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1.
Nucleic Acids Res ; 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31511901

RESUMO

Predicting the functional or pathogenic regulatory variants in the human non-coding genome facilitates the interpretation of disease causation. While numerous prediction methods are available, their performance is inconsistent or restricted to specific tasks, which raises the demand of developing comprehensive integration for those methods. Here, we compile whole genome base-wise aggregations, regBase, that incorporate largest prediction scores. Building on different assumptions of causality, we train three composite models to score functional, pathogenic and cancer driver non-coding regulatory variants respectively. We demonstrate the superior and stable performance of our models using independent benchmarks and show great success to fine-map causal regulatory variants on specific locus or at base-wise resolution. We believe that regBase database together with three composite models will be useful in different areas of human genetic studies, such as annotation-based casual variant fine-mapping, pathogenic variant discovery as well as cancer driver mutation identification. regBase is freely available at https://github.com/mulinlab/regBase.

2.
Br J Ophthalmol ; 103(11): 1553-1560, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31481392

RESUMO

PURPOSE: To establish and validate a universal artificial intelligence (AI) platform for collaborative management of cataracts involving multilevel clinical scenarios and explored an AI-based medical referral pattern to improve collaborative efficiency and resource coverage. METHODS: The training and validation datasets were derived from the Chinese Medical Alliance for Artificial Intelligence, covering multilevel healthcare facilities and capture modes. The datasets were labelled using a three-step strategy: (1) capture mode recognition; (2) cataract diagnosis as a normal lens, cataract or a postoperative eye and (3) detection of referable cataracts with respect to aetiology and severity. Moreover, we integrated the cataract AI agent with a real-world multilevel referral pattern involving self-monitoring at home, primary healthcare and specialised hospital services. RESULTS: The universal AI platform and multilevel collaborative pattern showed robust diagnostic performance in three-step tasks: (1) capture mode recognition (area under the curve (AUC) 99.28%-99.71%), (2) cataract diagnosis (normal lens, cataract or postoperative eye with AUCs of 99.82%, 99.96% and 99.93% for mydriatic-slit lamp mode and AUCs >99% for other capture modes) and (3) detection of referable cataracts (AUCs >91% in all tests). In the real-world tertiary referral pattern, the agent suggested 30.3% of people be 'referred', substantially increasing the ophthalmologist-to-population service ratio by 10.2-fold compared with the traditional pattern. CONCLUSIONS: The universal AI platform and multilevel collaborative pattern showed robust diagnostic performance and effective service for cataracts. The context of our AI-based medical referral pattern will be extended to other common disease conditions and resource-intensive situations.

3.
Aging (Albany NY) ; 11(16): 6069-6088, 2019 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-31444970

RESUMO

Family with sequence similarity 83, member A (FAM83A), as a potential tumor promoter, was reported to contribute to the progression of several malignant tumors. However, the significance of FAM83A in invasion and metastasis of non-small cell lung cancer (NSCLC) remains largely unknown. In this study, we found that FAM83A expression was significantly increased in NSCLC tissues. High expression of FAM83A was positively associated with tumor metastasis and poor survival of NSCLC patients. Functional experiments revealed that FAM83A knockdown could suppress NSCLC cell migration and invasion both in vivo and in vitro. While opposite results were observed in FAM83A-transfected cells. Mechanically, we found that FAM83A promoted NSCLC cell migration and invasion by inducing epithelial-mesenchymal transition (EMT) via PI3K/ATK/Snail signaling. Rescue experiment demonstrated that inhibition of either AKT or Snail could partially counteract the promoting effect of FAM83A overexpression in NSCLC metastasis. Taken together, our findings are the first time to demonstrate that increased expression of FAM83A in NSCLC was correlated with EMT and tumor metastasis, which may provide a novel therapeutic target in NSCLC treatment.

4.
Lancet Respir Med ; 7(10): 881-891, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31326317

RESUMO

BACKGROUND: Genetic variation has an important role in the development of non-small-cell lung cancer (NSCLC). However, genetic factors for lung cancer have not been fully identified, especially in Chinese populations, which limits the use of existing polygenic risk scores (PRS) to identify subpopulations at high risk of lung cancer for prevention. We therefore aimed to identify novel loci associated with NSCLC risk, and generate a PRS and evaluate its utility and effectiveness in the prediction of lung cancer risk in Chinese populations. METHODS: To systematically identify genetic variants for NSCLC risk, we newly genotyped 19 546 samples from Chinese NSCLC cases and controls from the Nanjing Medical University Global Screening Array Project and did a meta-analysis of genome-wide association studies (GWASs) of 27 120 individuals with NSCLC and 27 355 without NSCLC (13 327 cases and 13 328 controls of Chinese descent as well as 13 793 cases and 14 027 controls of European descent). We then built a PRS for Chinese populations from all reported single-nucleotide polymorphisms that have been reported to be associated with lung cancer risk at genome-wide significance level. We evaluated the utility and effectiveness of the generated PRS in predicting subpopulations at high-risk of lung cancer in an independent prospective cohort of 95 408 individuals from the China Kadoorie Biobank (CKB) with more than 10 years' follow-up. FINDINGS: We identified 19 susceptibility loci to be significantly associated with NSCLC risk at p≤5·0 × 10-8, including six novel loci. When applied to the CKB cohort, the PRS of the risk loci successfully predicted lung cancer incident cases in a dose-response manner in participants at a high genetic risk (top 10%) than those at a low genetic risk (bottom 10%; adjusted hazard ratio 1·96, 95% CI 1·53-2·51; ptrend=2·02 × 10-9). Specially, we observed consistently separated curves of lung cancer events in individuals at low, intermediate, and high genetic risk, respectively, and PRS was an independent effective risk stratification indicator beyond age and smoking pack-years. INTERPRETATION: We have shown for the first time that GWAS-derived PRS can be effectively used in discriminating subpopulations at high risk of lung cancer, who might benefit from a practically feasible PRS-based lung cancer screening programme for precision prevention in Chinese populations. FUNDING: National Natural Science Foundation of China, the Priority Academic Program for the Development of Jiangsu Higher Education Institutions, National Key R&D Program of China, Science Foundation for Distinguished Young Scholars of Jiangsu, and China's Thousand Talents Program.

5.
Crit Rev Anal Chem ; : 1-21, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31352789

RESUMO

Silica nanochannel membranes, particularly those consisting of highly ordered and vertically aligned channels (designated as SNM for simplicity in this review), have recently emerged as a class of attractive nanomaterials, because of their controllable and tunable pore structure, large surface area, high selectivity, and permeability, as well as diverse promising applications. This review describes recent developments in the field of SNM and their applications in electrochemical analysis and molecular separation. We summarize and highlight (i) the synthesis and functionalization strategies; (ii) the basic properties with emphasis on the selectivity and permeability, and factors affecting them; (iii) electrochemical analysis based on the electrode-supported SNM in terms of electrostatic, hydrophobic extraction, size-exclusion, and anti-fouling effects; (iv) molecular separation using the flow-through SNM according to molecular properties (size, charge, and lipophilicity) and gated, rectified molecular transport. Finally, we present an outlook and perspective on the further applications of SNM in the relevant fields.

6.
Appl Opt ; 58(15): 4091-4098, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31158160

RESUMO

We demonstrate an optical beam steering setup based on a liquid crystal-optical phased array (LC-OPA) with high angular resolution and low beam divergence, due to the use of double-grating configuration to enhance the corresponding angular resolution of LC-OPA. The introduction of two nonparallel blazed gratings with a special included angle can achieve multiple diffractions for the incident light, leading to the realization of angular compression. Numerical simulation results show the angular compression ratio can be optimized by selecting the appropriate grating constant and the included angle of double-grating. Experimental results verify that the steered angle of the incident light can be compressed so that the angular resolution of the steered beam can correspondingly be improved more than six times. In addition, when the beam is multiply diffracted within the double-grating configuration, the divergence angle becomes smaller as the beam size is enlarged. Therefore, both the microradian steering resolution and the narrow beam divergence can be simultaneously obtained with our proposed setup. The efficiency of the steering where the beam diffracted four times within the double-grating configuration is 80%.

7.
Adv Mater ; 31(32): e1901115, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31199019

RESUMO

Realizing new functions through the construction of ordered structures not only exists naturally in nature, but also in artificial materials. However, much research focuses more on the relationship between structure and performance rather than on the impact of functional units themselves. Reviewing previous research findings, a "paradigm" of material research is proposed, which is based on ordered structures with functional units (OSFU) such as compositions, phases, domains, and twins. The goal is to draw more intensive attention of researchers to this concept and thus to promote the development of this field toward a deeper and broader direction, producing highly influential research results.

8.
J Am Chem Soc ; 141(21): 8608-8615, 2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31067855

RESUMO

Thermosensation, the ability to detect environmental temperature change, is one of most ancient and crucial processes for the survival of all living organisms. Mammals use temperature-sensitive transient receptor potential (thermoTRP) cation channels as thermometers to convert the temperature change into electrical signals that are finally received as action potentials by nerve endings. In this work, we report the bionic thermosensation by solid-state hybrid nanochannels based on the principle of thermally sensitive permselective ion transport. The hybrid nanochannels possess an asymmetric structure, consisting of ultrasmall silica nanochannels (∼2.3 nm in diameter, ∼100 nm in length) supported by large-sized track-etched poly(ethylene terephthalate) conical nanochannels. When the hybrid nanochannels are engineered to separate two electrolyte solutions, the temperature change in one solution can be directly converted into trans-nanochannel diffusion potential, akin to the natural thermosensation process. Two bionic modes, namely, in the absence and presence of a concentration gradient, were studied to imitate the natural thermosensation of thermoTRP ion channels and shark, respectively. In both cases, real-time thermoelectric response was captured with a fast relative response speed (electrical response time versus temperature change time) of higher than 98%, as well as excellent stability and reversibility. Moreover, the nanochannels are highly sensitive to thermal stimulus, showing a sensitivity of 0.71 mV/K comparable to the natural thermosensation. The experimental results coincide well with the theoretical relationship between electrical response and temperature change derived in terms of a quasi-steady-state ion transport model. Finite element simulations based on coupled Poisson-Nernst-Planck (PNP) and Einstein-Stokes equations were also performed, confirming that the sensitive thermoelectric response originates from the highly cationic selectivity of nanochannels.

10.
Carcinogenesis ; 40(10): 1209-1219, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31083717

RESUMO

To date, the 5-year overall survival of epithelial ovarian cancer (EOC) remains poor. Because studies suggest that RUVBL1 may be a chemotherapeutic target for the treatment of cancer, in this study, therefore, we investigated the role of potentially functional single nucleotide polymorphisms (SNPs) of RUVBL1 in the survival of Chinese patients with EOC, and we subsequently performed functional prediction and validation of the identified significant SNPs. We found that RUVBL1 rs1057156 A>G and RUVBL1 rs149652370 A>G were associated with survival of EOC patients in the multivariate Cox proportional hazards regression analysis. Specifically, the RUVBL1 rs149652370 AG genotype was associated with a shorter progression-free survival ([adjusted hazards ratio (HR)] = 3.32, 95% confidence interval (CI) = 1.76-6.25 and P = 2.01E-04), compared with the AA genotype. The RUVBL1 rs1057156 AG (only nine had GG) genotype was also associated with a poor overall survival (adjusted HR = 1.73, 95% CI = 1.19-2.52, P = 0.004), compared with the AA genotype. Further experiments showed that the RUVBL1 rs1057156 A>G change lowered its binding affinity to microRNA-4294 and led to upregulation of the RUVBL1 expression. We further found that overexpression of RUVBL1 promoted cell proliferation and metastatic potential. Overall, RUVBL1 enhanced EOC cell proliferation, invasion and migration presumably by stimulating the process of glycolysis. Thus, this study provides evidence that functional variants of RUVBL1 may regulate its gene expression, a possible mechanism affecting survival of EOC patients and that RUVBL1 may be a potential chemotherapeutic target for the treatment of EOC patients.

11.
Cancer Med ; 8(8): 4012-4022, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31145551

RESUMO

Age at menarche (AAM) was found to be associated with ovarian cancer risk in previous observational studies. However, the causality of this association remains unclear. Here, after systematic meta-analyses, we performed two-sample Mendelian randomization (MR) analyses to evaluate the causal effect of AAM in epithelial ovarian cancer (EOC) etiology. We performed meta-analyses including 11 410 cases and 1 163 117 noncases to quantitatively evaluate the association between AAM and ovarian cancer risk. In MR analyses, we used 25 single nucleotide polymorphisms (SNPs) associated with AAM for Chinese and 390 SNPs for Europeans as instrumental variables. MR estimates were calculated using inverse-variance weighted methods from 1044 cases and 1172 controls in a Chinese genome-wide association study and validated by the Ovarian Cancer Association Consortium and Consortium of Investigators of Modifiers of BRCA1/2 studies with 29 396 cases and 68 502 controls of European ancestry. In meta-analyses, we observed an inverse association (odds ratio [OR] = 0.96, 95% confidence interval [CI] = 0.93 to 1.00, P = 0.036) between per year older AAM and ovarian cancer risk in case-control studies, but no association was observed in cohort studies. In MR analyses, the OR of EOC risk per year increase in AAM was 0.81 (95% CI = 0.67 to 0.97, P = 0.026) in Chinese and 0.94 (95% CI = 0.90 to 0.98, P = 0.003) in Europeans, respectively. Our study supports a causal association between AAM and EOC risk.

12.
13.
Gynecol Oncol ; 153(2): 343-355, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30898391

RESUMO

OBJECTIVE: Genome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women. METHODS: Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations. RESULTS: At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10-9) and high-grade serous EOC (HGSOC) (OR = 1.34, P = 4.3 × 10-9). SNP rs6902488 at 6p25.2 (r2 = 0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP <10%). At chromosome 20q11.22, rs74272064 was associated with HGSOC risk (OR = 1.27, P = 9.0 × 10-8). Overall EOC risk was associated with rs10260419 at chromosome 7p21.3 (OR = 1.33, P = 1.2 × 10-7) and rs74917072 at chromosome 2q37.3 (OR = 1.25, P = 4.7 × 10-7). At 2q37.3, expression quantitative trait locus analysis in 404 HGSOC tissues identified ESPNL as a putative candidate susceptibility gene (P = 1.2 × 10-7). CONCLUSION: While some risk loci were shared between East Asian and European populations, others were population-specific, indicating that the landscape of EOC risk in Asian women has both shared and unique features compared to women of European ancestry.


Assuntos
Carcinoma Epitelial do Ovário/genética , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
15.
Exp Mol Med ; 51(3): 24, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30816108

RESUMO

Apatinib (YN968D1) is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR-2). We conducted a single-arm, nonrandomized phase II study (NCT03121846) to assess the efficacy and safety of apatinib in patients with stage IV sarcoma. We recruited 64 patients with stage IV sarcoma who had failed chemotherapy. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were progression-free survival rate (PFR), objective response rate (ORR), and disease control rate (DCR) at week 12. Treatment-related adverse effects (AEs) were evaluated. Fifty-nine patients were assessed for efficacy and 64 patients for AEs. The median PFS was 7.93 months. At 12 weeks, the PFR was 74%, the ORR was 16.95% (10/59), and the DCR was 86.44% (51/59). The final ORR was 15.25% (9/59) and the DCR was 57.63% (34/59). Notably, 22 patients (34.38%) who developed hypertension, hand-foot-skin reaction, or proteinuria had significantly longer OS than those without these AEs (18.20 vs. 10.73 months; P = 0.002). We conclude that apatinib is effective and well tolerated in patients with advanced sarcoma. The development of hypertension, hand-foot-skin reaction, or proteinuria may indicate a favorable prognosis, representing a novel finding in sarcoma patients.

16.
World Neurosurg ; 127: 1-7, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30844524

RESUMO

BACKGROUND: Congenital microcephaly could result from a gene mutation. Asparagine synthetase deficiency, which is caused by the asparagine synthetase (ASNS) mutation, is a rare autosomal-recessive neurometabolic disorder. It is characterized by severe developmental delay, congenital microcephaly, and seizures. CASE DESCRIPTION: Here we present the first report on a progressive intracerebral cyst associated with ASNS mutation, which caused neurodevelopmental dysplasia. ASNS mutation was confirmed by whole-exome sequencing and is the most likely reason for the neurodevelopmental dysplasia, which results in microcephaly, refractory seizures, and congenital visual impairment. Antiepileptic drugs have limited therapeutic effect on these epileptic seizures. CONCLUSIONS: Although there is no cure for this disorder so far, the huge progressive intracerebral cyst can be cured by a cyst-peritoneal shunt.

17.
Cancer Med ; 8(4): 1882-1892, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30761775

RESUMO

Epidemiological studies have a clear definition of the risk factors for breast cancer. However, it is unknown whether the distribution of these factors differs among breast cancer subtypes. We conducted a hospital-based case-only study consisting of 8067 breast cancer patients basing on the Tianjin Cohort of Breast Cancer Cases. Major breast cancer subtypes including luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched and basal-like were defined by estrogen receptor, progesterone receptor, HER2, and Ki-67 status. Variables including demographic characteristics, reproductive factors, lifestyle habits, imaging examination, and clinicopathologic data were collected for patients. Chi-square test and one-way analysis of variance were used to compare the distributions of variables among the four breast cancer subtypes. Multivariate logistic regression was used to estimate the odds ratios and associated 95% confidence intervals where luminal A patients served as the reference group. Overall, more commonality rather than heterogeneity on the distributions of factors was found between the four molecular subtypes of breast cancer. The proportion of overweight and obesity were lower in HER2-enriched subtype. Women with age at menarche ≤13 years were more likely to be found in basal-like subtype. Postmenopausal women were more frequent in HER2-enriched and basal-like subtypes. Women with benign breast disease and higher breast density were more common in HER2-enriched subtype. Risk factor scoring showed that total risk scores were similar among the four subtypes. HER2-enriched and basal-like subtypes were more frequently diagnosed with large tumors. Calcification was more likely to be found in luminal B and HER2-enriched subtypes, whereas less distributed in basal-like subtype. Most of the breast cancer risk factors were similarly distributed among the four major breast cancer subtypes; commonality is predominant.

18.
Chemosphere ; 220: 723-730, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30611070

RESUMO

Highly active and visible light-driven Ag-loaded CdS photocatalysts were prepared via a hydrothermal synthesis and photodeposition method. The removal and debromination of 2,2',4,4'-tetrabromodiphenyl ether was achieved efficiently using this Ag-loaded CdS under visible light, with a removal efficiency of 100% and a debromination ratio of 44.3% being achieved within 30 min. Both the reaction solvent and the water content were found to have a strong influence on the removal efficiency and the debromination ratio. In addition, the stepwise debromination preference was ortho ≫ para, thereby indicating that the main debromination pathway was electron reduction. The stability and efficiency of these Ag-loaded CdS photocatalysts for the removal of BDE47 were satisfactory, and so our results confirmed the development of a promising visible light-driven catalyst for the removal of polybrominated diphenyl ethers.


Assuntos
Compostos de Cádmio/química , Éteres Difenil Halogenados/efeitos da radiação , Luz , Prata/química , Sulfetos/química , Catálise , Halogenação , Solventes
19.
Cancer Res ; 79(3): 505-517, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30559148

RESUMO

DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.

20.
Anal Chem ; 91(2): 1227-1231, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30569707

RESUMO

Ionic current rectification (ICR) is one of interesting characteristics displayed by nanochannels with asymmetric geometry, ionic concentration or charge distribution, which has been utilized for the development of chemical sensors and biosensors. Herein we report the ICR phenomenon observed with ultrathin silica isoporous membrane (SIM), which was prepared by laminating two layers of SIM with opposite charges and different pore diameters, designated as bipolar SIM (bp-SIM). The negatively charged layer, called as n-SIM, was 86 nm-thick and consisted of channels with a diameter of 2-3 nm. The positively charged layer with a thickness of 59 nm, termed as p-SIM, was comprised of channels of 4.5-5.5 nm in diameter. They were primarily grown on the solid surface using the Stöber-solution and biphasic-stratification growth approaches, respectively, and then exfoliated to obtain perforated structures by the polymer-protected chemical etching and transfer method. The negative charges of n-SIM and positive ones of p-SIM were generated by the deprotonation of pristine surface silanol and postmodified ammonium groups, respectively. Neither n-SIM nor p-SIM alone displays the ICR characteristic, because of their symmetric structure and uniform charge distribution. When laminating two of them, an apparent ICR characteristic was observed for the bp-SIM with a typical diode-like current-voltage response. This behavior was rationalized to arise from the asymmetric charge distribution on two layers by finite element simulations. Considering the facile preparation and diverse surface functionalities, as well as its uniform and highly porous structure, the bp-SIM provides an attractive platform for designing ICR-based sensors.

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