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1.
Biol Pharm Bull ; 42(11): 1789-1798, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31685763

RESUMO

Autophagy plays key roles in the development of acute pancreatitis (AP) and the regulation of impaired autophagy has therapeutic potential. The objective of the present study was to investigate whether pharmacological inhibition of autophagy could ameliorate AP in mice and examine the underlying mechanisms. In current study, by imaging-based high-throughput screening, a novel spautin-1 derivative spautin-A41 was identified as a potent autophagy inhibitor. Mice treated with spautin-A41 were resistant to the cerulein-induced elevation of serum pancreatic enzyme activities and pancreatic apoptosis. Mechanistically, spautin-A41 effectively reduced the expression levels of Class III phosphatidylinositol 3 (PI3) kinase complexes and subsequently ameliorated pancreatitis by inhibiting the formation of autophagosome. Therefore, pharmacological inhibition of autophagy by spautin-A41 may serve as new target for treating or lessening the severity of AP.

3.
Int J Radiat Biol ; : 1-9, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31692404

RESUMO

Purpose: Heavy-ion beams and γ-rays are popular physical mutagenesis to generate mutations in higher plants. It has been found that they show different mutation frequencies and spectrums of phenotype induction, however, the characteristics of heavy-ion beams on genetic polymorphism have not been clarified by comparing with γ-rays.Materials and methods: In the present study, seeds of Arabidopsis thaliana were exposed to carbon-ion beams (with linear energy transfer (LET) of 50 keV/µm) and γ-rays (with average LET of 0.2 keV/µm) irradiation. By using inter-simple sequence repeat (ISSR) and random amplified polymorphic DNA (RAPD) analysis, the genetic polymorphism of both M1 and M3 plants were investigated, respectively.Results: Carbon-ion beams induced relatively higher polymorphism rate in both M1 and M3 generation than γ-rays: the polymorphism rates of M1 plants derived from carbon-ion beams irradiation are 12.87% (ISSR-C) and 9.01% (RAPD-C), while are 7.67% (ISSR-γ) and 1.45% (RAPD-γ) of plants derived from γ-rays. In M3 generation, the polymorphism rates of ISSR-C, RAPD-C, ISSR-γ, and RAPD-γ are 17.64%, 22.79%, 12.10%, and 2.82%, respectively.Conclusions: In summary, the exposure to carbon-ion beams and γ-rays lead to the change of genomic DNA of A. thaliana, which could be tested in M1 plants and M3 plants by ISSR and RAPD technology. So, both carbon-ion beams and γ-rays can induce variations of genetic polymorphisms in M1 plants and M3 plants. The genetic polymorphisms of M1 plants and M3 plants induced by carbon-ion beams are higher than γ-rays, indicating that heavy-ion beams irradiations mutation breeding is more advantageous than conventional ionizing radiations. Average molecular polymorphism of M1 plants is lower than M3 mutants, by nearly 4.77% (ISSR-C), 13.78% (RAPD-C), 4.43% (ISSR-γ), and 1.37% (RAPD-γ). We hope our study will provide basic information for understanding the effects of carbon-ion beams and γ-rays for plant mutation breeding.

4.
Opt Lett ; 44(20): 5081-5084, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31613269

RESUMO

We propose and experimentally demonstrate an apodized bidirectional grating coupler for high-efficiency, perfectly vertical coupling. Through grating apodization, the coupling efficiency (CE) can be notably improved, and the parasitic reflections can be minimized. For ease of fabrication, subwavelength gratings are introduced, which are also beneficial for the coupling performance. Simulation shows a record CE of 72%. We found that the coupler is quite robust to the variation of incidence mode field diameter and fiber misalignment. A CE of -1.8 dB is experimentally measured with a 1-dB bandwidth of 37 nm.

5.
PLoS One ; 14(10): e0223763, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618238

RESUMO

We aimed to investigate the effects of genome, age, and soil factors on cultivated Panax ginseng C. A. Meyer (CPG) compounds under identical climate and agronomic practices. Eight populations of CPG from different years and rhizosphere soils were collected from garden and cropland in the city of Ji'an, China. Inter-simple sequence repeat (ISSR) primers were used to detect genetic diversity and identity, and soil microbial community diversity. Soil enzyme activities and nutrients were also measured. The contents of total ginsenosides (TG), Rg1, Re, Rf, Rd, and ginsenoside extractions of CPG were analyzed by spectrophotometry and HPLC. The relative importance of each factor was analyzed by mathematical methods such as correlation analysis, stepwise line regression, and path analysis. Regression equations of similarity values of HPLC fingerprint (SVHF), richness index of HPLC fingerprint (RIHF) and the TG, Rg1, Re, Rf, and Rd contents with their respective significant correlation factors were obtained. For SVHF, the relative importance is age>microbial community diversity>genetic diversity. For RIHF, the relative importance is age>genetic diversity>microbial community diversity. For TG, Rg1, and Rf contents, the relative importance is age>microbial community diversity. Ginseng age and genetic identity influenced Rd content, and age was more important. Total phosphorus was the only directly negative effect on Re. According to regression equations and path analysis, increasing age and decreasing Shannon (H') could improve the TG, Rg1, and Rf contents, with little effect on SVHF. Adding age, genetic diversity, and decreasing Shannon (H') increased RIHF. Adding age and genetic identity could also improve Rd content. Appropriate decreases in total phosphorus might increase Re content. These findings are significant for CPG scientific cultivation methods, through which CPG bioactive ingredients could be finely controlled via regulation of genotypes and cultural conditions.

6.
Am J Pharm Educ ; 83(7): 6925, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31619817

RESUMO

Objective. To compare the mean national enrollment rates of underrepresented minority (URM) students in a pharmacy school with mean rates in California pharmacy schools, and identify barriers faced by URM students during the application process. Methods. The American Association of Colleges of Pharmacy (AACP) enrollment data from 2005 to 2014 were used to compare the demographics of California pharmacy schools with the average enrollment of URM students in pharmacy schools nationally. A survey was administered to students in the 2017 and 2018 classes at Touro University California College of Pharmacy to identify common barriers that students faced in pursuing pharmacy education. Results. The average enrollment of URM in pharmacy programs nationally was 12.3% in 2005, compared to 12.4% in 2014. The average enrollment of URM in California pharmacy schools was 9.4% in 2005 compared to 8.5% in 2014. The top barriers to pursuing pharmacy education that students reported included the cost of tuition (43.4%), prerequisite requirements (36.9%), and obtaining letters of recommendation (32.3%). Conclusion. The average enrollment of URM students in pharmacy schools nationally has remained higher than that in California pharmacy schools across the years studied. California pharmacy programs should develop strategies to alleviate the barriers identified and further diversify pharmacy education.

7.
Pathol Res Pract ; 215(12): 152650, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31585811

RESUMO

BACKGROUND: (Interleukin 17 Receptor Beta) IL17RB has been implicated in several malignancies. However, its role in the progression of and chemosensitivity in pancreatic cancer remains unknown. We aimed to determine the clinical significance of IL17RB expression in the prognosis of resectable pancreatic cancer and in the benefits from gemcitabine treatment. MATERIALS AND METHODS: We used microarray and immunohistochemical staining techniques to evaluate IL17RB expression in 91 resectable pancreatic cancer tissues and their respective matched adjacent non-cancerous tissues. Quantitative real-time PCR and Western blotting were used to evaluate IL17RB in human pancreatic cancer cell lines after gemcitabine treatment. The correlation between IL17RB expression and overall survival and disease-free survival times were analyzed. RESULTS: IL17RB expression correlated with lymph node metastasis and (Vascular endothelial growth factor) VEGF expression. Cox proportional model showed that high IL17RB expression is a significant negative prognostic factor for both (overall survival) OS and (disease-free survival) DFS. Kaplan-Meier survival curves confirmed significantly reduced median overall and DFS time in high IL17RB patients as compared with low IL17RB patients. Furthermore, Cox proportional model confirmed a correlation between adjuvant treatment with gemcitabine-based chemotherapy and IL17RB expression. Kaplan-Meier survival curves showed that low IL17RB expression was associated with longer OS and DFS in patients than high IL17RB expression and gemcitabine-based adjuvant chemotherapy. In human pancreatic cancer cell lines, the messenger RNA and protein levels of IL17RB were significantly enhanced after gemcitabine treatment. CONCLUSIONS: IL17RB predicts the prognosis and benefit from gemcitabine in patients with resectable pancreatic cancer.

9.
Medicine (Baltimore) ; 98(41): e17468, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593107

RESUMO

INTRODUCTION: Microtia is a congenital malformation of the external and middle ear caused by the abnormal development of the first and second zygomatic arch and the first sulcus. There is currently no consensus concerning the pathogenesis and etiology of microtia; genetic and environmental factors may play a role. Gene-based studies have focused on finding the genes that cause microtia and on gene function defects. However, no clear pathogenic genes have so far been identified. Microtia is multifactorial; gene function defects cannot completely explain its pathogenesis. In recent years, the epigenetic aspects of microtia have begun to receive attention. CONCLUSIONS: Analysis of the existing data suggests that certain key genes and pathways may be the underlying cause of congenital microtia. However, further exploration is needed.


Assuntos
Microtia Congênita/genética , Epigênese Genética/genética , Epigenômica , Humanos
10.
Int J Mol Med ; 44(6): 2201-2212, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31638173

RESUMO

The aim of the present study was to investigate the role of microRNA­21 (miR­21) in regulating the classical WNT/ß­catenin signaling pathway by targeting low­density lipoprotein­related receptor 6 (LRP6) in non­alcoholic fatty liver disease (NAFLD). For this purpose, we established a NAFLD model by feeding C57BL/6J mice a methionine­choline­â€‹deficient diet. Antagomir­21 was then injected via the tail vein, and the expression levels of WNT/ß­catenin signaling pathway­related proteins, such as LRP6, glycogen synthase kinase­3ß (GSK3ß), p­ß­catenin, ß­catenin and the downstream protein, peroxisome proliferator­activated receptor Î³ (PPAR­Î³), and lipid metabolism­related genes, including sterol regulatory element­binding transcription factor 1c (SREBP1c), fatty acid synthase (FAS), carnitine palmitoyl transferase 1α (CPT1α) and adenosine 5­monophosphate (AMP)­activated protein kinase α (AMPKα), were detected. The results revealed that in the NAFLD model, LRP6 expression was negatively associated with miR­21 expression. After antagonizing the expression of miR­21, the protein level of LRP6 was increased. In addition, the WNT/ß­catenin signaling pathway was activated, and lipid accumulation and inflammation were alleviated in the liver. However, the expression of PPAR­Î³ was not inhibited following the upregulation of the WNT signaling pathway. Taken together, the results of this study demonstrate that the inhibition of miR­21 expression can alleviate NAFLD by targeting LRP6 to activate the WNT/ß­catenin signaling pathway.

11.
Cell Cycle ; 18(20): 2800-2813, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31478454

RESUMO

Myotubularin related protein 7 (MTMR7), a key member of the MTMR family, depicts phosphatase activity and is involved in myogenesis and tumor growth. We have previously identified MTMR7 in the proteomic profile of mouse spermatogonial stem cell (SSC) maturation and differentiation, implying that MTMR7 is associated with neonatal testicular development. In this study, to further explore the distribution and function of MTMR7 in mouse testis, we studied the effect of Mtmr7 knockdown on neonatal testicular development by testicular and SSC culture methods. Our results revealed that MTMR7 is exclusively located in early germ cells. Deficiency of MTMR7 by morpholino in neonatal testis caused excessive SSC proliferation, which was attributable to the aberrant PI3K/AKT signaling activation. Altogether, our study demonstrates that MTMR7 maintains SSC homeostasis by inhibiting PI3K/AKT signaling activation.

12.
Nat Commun ; 10(1): 4161, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31551422

RESUMO

Development of treatments for vocal dysphonia has been inhibited by lack of human vocal fold (VF) mucosa models because of difficulty in procuring VF epithelial cells, epithelial cells' limited proliferative capacity and absence of cell lines. Here we report development of engineered VF mucosae from hiPSC, transfected via TALEN constructs for green fluorescent protein, that mimic development of VF epithelial cells in utero. Modulation of FGF signaling achieves stratified squamous epithelium from definitive and anterior foregut derived cultures. Robust culturing of these cells on collagen-fibroblast constructs produces three-dimensional models comparable to in vivo VF mucosa. Furthermore, we demonstrate mucosal inflammation upon exposure of these constructs to 5% cigarette smoke extract. Upregulation of pro-inflammatory genes in epithelium and fibroblasts leads to aberrant VF mucosa remodeling. Collectively, our results demonstrate that hiPSC-derived VF mucosa is a versatile tool for future investigation of genetic and molecular mechanisms underlying epithelium-fibroblasts interactions in health and disease.

13.
Aging (Albany NY) ; 11(17): 7070-7082, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492826

RESUMO

Stable cartilage regeneration has always been a challenge in both tissue engineering research and clinical practice. This study explored the feasibility of using a chondrocyte sheet technique stimulated by microRNAs to regenerate cartilage. We tested the involvement of hsa-miR-193b-3p in the microtia patient remnant auricular chondrocyte extracellular matrix (ECM). We observed in vitro chondrocyte proliferation, ECM synthesis, as well as the increase in the expression of type II collagen (COL2A1) and decrease in the expression of matrix metalloproteinase 16 (MMP16) of the chondrocyte sheets. COL2A1 deposition and MMP16 degradation of regenerative cartilage tissue were examined in vivo. A dual-luciferase reporter showed that the MMP16 gene was the direct target of miR-193b-3p. These results suggested that miR-193b-3p promotes chondrocyte sheet ECM synthesis by inhibiting MMP16. Since the evidence suggests that MMP16 is a critical regulator of chondrocyte ECM, this finding points the way towards a method that both strengthens the ECM and inhibits MMPs.

14.
Pestic Biochem Physiol ; 160: 127-135, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31519247

RESUMO

Environmental xenobiotics can influence the tolerance of insects to chemical insecticides. Heavy metals are widespread distributed, can be easily bio-accumulated in plants and subsequently within phytophagous insects via the food chains. However, less attention has been paid to the effect of heavy metal exposure on their insecticide tolerance. In this study, pre-exposure of copper (Cu, 25-100 mg kg-1) significantly enhanced the subsequent tolerance of Spodoptera litura to ß-cypermethrin, a widely used pyrethroid insecticide in crop field. Cytochrome P450 monooxygenases (CYPs) activities were cross-induced in larvae exposed to Cu and ß-cypermethrin, while the activities of glutathione S-transferase (GST) and carboxylesterase (CarE) were not affected. Application of piperonyl butoxide (PBO), a P450 synergist, effectively impaired the tolerance to ß-cypermethrin in Cu-exposed S. litura larvae with a synergistic ratio of 1.72, indicating that P450s contribute to larval tolerance to ß-cypermethrin induced by Cu exposure. Among the four CYP6AB family genes examined, only larval midgut-specific CYP6AB12 was found to be cross-induced by Cu and ß-cypermethrin. RNA interference (RNAi)-mediated silencing of CYP6AB12 effectively decreased the mRNA levels of the target gene, and significantly reduced the larval tolerance to ß-cypermethrin following exposure to Cu. These results showed that pre-exposure of heavy metal Cu enhanced larval tolerance to ß-cypermethrin in S. litura, possibly through the cross-induction of P450s. Our findings provide new insights on the relationship between heavy metals and chemical insecticides that may benefit both the risk evaluation of heavy metal contamination and development of pest management strategies.

15.
Mater Sci Eng C Mater Biol Appl ; 104: 109880, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31500020

RESUMO

The direct electron transfer and enzyme catalytic activity were investigated in electrochemical biosensor based on glucose oxidase (GOx) and electrochemical reduced graphene oxide-poly-(l-lysine) (ERGO-PLL) hybrid composite film embedded in a biocompatible matrix of Nafion. The ERGO-PLL was fabricated onto glassy carbon electrode (GCE) through one step electrodeposition of RGO incorporating PLL from graphene oxide-l-lysine aqueous dispersion. The fabrication process of Nafion/GOx/ERGO-PLL/GCE has been characterized by cyclic voltammetry and electrochemical impedance spectroscopy, and the surface morphology of modified electrodes were characterized by scanning electron microscopy. A pair of well-defined redox peaks with formal potential and peak separation of -0.461 V and 30 mV were observed at scan rate of 50 mV s-1, the electron transfer rate constant was calculated to be 18.7 s-1, demonstrated that direct electron transfer between immobilized GOx with ERGO-PLL and GCE was achieved. Moreover, the fabricated enzyme biosensor exhibited excellent electrocatalytic activity for determination of glucose in O2-free PBS (7.40) with linear voltammetric response from 0.005 to 9.0 mmol L-1, and detection limits (S/N = 3) of 2.0 µmol L-1. This work indicates that ERGO-PLL based modified electrode is superior to that of graphene based, and could be applied in biosensors, bioelectronics and electrocatalysis, etc.

16.
J Nanobiotechnology ; 17(1): 95, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506085

RESUMO

BACKGROUND: It is extremely difficult to develop targeted treatments for triple-negative breast (TNB) cancer, because these cells do not express any of the key biomarkers usually exploited for this goal. RESULTS: In this work, we develop a solution in the form of a cascade responsive nanoplatform based on thermo-sensitive poly(N-vinylcaprolactam) (PNVCL)-chitosan (CS) nanoparticles (NPs). These are further modified with the cell penetrating peptide (CPP) and loaded with the chemotherapeutic drug doxorubicin (DOX). The base copolymer was optimized to undergo a phase change at the elevated temperatures of the tumor microenvironment. The acid-responsive properties of CS provide a second trigger for drug release, and the inclusion of CPP should ensure the formulations accumulate in cancerous tissue. The resultant CPP-CS-co-PNVCL NPs could self-assemble in aqueous media into spherical NPs of size < 200 nm and with low polydispersity. They are able to accommodate a high DOX loading (14.8% w/w). The NPs are found to be selectively taken up by cancerous cells both in vitro and in vivo, and result in less off-target cytotoxicity than treatment with DOX alone. In vivo experiments employing a TNB xenograft mouse model demonstrated a significant reduction in tumor volume and prolonging of life span, with no obvious systemic toxicity. CONCLUSIONS: The system developed in this work has the potential to provide new therapies for hard-to-treat cancers.

17.
Int J Biol Macromol ; 141: 1175-1182, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31473310

RESUMO

An edible hydroxypropyl starch (HPS) based bilayer film with a waterproof layer of zein was successfully prepared through a two-step solvent casting method. The morphology, mechanical properties, as well as water barrier properties of the bilayer film were systematically studied. Results showed that bilayer film presented smooth surface morphology with an improved visibility, and there was an adhesion interface between two layers. Water resistance and UV barrier property, as well as mechanical property, were significantly improved. In addition, the interactions between starch and zein through hydrogen bonding were analyzed by Fourier-transform infrared spectroscopy (FTIR) and molecular dynamics (MD) simulation. In MD simulation, the relative trajectories were dynamically presented. Conjunction of starch and zein through hydrogen bonding among the hydroxyl and amino (carboxyl) groups was identified, and stronger affinity with starch mainly rooted from asparagine (ASN) and tyrosine (TYR) residues.

18.
Carbohydr Polym ; 223: 115104, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31426957

RESUMO

Crude polysaccharides were obtained from fruits of Lycium ruthenicum Murr using hot water extraction followed by ethanol precipitation. A homogeneous polysaccharide, LRP3-S1 with a relative molecular weight of 114.8 kDa was purified by anion-exchange chromatography on DEAE Sepharose™Fast Flow and Sephacryl S-300 HR column. Monosaccharide composition analysis revealed that LRP3-S1 was composed of rhamnose, galacturonic acid, galactose, xylose and arabinose in a molar ratio of 14.4: 17.7: 26.6: 16.4: 24.9. LRP3-S1 contained a rhamnogalacturonan I (RG-I) backbone partially substituted at C-4 of rhamnose units by side chains, which included T-linked ß-D-Galp, 1,3-linked ß-D-Galp, 1,6-linked ß-D-Galp, 1,3,6-linked ß-D-Galp, 1,5-linked α-L-Araf, 1,3,5-linked α-L-Araf, T-linked α-L-Araf and T-linked ß-D-Xylp. Biological activity tests showed that LRP3-S1 could inhibit the growth of pancreatic cancer cells. In addition, LRP3-S1 could attenuate invasion ability of BxPC-3 cells and down-regulate protein expression of p-FAK, p-AKT, p-GSK-3ß and p-p38 MAP kinase.

19.
Carbohydr Polym ; 223: 115038, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31426978

RESUMO

To understand whether polysaccharides may have impact on gut microbiota, a neutral polysaccharide CDA-0.05 with an average molecular weight of 7.96 kDa was obtained from Cistanche deserticola Y. C. Ma. The monosaccharide composition analysis indicated that CDA-0.05 was composed of glucose and galactose in a molar ratio of 96.4: 3.6. The backbone of CDA-0.05 contained 1, 4-linked α-D-Glcp, 1, 4, 6-linked α-D-Glcp and 1, 4-linked ß-D-Galp, with branches of T-linked α-D-Glcp attached at C-6 of 1, 4, 6-linked α-D-Glcp residues. Bioactivity test results suggested that CDA-0.05 could promote the growth of three species of Bacteroides (B. thetaiotaomicron, B. ovatus and B. fragilis) significantly. Furthermore, CDA-0.05 could also promote some probiotics growth, such as Lactobacillus casei, Lactobacillus plantarum and Lactobacillus reuteri. These results suggested that CDA-0.05 might help to maintain intestinal homeostasis and could be recommended as part of fibers or drugs candidate to benefit human body by regulating gut bacteria.

20.
PLoS Biol ; 17(8): e3000420, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31433805

RESUMO

Dendritic cells (DCs) play pivotal roles in T-cell homeostasis and activation, and metabolic programing has been recently linked to DC development and function. However, the metabolic underpinnings corresponding to distinct DC functions remain largely unresolved. Here, we demonstrate a special metabolic-epigenetic coupling mechanism orchestrated by tuberous sclerosis complex subunit 1 (TSC1)-mechanistic target of rapamycin (mTOR) for homeostatic DC function. Specific ablation of Tsc1 in the DC compartment (Tsc1DC-KO) largely preserved DC development but led to pronounced reduction in naïve and memory-phenotype cluster of differentiation (CD)8+ T cells, a defect fully rescued by concomitant ablation of mTor or regulatory associated protein of MTOR, complex 1 (Rptor) in DCs. Moreover, Tsc1DC-KO mice were unable to launch efficient antigen-specific CD8+ T effector responses required for containing Listeria monocytogenes and B16 melanomas. Mechanistically, our data suggest that the steady-state DCs tend to tune down de novo fatty acid synthesis and divert acetyl-coenzyme A (acetyl-CoA) for histone acetylation, a process critically controlled by TSC1-mTOR. Correspondingly, TSC1 deficiency elevated acetyl-CoA carboxylase 1 (ACC1) expression and fatty acid synthesis, leading to impaired epigenetic imprinting on selective genes such as major histocompatibility complex (MHC)-I and interleukin (IL)-7. Remarkably, tempering ACC1 activity was able to divert cytosolic acetyl-CoA for histone acetylation and restore the gene expression program compromised by TSC1 deficiency. Taken together, our results uncover a crucial role for TSC1-mTOR in metabolic programing of the homeostatic DCs for T-cell homeostasis and implicate metabolic-coupled epigenetic imprinting as a paradigm for DC specification.

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