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1.
Circulation ; 141(9): 709-711, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32119583
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(2): 182-185, 2020 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-32034751

RESUMO

OBJECTIVE: To perform prenatal diagosis for two fetuses carrying partial deletion of Y chromosome. METHODS: Routine G- and C-banding were carried out to analyze the chromosomal karyotypes of the fetuses and their fathers. Fetal DNA was also subjected to low-coverage massively parallel copy number variation sequencing (CNV-seq), fluorescence in situ hybridization (FISH), SRY gene and AZF factor testing. RESULTS: Both fetuses showed a 46, XN, del(Y) (q11.2) karyotype at 320-400 band level by the analysis of amniotic fluid chromosomes. FISH with Y chromosome centromere probe indicated that in both cases the number of Y chromosome was normal. Both fathers had an apparently normal karyotype at 320-400 band level. For fetus 1, CNV-seq test revealed a 12.88 Mb deletion at Yq11.221-q12, which encompassed the whole of AZFb+AZFc regions and may lead to male infertility, sperm deficiency and/or severe oligospermia. In fetus 2, CNV-seq also detected a 14.84 Mb deletion at Yq11.21-q12, which encompassed the whole of the AZF region and may lead to severe spermatogenesis disorder resulting in severe oligoasthenospermia and azoospermia. In both cases, testing of SRY gene was positive. No point mutation of the SRY gene was identified. Analysis of amniotic fluid DNA confirmed partial or total absence of AZF in the two fetuses, respectively. CONCLUSION: Combined use of various technologies can enable accurate detection of structural abnormalities of the Y chromosome and facilitate genetic counseling. CNV-seq can help with rapid screening of Y chromosome microdeletions and may be used as a complementary test for chromosomal karyotyping.


Assuntos
Cromossomos Humanos Y , Oligospermia , Deleção Cromossômica , Variações do Número de Cópias de DNA , Feminino , Feto , Humanos , Hibridização in Situ Fluorescente , Infertilidade Masculina , Masculino , Gravidez , Diagnóstico Pré-Natal , Aberrações dos Cromossomos Sexuais , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual
3.
Int J Comput Assist Radiol Surg ; 15(2): 193-201, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31673961

RESUMO

PURPOSE: Acute ischemic stroke is one of the most causes of death all over the world. Onset to treatment time is critical in stroke diagnosis and treatment. Considering the time consumption and high price of MR imaging, CT perfusion (CTP) imaging is strongly recommended for acute stroke. However, too much CT radiation during CTP imaging may increase the risk of health problems. How to reduce CT radiation dose in CT perfusion imaging has drawn our great attention. METHODS: In this study, the original 30-pass CTP images are downsampled to 15 passes in time sequence, which equals to 50% radiation dose reduction. Then, a residual deep convolutional neural network (DCNN) model is proposed to restore the downsampled 15-pass CTP images to 30 passes to calculate the parameters such as cerebral blood flow, cerebral blood volume, mean transit time, time to peak for stroke diagnosis and treatment. The deep restoration CNN is implemented simply and effectively with 16 successive convolutional layers which form a wide enough receptive field for input image data. 18 patients' CTP images are employed as training set and the other six patients' CTP images are treated as test dataset in this study. RESULTS: Experiments demonstrate that our CNN can restore high-quality CTP images in terms of structural similarity index (SSIM) and peak signal-to-noise ratio (PSNR). The average SSIM and PSNR for test images are 0.981 and 56.25, and the SSIM and PSNR of regions of interest are 0.915 and 42.44, respectively, showing promising quantitative level. In addition, we compare the perfusion maps calculated from the restored images and from the original images, and the average perfusion results of them are extremely close. Areas of hypoperfusion of six test cases could be detected with comparable accuracy by radiologists. CONCLUSION: The trained model can restore the temporally downsampled 15-pass CTP to 30 passes very well. According to the contrast test, sufficient information cannot be restored with, e.g., simple interpolation method and deep convolutional generative adversarial network, but can be restored with the proposed CNN model. This method can be an optional way to reduce radiation dose during CTP imaging.

4.
Protein Cell ; 11(2): 108-123, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31691194

RESUMO

Common γ chain cytokines are important for immune memory formation. Among them, the role of IL-2 remains to be fully explored. It has been suggested that this cytokine is critically needed in the late phase of primary CD4 T cell activation. Lack of IL-2 at this stage sets for a diminished recall response in subsequent challenges. However, as IL-2 peak production is over at this point, the source and the exact mechanism that promotes its production remain elusive. We report here that resting, previously antigen-stimulated CD4 T cells maintain a minimalist response to dendritic cells after their peak activation in vitro. This subtle activation event may be induced by DCs without overt presence of antigen and appears to be stronger if IL-2 comes from the same dendritic cells. This encounter reactivates a miniature IL-2 production and leads a gene expression profile change in these previously activated CD4 T cells. The CD4 T cells so experienced show enhanced reactivation intensity upon secondary challenges later on. Although mostly relying on in vitro evidence, our work may implicate a subtle programing for CD4 T cell survival after primary activation in vivo.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31696405

RESUMO

Tremendous progress in cancer detection and therapy has improved survival. However, cardiovascular complications are a major source of morbidity in cancer survivors. Cardiotoxicity is currently defined by structural myocardial changes and cardiac injury biomarkers. In many instances, such changes are late and irreversible. Therefore, diagnostic modalities that can identify early alterations in potentially reversible biochemical and molecular signaling processes are of interest. This review is focused on emerging translational metabolic imaging modalities. We present in context relevant mitochondrial biology aspects that ground the development and application of these technologies for detection of cancer therapy-related cardiac dysfunction (CTRCD). The application of these modalities may improve the assessment of cardiovascular risk when anticancer treatments with a defined cardiometabolic toxic mechanism are to be used. Also, they may serve as screening tools for cardiotoxicity when novel lines of cancer therapies are applied.

7.
Proc Natl Acad Sci U S A ; 116(49): 24463-24469, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31740599

RESUMO

From 2013 to 2017, with the implementation of the toughest-ever clean air policy in China, significant declines in fine particle (PM2.5) concentrations occurred nationwide. Here we estimate the drivers of the improved PM2.5 air quality and the associated health benefits in China from 2013 to 2017 based on a measure-specific integrated evaluation approach, which combines a bottom-up emission inventory, a chemical transport model, and epidemiological exposure-response functions. The estimated national population-weighted annual mean PM2.5 concentrations decreased from 61.8 (95%CI: 53.3-70.0) to 42.0 µg/m3 (95% CI: 35.7-48.6) in 5 y, with dominant contributions from anthropogenic emission abatements. Although interannual meteorological variations could significantly alter PM2.5 concentrations, the corresponding effects on the 5-y trends were relatively small. The measure-by-measure evaluation indicated that strengthening industrial emission standards (power plants and emission-intensive industrial sectors), upgrades on industrial boilers, phasing out outdated industrial capacities, and promoting clean fuels in the residential sector were major effective measures in reducing PM2.5 pollution and health burdens. These measures were estimated to contribute to 6.6- (95% CI: 5.9-7.1), 4.4- (95% CI: 3.8-4.9), 2.8- (95% CI: 2.5-3.0), and 2.2- (95% CI: 2.0-2.5) µg/m3 declines in the national PM2.5 concentration in 2017, respectively, and further reduced PM2.5-attributable excess deaths by 0.37 million (95% CI: 0.35-0.39), or 92% of the total avoided deaths. Our study confirms the effectiveness of China's recent clean air actions, and the measure-by-measure evaluation provides insights into future clean air policy making in China and in other developing and polluting countries.

8.
Proc Natl Acad Sci U S A ; 116(35): 17193-17200, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31405979

RESUMO

In recent years, air pollution has caused more than 1 million deaths per year in China, making it a major focus of public health efforts. However, future climate change may exacerbate such human health impacts by increasing the frequency and duration of weather conditions that enhance air pollution exposure. Here, we use a combination of climate, air quality, and epidemiological models to assess future air pollution deaths in a changing climate under Representative Concentration Pathway 4.5 (RCP4.5). We find that, assuming pollution emissions and population are held constant at current levels, climate change would adversely affect future air quality for >85% of China's population (∼55% of land area) by the middle of the century, and would increase by 3% and 4% the population-weighted average concentrations of fine particulate matter (PM2.5) and ozone, respectively. As a result, we estimate an additional 12,100 and 8,900 Chinese (95% confidence interval: 10,300 to 13,800 and 2,300 to 14,700, respectively) will die per year from PM2.5 and ozone exposure, respectively. The important underlying climate mechanisms are changes in extreme conditions such as atmospheric stagnation and heat waves (contributing 39% and 6%, respectively, to the increase in mortality). Additionally, greater vulnerability of China's aging population will further increase the estimated deaths from PM2.5 and ozone in 2050 by factors of 1 and 3, respectively. Our results indicate that climate change and more intense extremes are likely to increase the risk of severe pollution events in China. Managing air quality in China in a changing climate will thus become more challenging.

9.
BMC Nephrol ; 20(1): 244, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31272400

RESUMO

BACKGROUND: IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide and is an important cause of end-stage renal disease (ESRD). Exploring novel biomarkers is necessary for predicting the disease activity and progression of IgAN patients. The present study sought to investigate the value of serum C4 for predicting the prognosis of IgAN patients. METHODS: The primary endpoint of this retrospective study was a composite event of either a ≥ 50% reduction in estimated glomerular filtration rate (eGFR) or end-stage renal disease (ESRD) or death. The associations between serum C4 and clinicopathological parameters and prognosis of this cohort of IgAN patients were evaluated. RESULTS: The present study included 1356 IgAN patients. Serum C4 levels correlated significantly with clinical prognostic factors. Serum C4 levels correlated positively with urinary protein excretion (r = 0.307, P < 0.001), and negatively correlated with estimated glomerular filtration rate (r = - 0.281, P < 0.001). Furthermore, serum C4 levels increased with aggravation of tubulointerstitial injury, crescents and ratios of global sclerosis (all P < 0.05). Prognostic analyses with the Cox proportional hazards regression model and Kaplan-Meier survival curves further identified serum C4 as an independent risk factor for the prognosis of IgAN. CONCLUSIONS: The present study identified serum C4 as a useful predictor for the prognosis of IgAN patients. The mechanism of the trend of serum C4 in IgAN needs to be illustrated in further research.

10.
Nature ; 572(7769): 373-377, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31261374

RESUMO

Net anthropogenic emissions of carbon dioxide (CO2) must approach zero by mid-century (2050) in order to stabilize the global mean temperature at the level targeted by international efforts1-5. Yet continued expansion of fossil-fuel-burning energy infrastructure implies already 'committed' future CO2 emissions6-13. Here we use detailed datasets of existing fossil-fuel energy infrastructure in 2018 to estimate regional and sectoral patterns of committed CO2 emissions, the sensitivity of such emissions to assumed operating lifetimes and schedules, and the economic value of the associated infrastructure. We estimate that, if operated as historically, existing infrastructure will cumulatively emit about 658 gigatonnes of CO2 (with a range of 226 to 1,479 gigatonnes CO2, depending on the lifetimes and utilization rates assumed). More than half of these emissions are predicted to come from the electricity sector; infrastructure in China, the USA and the 28 member states of the European Union represents approximately 41 per cent, 9 per cent and 7 per cent of the total, respectively. If built, proposed power plants (planned, permitted or under construction) would emit roughly an extra 188 (range 37-427) gigatonnes CO2. Committed emissions from existing and proposed energy infrastructure (about 846 gigatonnes CO2) thus represent more than the entire carbon budget that remains if mean warming is to be limited to 1.5 degrees Celsius (°C) with a probability of 66 to 50 per cent (420-580 gigatonnes CO2)5, and perhaps two-thirds of the remaining carbon budget if mean warming is to be limited to less than 2 °C (1,170-1,500 gigatonnes CO2)5. The remaining carbon budget estimates are varied and nuanced14,15, and depend on the climate target and the availability of large-scale negative emissions16. Nevertheless, our estimates suggest that little or no new CO2-emitting infrastructure can be commissioned, and that existing infrastructure may need to be retired early (or be retrofitted with carbon capture and storage technology) in order to meet the Paris Agreement climate goals17. Given the asset value per tonne of committed emissions, we suggest that the most cost-effective premature infrastructure retirements will be in the electricity and industry sectors, if non-emitting alternatives are available and affordable4,18.

11.
Sci Total Environ ; 692: 361-370, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31351280

RESUMO

In 2013, the Chinese government announced its first air quality standard for PM2.5 (particulate matter with a diameter < 2.5 µm) which requires annual mean PM2.5 concentration to achieve the World Health Organization (WHO) interim target 1 of 35 µg/m3 nationwide including the most polluted region of Beijing-Tianjin-Hebei (BTH). Here, we explore the future mitigation pathways for the BTH region to investigate the possibility of air quality attainment by 2030 in that region, by developing two energy scenarios (i.e., baseline energy scenario and enhanced energy scenario) and two end-of-pipe scenarios (i.e., business as usual scenario and best available technology scenario) and simulating future air quality for different scenarios using the WRF/CMAQ model. Results showed that without stringent energy and industrial structure adjustment, even the most advanced end-of-pipe technologies did not allow the BTH region to attain the 35 µg/m3 target. Under the most stringent scenario that coupled the enhanced structure adjustment measures and the best available end-of-pipe measures, the emissions of SO2, NOx, PM2.5 and NMVOCs (nonmethane volatile organic compounds) were estimated to be reduced by 85%, 74%, 82% and 72%, respectively, in 2030 over the BTH region. As a result, the simulated annual mean PM2.5 concentrations in Beijing, Tianjin and Hebei could decline to 23, 28 and 28 µg/m3, respectively, all of which achieved the 35 µg/m3 target by 2030. Our study identified a feasible pathway to achieve the 2030 target and highlighted the importance of reshaping the energy and industrial structure of the BTH region for future air pollution mitigation.

12.
Circulation ; 140(11): 921-936, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31220931

RESUMO

BACKGROUND: Polycystin-1 (PC1) is a transmembrane protein originally identified in autosomal dominant polycystic kidney disease where it regulates the calcium-permeant cation channel polycystin-2. Autosomal dominant polycystic kidney disease patients develop renal failure, hypertension, left ventricular hypertrophy, and diastolic dysfunction, among other cardiovascular disorders. These individuals harbor PC1 loss-of-function mutations in their cardiomyocytes, but the functional consequences are unknown. PC1 is ubiquitously expressed, and its experimental ablation in cardiomyocyte-specific knockout mice reduces contractile function. Here, we set out to determine the pathophysiological role of PC1 in cardiomyocytes. METHODS: Wild-type and cardiomyocyte-specific PC1 knockout mice were analyzed by echocardiography. Excitation-contraction coupling was assessed in isolated cardiomyocytes and human embryonic stem cell-derived cardiomyocytes, and functional consequences were explored in heterologous expression systems. Protein-protein interactions were analyzed biochemically and by means of ab initio calculations. RESULTS: PC1 ablation reduced action potential duration in cardiomyocytes, decreased Ca2+ transients, and myocyte contractility. PC1-deficient cardiomyocytes manifested a reduction in sarcoendoplasmic reticulum Ca2+ stores attributable to a reduced action potential duration and sarcoendoplasmic reticulum Ca2+ ATPase (SERCA) activity. An increase in outward K+ currents decreased action potential duration in cardiomyocytes lacking PC1. Overexpression of full-length PC1 in HEK293 cells significantly reduced the current density of heterologously expressed Kv4.3, Kv1.5 and Kv2.1 potassium channels. PC1 C terminus inhibited Kv4.3 currents to the same degree as full-length PC1. Additionally, PC1 coimmunoprecipitated with Kv4.3, and a modeled PC1 C-terminal structure suggested the existence of 2 docking sites for PC1 within the N terminus of Kv4.3, supporting a physical interaction. Finally, a naturally occurring human mutant PC1R4228X manifested no suppressive effects on Kv4.3 channel activity. CONCLUSIONS: Our findings uncover a role for PC1 in regulating multiple Kv channels, governing membrane repolarization and alterations in SERCA activity that reduce cardiomyocyte contractility.

13.
J Environ Sci (China) ; 83: 8-20, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31221390

RESUMO

With rapid economic growth and urbanization, the Yangtze River Delta (YRD) region in China has experienced serious air pollution challenges. In this study, we analyzed the air pollution characteristics and their relationship with emissions and meteorology in the YRD region during 2014-2016. In recent years, the concentrations of all air pollutants, except O3, decreased. Spatially, the PM2.5, PM10, SO2, and CO concentrations were higher in the northern YRD region, and NO2 and O3 were higher in the central YRD region. Based on the number of non-attainment days (i.e., days with air quality index greater than 100), PM2.5 was the largest contributor to air pollution in the YRD region, followed by O3, PM10, and NO2. However, particulate matter pollution has declined gradually, while O3 pollution worsened. Meteorological conditions mainly influenced day-to-day variations in pollutant concentrations. PM2.5 concentration was inversely related to wind speed, while O3 concentration was positively correlated with temperature and negatively correlated with relative humidity. The air quality improvement in recent years was mainly attributed to emission reductions. During 2014-2016, PM2.5, PM10, SO2, NOx, CO, NH3, and volatile organic compound (VOC) emissions in the YRD region were reduced by 26.3%, 29.2%, 32.4%, 8.1%, 15.9%, 4.5%, and 0.3%, respectively. Regional transport also contributed to the air pollution. During regional haze periods, pollutants from North China and East China aggravated the pollution in the YRD region. Our findings suggest that emission reduction and regional joint prevention and control helped to improve the air quality in the YRD region.


Assuntos
Poluentes Atmosféricos/análise , Poluição do Ar/estatística & dados numéricos , Monitoramento Ambiental , Conceitos Meteorológicos , China , Meteorologia , Ozônio , Material Particulado/análise , Rios , Estações do Ano , Temperatura Ambiente , Urbanização
14.
Cancer Lett ; 459: 1-12, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31150822

RESUMO

High grade serous ovarian cancer (HGSOC) is the most frequent type of ovarian cancer. Most patients have primary response to platinum-based chemotherapy but frequently relapse, which leads to patient death. A lack of well documented and characterized patient-derived HGSOC cell lines is so far a major barrier to define tumor specific therapeutic targets and to study the molecular mechanisms underlying disease progression. We established 34 patient-derived HGSOC cell lines and characterized them at cellular and molecular level. Particularly, we demonstrated that a cancer-testis antigen PRAME and Estrogen Receptor could serve as therapeutic targets. Notably, data from the cell lines did not demonstrate acquired resistance due to tumor recurrence that matched with clinical observations. Finally, we presented that all HGSOC had no or very low CDKN1A (p21) expression due to loss of wild-type TP53, suggesting that loss of cell cycle control is the determinant for tumorigenesis and progression. In conclusion, patient-derived cell lines reveal that PRAME is a potential tumor specific therapeutic target in HGSOC and counteracting the down-regulation of p21 caused by loss of wild-type TP53 might be the key to impede disease progression.

15.
Sci Adv ; 5(5): eaav3235, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31086816

RESUMO

Resistance to platinum-based chemotherapy is a common event in patients with cancer, generally associated with tumor dissemination and metastasis. Whether platinum treatment per se activates molecular pathways linked to tumor spreading is not known. Here, we report that the ubiquitin-specific protease 1 (USP1) mediates ovarian cancer cell resistance to platinum, by regulating the stability of Snail, which, in turn, promotes tumor dissemination. At the molecular level, we observed that upon platinum treatment, USP1 is phosphorylated by ATM and ATR and binds to Snail. Then, USP1 de-ubiquitinates and stabilizes Snail expression, conferring resistance to platinum, increased stem cell-like features, and metastatic ability. Consistently, knockout or pharmacological inhibition of USP1 increased platinum sensitivity and decreased metastatic dissemination in a Snail-dependent manner. Our findings identify Snail as a USP1 target and open the way to a novel strategy to overcome platinum resistance and more successfully treat patients with ovarian cancer.

16.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(6): 543-546, 2019 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-31055801

RESUMO

OBJECTIVE: To explore the genetic basis for a fetus featuring growth restriction and validate the effectiveness of a novel noninvasive prenatal testing (NIPT) technique for the detection of chromosomal microdeletions. METHODS: Next-generation sequencing(NGS) and fluorescence in situ hybridization(FISH) were used to analyze the DNA of the fetus. Conventional G-banding was used to analyze the karyotypes of the fetus and its parents. High-throughput sequencing was used to analyze free fetal DNA. RESULTS: NGS analysis has revealed a 4.88 Mb deletion at 15q11.2-q13.1 region in the fetus, which has a 99% overlap with the critical region of Prader-Willi syndrome (Type 2) and Angelman syndrome (Type 2) and encompassed critical genes including SNRPN and UBE3A. NIPT also revealed a 4.6 Mb deletion at 15q12, which was consistent with the results of fetal cord blood and amniotic DNA testing. FISH assay has confirmed the result of NGS. By karyotying, all subjects showed a normal karyotypes at a level of 320~400 bands. CONCLUSION: It is quite necessary to carry out genetic testing on fetuses showing growth restriction. NIPT for fetal chromosomal microdeletions/microduplication syndromes is highly accurate for the diagnosis of Prader-Willi/Angelman syndrome.


Assuntos
Síndrome de Angelman , Síndrome de Prader-Willi , Bandeamento Cromossômico , Cromossomos Humanos Par 15 , Feminino , Feto , Humanos , Hibridização in Situ Fluorescente , Gravidez
17.
Comput Struct Biotechnol J ; 17: 537-560, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049165

RESUMO

The sphingolipid and lysophosphatidate regulatory networks impact diverse mechanisms attributed to cancer cells and the tumor immune microenvironment. Deciphering the complexity demands implementation of a holistic approach combined with higher-resolution techniques. We implemented a multi-modular integrative approach consolidating the latest accomplishments in gene expression profiling, prognostic/predictive modeling, next generation digital pathology, and systems biology for epithelial ovarian cancer. We assessed patient-specific transcriptional profiles using the sphingolipid/lysophosphatidate/immune-associated signature. This revealed novel sphingolipid/lysophosphatidate-immune gene-gene associations and distinguished tumor subtypes with immune high/low context. These were characterized by robust differences in sphingolipid-/lysophosphatidate-related checkpoints and the drug response. The analysis also nominates novel survival models for stratification of patients with CD68, LPAR3, SMPD1, PPAP2B, and SMPD2 emerging as the most prognostically important genes. Alignment of proprietary data with curated transcriptomic data from public databases across a variety of malignancies (over 600 categories; over 21,000 arrays) showed specificity for ovarian carcinoma. Our systems approach identified novel sphingolipid-lysophosphatidate-immune checkpoints and networks underlying tumor immune heterogeneity and disease outcomes. This holds great promise for delivering novel stratifying and targeting strategies.

18.
Nature ; 568(7752): 351-356, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30971818

RESUMO

Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with high morbidity and mortality for which there are no evidence-based therapies. Here we report that concomitant metabolic and hypertensive stress in mice-elicited by a combination of high-fat diet and inhibition of constitutive nitric oxide synthase using Nω-nitro-L-arginine methyl ester (L-NAME)-recapitulates the numerous systemic and cardiovascular features of HFpEF in humans. Expression of one of the unfolded protein response effectors, the spliced form of X-box-binding protein 1 (XBP1s), was reduced in the myocardium of our rodent model and in humans with HFpEF. Mechanistically, the decrease in XBP1s resulted from increased activity of inducible nitric oxide synthase (iNOS) and S-nitrosylation of the endonuclease inositol-requiring protein 1α (IRE1α), culminating in defective XBP1 splicing. Pharmacological or genetic suppression of iNOS, or cardiomyocyte-restricted overexpression of XBP1s, each ameliorated the HFpEF phenotype. We report that iNOS-driven dysregulation of the IRE1α-XBP1 pathway is a crucial mechanism of cardiomyocyte dysfunction in HFpEF.


Assuntos
Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Estresse Nitrosativo , Volume Sistólico , Animais , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Endorribonucleases/metabolismo , Insuficiência Cardíaca/prevenção & controle , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/deficiência , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Fenótipo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/metabolismo
19.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(3): 263-266, 2019 Mar 10.
Artigo em Chinês | MEDLINE | ID: mdl-30835361

RESUMO

OBJECTIVE: To explore the genetic basis of a fetus with ventricular septal defect (VSD) by using modified noninvasive prenatal testing (NIPT) for the detection of microdeletion syndromes. METHODS: Chromosomal karyotypes of the fetus and its parents were analyzed by G-banding technique. Next generation sequencing (NGS) was used to detect genomic copy number variations (CNVs) in cell-free fetal DNA. The results were verified by fluorescence in situ hybridization (FISH). RESULTS: The fetus and its parents all had a normal karyotype at 320-400 band level. NGS revealed a deletion of 1.30 Mb at 7q11.23 in the fetus, with a 93% overlap with that of Williams-Beuren syndrome (WBS). The father also had a deletion of 1.42 Mb at 7q11.23, with a 99% overlap with that of WBS. Modified NIPT also detected the 1.30 Mb deletion at 7q11.23 in the fetus. The result of FISH has confirmed the above results. CONCLUSION: It is necessary to carry out genetic testing on fetuses with VSD. NGS can detect fetal microdeletion syndromes and help to trace their parental origin. The modified NIPT for fetal chromosomal microdeletions/microduplication syndromes is highly accurate.


Assuntos
Síndrome de Williams , Variações do Número de Cópias de DNA , Feminino , Testes Genéticos , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Gravidez , Diagnóstico Pré-Natal
20.
Acta Neurol Belg ; 119(1): 5-14, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30430430

RESUMO

The tentorial middle region (TMR) includes the midline and paramedian tentorium. TMR dural arteriovenous fistulae (DAVFs) are complex. We performed a review of the literature on TMR DAVFs. TMR DAVFs are divided into the following four types: incisural DAVF, Galenic DAVF, straight sinus DAVF and torcular DAVF. TMR DAVFs often drain into pial veins; therefore, most TMR DAVFs are classified as Borden II-III and Cognard types IIb-IV, whose characteristics cause TMR DAVFs to be prone to hemorrhage. TMR DAVFs have a very disappointing natural progression, and treatment is necessary. TMR DAVFs have extensive arterial supply and complex venous drainages, making them difficult to treat. Currently, for TMR DAVF, endovascular treatment (EVT) has become a better option. In EVT, transarterial embolization is the first-line treatment. Many complications can occur when treating TMR DAVFs, but complete EVT can generally achieve good clinical outcomes. In this review, three educational cases with demonstrating figures are provided to elaborate TMR DAVFs.


Assuntos
Malformações Vasculares do Sistema Nervoso Central/terapia , Embolização Terapêutica/métodos , Procedimentos Endovasculares/métodos , Humanos
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