Clinical analysis from our cohort and TCGA database indicated that patients carrying DNMT3A R882 mutation exhibited significantly higher levels of peripheral blood hemoglobin and non-significantly inferior prognosis compared with patients with DNMT3A frameshift mutations. Integrative analysis indicated that miR-10b, miR-143, and miR-30a were significantly decreased in the DNMT3A R882 group. High miR-143 expression is significantly associated with better prognosis in AML patients with DNMT3A mutations. Conclusion: Different molecular and clinical characteristics existed between patients with DNMT3A variant subtypes. The distinct microRNA expression pattern for DNMT3A R882 AML patients might not only act as markers to predict disease prognosis, but also could be further investigated to develop novel therapeutic targets for patients with DNMT3A mutations.

12.
Curr Alzheimer Res ; 16(13): 1175-1182, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31763973

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease. However, few studies have investigated the heterogeneous gene expression patterns in AD. OBJECTIVE AND METHODS: We examined the gene expression patterns in four brain regions of AD based on the within-sample relative expression orderings (REOs). Gene pairs with significantly reversed REOs in AD samples compared to non-AD controls were identified for each brain region using Fisher's exact test, and filtered according to their transcriptional differences between AD samples. Subgroups of AD were classified by cluster analysis. RESULTS: REO-based gene expression profiling analyses revealed that transcriptional differences, as well as distinct disease subsets, existed within AD patients. For each brain region, two main subgroups were classified: one subgroup reported differentially expressed genes overlapped with the age-related genes, and the other was related to neuroinflammation. CONCLUSION: AD transcriptional subgroups might help understand the underlying pathogenesis of AD, and lend support to a personalized approach to AD management.

13.
PLoS One ; 14(10): e0224096, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31661493

RESUMO

Staphylococcus aureus (S. aureus) infections are a leading cause of death by an infectious agent. Survival within host phagocytic cells is one mechanism by which S. aureus evades antibiotic treatment. A novel THIOMAB™ antibody-antibiotic conjugate (TAC) strategy was developed to kill S. aureus intracellularly and mitigate the spread of infection. In this report, we used a longitudinal whole-body bioluminescence imaging method to study the antibacterial dynamics of TAC alone or in combination with vancomycin in a mouse infection model. Injections of stably luminescent S. aureus bacteria into mice resulted in exponential increases in whole body bioluminescence with a reduction in body weight and survival rate. Vancomycin, a standard-of-care antibiotic, suppressed bacterial growth in mice. However, bacterial growth rebounded in these animals once treatment was discontinued. In contrast, single dose of TAC showed rapid reduction of bioluminescence intensity, which persisted for up to 19 days. The combination of TAC and vancomycin achieved a more sustained and significantly greater reduction of bioluminescence compared with vancomycin alone. In summary, the present study showed an imaging method to longitudinally assess antibacterial drug dynamics in mice and demonstrated that TAC monotherapy or in combination with vancomycin had superior and sustained activity compared to vancomycin alone.

14.
Environ Sci Technol ; 53(21): 12904-12913, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31609593

RESUMO

Heavy-duty vehicles require expensive aftertreatment systems for control of emissions such as particulate matter (PM) and nitrogen oxides (NOx) to comply with stringent emission standards. Reduced engine-out emissions could potentially alleviate the emission control burden, and thus bring about reductions in the cost associated with aftertreatment systems, which translates into savings in vehicle ownership. This study evaluates potential reductions in manufacturing and operating costs of redesigned emission aftertreatment systems of line-haul heavy-duty diesel vehicles (HDDVs) with reduced engine-out emissions brought about by co-optimized fuel and engine technologies. Three emissions reduction cases representing conservative, medium, and optimistic engine-out emission reduction benefits are analyzed, compared to a reference case: the total costs of aftertreatment systems (TCA) of the three cases are reduced to $11,400(1.63 ¢/km), $9,100 (1.30 ¢/km), and $8,800 (1.26 ¢/km), respectively, compared to $12,000 (1.71 ¢/km) for the reference case. The largest potential reductions result from reduced diesel exhaust fluid (DEF) usage due to lower NOx emissions. Downsizing aftertreatment devices is not likely, because the sizes of devices are dependent on not only engine-out emissions, but also other factors such as engine displacement. Sensitivity analysis indicates that the price and usage of DEF have the largest impacts on TCA reduction.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Análise Custo-Benefício , Gasolina , Veículos Automotores , Material Particulado , Emissões de Veículos
15.
Genes (Basel) ; 10(11)2019 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-31652881

RESUMO

Loss-of-function approaches provide strong evidence for determining the role of particular genes. The prevalent CRISPR/Cas9 technique is widely used to disrupt target gene with uncontrolled non-homologous end joining after the double strand breaks, which results in mosaicism and multiple genotypes in the founders. In animal models with long generation time such as the salamanders, producing homozygous offspring mutants would be rather labor intensive and time consuming. Here we utilized the base editing technique to create the loss-of-function F0 mutants without the random indels. As a proof of principle, we successfully introduced premature stop codons into the tyrosinase locus and produced the albino phenotype in the newts (Pleurodeles waltl). We further demonstrated that the knockout efficiency could be greatly improved by using multiplex sgRNAs target the same gene. The F0 mutated animals showed fully loss-of-function by both genotyping and phenotyping analysis, which could enable direct functional analysis in the founders and avoid sophisticated breeding. This study not only presented the high efficiency of single base editing in a gigantic animal genome (>20 G), but also provided new tools for interrogating gene function in other salamander species.

17.
J Biomed Nanotechnol ; 15(9): 1897-1908, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31387677

RESUMO

With the advance in nanomedicine, diagnostic and therapeutic nanoscale prodrugs have been rapidly developed in the field of cancer treatment. In this study, we constructed an enzyme-responsive polymer-paclitaxel (PTX) prodrug with a biocompatible saccharide-containing polymer backbone through the reversible addition-fragmentation chain transfer (RAFT) polymerization. A near-infrared fluorescent molecule (pheophorbide a) and magnetic resonance imaging (MRI) contrast agent (gadolinium-tetraazacyclododecanetetraacetic acid) were further conjugated onto the copolymer backbone to impart the ability of multimode imaging and tracing, forming the final diagnosis and treatment polymeric prodrug. This prodrug was amphiphilic and was able to self-assemble into uniform-size nanoparticles (80.1 nm). With the specific catalysis of enzymes, the anti-cancer drug, PTX, in the nanoparticles could be effectively released to kill cancer cells. The results of near-infrared fluorescence imaging and MRI showed that the diagnostic prodrug was preferentially concentrated at the tumor site compared with the free imaging reagents, suggesting improved and durable tumor imaging effects, which are beneficial for precise cancer diagnosis. The tumor growth in the mice could be effectively retarded after the administration of the prodrug. The tumor almost completely disappeared till the final treatment, and the tumor inhibition rate was as high as 96.4%. Immunohistochemical analysis indicated that the high anti-tumor effects might be attributed to the result that the prodrug not only induced the apoptosis of tumor cells, but also inhibited the formation of new blood vessels in the tumor environment. Therefore, this theranostic prodrug, which is based on the saccharide-containing polymer, holds potency for the development of a robust nanoscale platform for the diagnosis and treatment of cancer.


Assuntos
Neoplasias/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Camundongos , Polímeros , Pró-Fármacos , Nanomedicina Teranóstica
18.
J Pharm Biomed Anal ; 174: 696-706, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31288192

RESUMO

Semen Cassiae, called Juemingzi in Chinese, is widely used in clinic for alleviating constipation, improving eyesight and preventing hyperlipidemia. It can be used as medicine or food including many application forms, such as traditional pieces and ultrafine granular powder (UGP). In this paper, comparative pharmacokinetics of Semen Cassiae in different forms of traditional pieces and UGP were achieved to research the clinical dosage of UGP. Also, the scientific connotation of brewing way for traditional pieces of Semen Cassiae application in clinic was revealed. To achieve this purpose, a rapid, sensitive and reliable UHPLC-MS/MS method was developed for simultaneous determination of rhein, emodin, aloe-emodin, chrysophanol, physcion, aurantio-obtusin, chryso-obtusin, obtusifolin and obtusin in rat plasma. Multiple reaction monitoring mode via an electrospray ionization was applied for the quantitation of the analytes. The separation was carried out on an Agilent Extend-C18 column (100 mm × 2.1 mm, 1.8 µm) with an 8.0 min gradient elution using ultra-purify water and acetonitrile as mobile phase. The samples were prepared by liquid-liquid extraction with ethyl acetate. The development and validation of bioanalytical method were performed according to the latest "Bioanalytical Method Validation: Guidance for Industry" issued by FDA in 2018. Finally, the clinical dosage of UGP was concluded to be 1/4 of Semen Cassiae traditional pieces in oral administration way by comparing the pharmacokinetic parameters of UGP to that of traditional pieces in the aspect of mathematical statics using plus of AUC values.


Assuntos
Antraquinonas/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Área Sob a Curva , Formas de Dosagem , Limite de Detecção , Extração Líquido-Líquido , Masculino , Modelos Teóricos , Pós , Controle de Qualidade , Ratos , Ratos Sprague-Dawley , Tecnologia Farmacêutica/métodos
19.
Nutr Metab (Lond) ; 16: 44, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31320919

RESUMO

Background: Visceral adiposity has been reported to play a key role in hypertension compared with other measurements of regional or general obesity. The aim of current study was to evaluate the relationship between visceral fat reduction and changes in blood pressure in a group of overweight or obese Chinese individuals. Methods: An observational study was conducted with 168 participants (ChiCTR-OOC-17012000). Body composition, blood parameters and blood pressure were assessed at the beginning and end of the intervention. Males and females were categorized separately into quartiles according to changes in visceral fat during the intervention. Multiple linear regression models were used to assess the associations of changes in systolic and diastolic blood pressure with changes of visceral fat area, adjusted for potential confounders. Results: Changes in visceral fat was significantly associated with systolic and diastolic blood pressure in men for systolic (ß = 0.234, 95% CI: 0.103, 0.365; p = 0.001) and diastolic blood pressure (ß = 0.237; 95% CI: 0.127, 0.346; p <0.001), but not in women after adjustment for the same potential confounders for systolic blood (ß = - 0.003, 95% CI: - 0.260, 0.255; p = 0.984) and diastolic blood pressure (ß = 0.101, 95% CI: - 0.072, 0.273; p = 0.249). Conclusions: A positive association was observed between reduction in visceral fat and improvements in both systolic blood and diastolic blood pressures in males but not females in a 12-week meal replacement intervention. Trial registration: The Ethics Committee of Peking University Health Science Center approved the study protocol on 6 July 2017. The authors confirm that all ongoing and related trials for this intervention were carried out following the rules of the Declaration of Helsinki of 1975 and registered (ChiCTR-OOC-17012000). http://www.chictr.org.cn/showprojen.aspx?proj=20426.

20.
Front Oncol ; 9: 629, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31355144

RESUMO

Background: Previously reported transcriptional signatures for predicting the prognosis of stage I-III bladder cancer (BLCA) patients after surgical resection are commonly based on risk scores summarized from quantitative measurements of gene expression levels, which are highly sensitive to the measurement variation and sample quality and thus hardly applicable under clinical settings. It is necessary to develop a signature which can robustly predict recurrence risk of BLCA patients after surgical resection. Methods: The signature is developed based on the within-sample relative expression orderings (REOs) of genes, which are qualitative transcriptional characteristics of the samples. Results: A signature consisting of 12 gene pairs (12-GPS) was identified in training data with 158 samples. In the first validation dataset with 114 samples, the low-risk group of 54 patients had a significantly better overall survival than the high-risk group of 60 patients (HR = 3.59, 95% CI: 1.34~9.62, p = 6.61 × 10-03). The signature was also validated in the second validation dataset with 57 samples (HR = 2.75 × 1008, 95% CI: 0~Inf, p = 0.05). Comparison analysis showed that the transcriptional differences between the low- and high-risk groups were highly reproducible and significantly concordant with DNA methylation differences between the two groups. Conclusions: The 12-GPS signature can robustly predict the recurrence risk of stage I-III BLCA patients after surgical resection. It can also aid the identification of reproducible transcriptional and epigenomic features characterizing BLCA metastasis.

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