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1.
Gen Comp Endocrinol ; 315: 113939, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34710471

RESUMO

Aromatase, encoded by CYP19A1, is responsible for the conversion of androgen to estrogen, which plays a vital role in the development and function of the ovary and functions in many other physiological processes in both sexes. Instead of being expressed in ovarian granulosa cells, as in mammals, CYP19A1 is expressed in chickens in the theca cells of ovarian follicles, and the mechanism of CYP19A1 expression regulation remains unknown. Here, using immunofluorescence and western blotting assay, we first confirmed that CYP19A1 and FOXL2 (Forkheadbox L2) were coexpressed in pre-granulosa cells of female chicken embryonic gonads, while FOXL2 did not affect aromatase expression at embryonic stages. Second, our research showed that CYP19A1, ESR1 (estrogen receptor alpha), ESR2 (estrogen receptor beta) and NR5A2 (liver receptor homologue-1) were coexpressed in the theca cell layers of chicken small yellow follicles. There was cross-talk between CYP19A1 and candidate transcription factors (ESR1, ESR2 and NR5A2), which was identified by generating a reliable theca cell culture model. Using luciferase assays in theca cells and chicken embryonic fibroblast (DF-1) cells, the results suggested that ESR1 and NR5A2 had potential effects on CYP19A1 promoter activity in chickens. Overexpression of ESR1, ESR2 and NR5A2 in chicken embryonic fibroblast (DF-1) cells upregulated the protein expression of CYP19A1, mutually restricted each other and formed a potential regulatory network to coordinate the expression of CYP19A1. To conclude, our results indicated that FOXL2 cannot regulate the expression of CYP19A1 at chicken embryonic stages and after sexual maturity, ESR1, ESR2 and NR5A2 form a functional network to affect the expression of CYP19A1. These results laid a foundation for further research on the transcriptional regulation of chicken aromatase.

2.
Zhongguo Zhen Jiu ; 41(12): 1405-8, 2021 Dec 12.
Artigo em Chinês | MEDLINE | ID: mdl-34936283

RESUMO

The published literature of insomnia in the elderly treated with acupuncture was retrieved in CNKI, Wanfang and VIP from the date of establishment to December 31, 2019. Association rule analysis and cluster analysis were used to summarize the acupoint selection rules of insomnia in the elderly treated with acupuncture. A total of 37 articles were included, involving 60 acupuncture prescriptions. The most commonly used acupoints were Sanyinjiao (SP 6), Shenmen (HT 7), Anmian (Extra), Baihui (GV 20), Sishencong (EX-HN 1), Neiguan (PC 6), Xinshu (BL 15) and Taixi (KI 3). The most commonly used acupoint combinations were Sanyinjiao (SP 6)-Anmian (Extra)-Baihui (GV 20)-Sishencong (EX-HN 1)-Shenting (GV 24)-Shenmen (HT 7)-Xinshu(BL 15), Xinshu(BL 15)-Pishu (BL 20)-Shenshu (BL 23)-Shenting (GV 24), Zhaohai (KI 6)-Shenmai (BL 62), Taichong (LR 3)-Ganshu (BL 18), Daling (PC 7)-Taixi (KI 3), Neiguan (PC 6)- Zusanli (ST 36) and Guanyuan (CV 4)-Qihai (CV 6)-Zhongwan (CV 12). On the basis of acupoint selection according to disease differentiation, the acupoint selection rules and characteristics of insomnia in the elderly treated with acupuncture are regulating and supplementing the spleen and kidney and treating according to spleen-kidney.


Assuntos
Terapia por Acupuntura , Distúrbios do Início e da Manutenção do Sono , Pontos de Acupuntura , Idoso , Diferenciação Celular , Humanos , Publicações , Distúrbios do Início e da Manutenção do Sono/terapia
3.
Front Pharmacol ; 12: 749626, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34925011

RESUMO

Background: Danshen Baibixiao (DB) is a traditional Chinese medicine formula, which has been used to treat psoriasis for decades. Although DB shows good efficacy in clinical practice, the pharmacological effects and underlying mechanisms of DB remain elusive. This study aimed to evaluate the anti-psoriatic effects of DB and explore its underlying mechanisms in an imiquimod (IMQ)-induced psoriasis-like mouse model. Materials and methods: DB was orally administered on IMQ-induced psoriatic mice. Psoriasis area severity index (PASI) was used to evaluate the severity of the inflammation in skin, and histological changes were evaluated by hematoxylin and eosin (H and E) staining. Levels of inflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin (IL)-17A, IL-23, IL-6, IL-1ß and IL-22 in serum were assessed by enzyme-linked immunosorbent assay (ELISA). mRNA expressions of IL-17A, IL-23, IL-6 and IL-22 were determined by real-time polymerase chain reaction (PCR). Expression levels of proteins related to NF-κB, STAT3 and MAPKs signaling pathways were measured by western blotting (WB). Results: DB significantly ameliorated the psoriatic symptoms in IMQ-induced mice. The serum levels of inflammatory cytokines (TNF-α, IL-17A, IL-23, IL-6, IL-1ß and IL-22) were decreased, and mRNA expressions of IL-17A, IL-23, IL-6 and IL-22 in skin tissues were down-regulated. Moreover, WB analysis indicated that DB inhibited the activation of NF-κB, STAT3 and MAPKs signaling pathways. Conclusion: This study confirms the anti-psoriatic activity of DB in IMQ-induced psoriasis-like mice. The possible mechanism may relate to the activities of regulating the IL-23/TH-17 axis and suppressing the activation of NF-κB, STAT3 and MAPKs signaling pathways.

4.
Pharmacol Ther ; : 108004, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34597754

RESUMO

The liver has the ability to repair itself after injury; however, a variety of pathological changes in the liver can affect its ability to regenerate, and this could lead to liver failure. Mesenchymal stem cells (MSCs) are considered a good source of cells for regenerative medicine, as they regulate liver regeneration through different mechanisms, and their efficacy has been demonstrated by many animal experiments and clinical studies. Induced pluripotent stem cells, another good source of MSCs, have also made great progress in the establishment of organoids, such as liver disease models, and in drug screening. Owing to the recent developments in MSCs and induced pluripotent stem cells, combined with emerging technologies including graphene, nano-biomaterials, and gene editing, precision medicine and individualized clinical treatment may be realized in the near future.

5.
Cell Tissue Res ; 386(3): 661-677, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34599689

RESUMO

Determining the source of primary cells is conductive to enriching sufficient cells with immortal potential thereby improving the success rate of establishing cell lines. However, most of the existing insect cell lines are established by mixing and fragmentation of explants. At present, the origin of cell lines can only be determined according to the cultured tissues, so it is impossible to determine which cell types they come from. In this study, a new cell line designated IOZCAS-Myse-1 was generated from pupal ovaries of the migratory pest Mythimna separata by explant tissues to derive adherent cultures. This paper mainly shows the further descriptive information on the origin of primary cells in the process of ovarian tissue isolation and culture. Phospho-histone H3 antibody-labeled cells with mitotic activity showed that the rapidly developing somatic cells in vivo gradually stopped proliferation when cultured ex vivo. The primary cells dissociated outside the tissue originated from the lumen cells, rather than the germ cells or the follicular epithelium cells. The results suggest that the newly established cell line IOZCAS-Myse-1 had two possible sources. One is the mutation of lumen cells in the vitellarium, and the other is the stem cells with differentiation potential in the germarium of the ovarioles. Moreover, the newly established cell line is sensitive to the infection of Autographa californica multiple nucleopolyhedrovirus, responds to 20-hydroxyecdysone and has weak encapsulation ability. Therefore, the new cell line can be a useful platform for replication of viral insecticides, screening of hormone-based insecticides and immunology research.

6.
Food Res Int ; 149: 110675, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34600677

RESUMO

Pharmacological and clinical studies have consistently demonstrated that polysaccharides exhibit great potential on immune regulation. Polysaccharides can interact directly or indirectly with the immune system, triggering cell-cell communication and molecular recognition, leading to immunostimulatory responses. Gut microbiota is adept at foraging polysaccharides as energy sources and confers benefits in the context of immunity and chronic autoimmune disease, such as multiple sclerosis. A compelling set of interconnectedness between the gut microbiota, natural polysaccharides, and immune regulation has emerged. In this review, we highlighted the available avenues supporting the existence of these interactions, with a focus on cytokines-mediated and SCFAs-mediated pathways. Additionally, the neuroimmune mechanisms for gut microbiota communication with the brain in multiple sclerosis are also discussed, which will lay the ground for ameliorate multiple sclerosis via polysaccharide intervention.


Assuntos
Microbioma Gastrointestinal , Esclerose Múltipla , Encéfalo , Ácidos Graxos Voláteis , Humanos , Esclerose Múltipla/tratamento farmacológico , Polissacarídeos
7.
Zhongguo Zhen Jiu ; 41(10): 1171-4, 2021 Oct 12.
Artigo em Chinês | MEDLINE | ID: mdl-34628753

RESUMO

Through analyzing the indication distribution of the different acupoints located at the upper limbs recorded in Science of Acupoints and Science of Meridians and Acupoints, the industry planning teaching materials of traditional Chinese medicine, it is discovered that the acupoints located at the upper arms are commonly selected for the treatment of scrofula and goiter, while the acupoints below the elbow at the hand meridians and those at the lower limbs of the foot meridians which running through the neck, do not have the similar indications. Based on a further analysis on the literature at ancient and modern times, it is believed that the acupoints located on the lateral side of the upper arms, especially those at the large intestine meridian of hand-yangming perhaps have the specific effect in treatment of scrofula and goiter.


Assuntos
Bócio , Meridianos , Tuberculose dos Linfonodos , Pontos de Acupuntura , Braço , Humanos
8.
Small ; 17(47): e2104083, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34655154

RESUMO

Nanozymes have offered remarkable advantages over natural enzymes and found widespread applications including biosensors, immunoassays, nanomedicines, and environmental remediation. Oxidation of o-phenylenediamine (OPD) by nanozymes has been listed as a standard protocol for determining nanozyme activities. Given the complexity of OPD oxidation processes, however, the mechanism of nanozyme-catalyzed oxidation of OPD remains elusive. In this report, mechanistic studies of nanozyme-catalyzed oxidation of OPD are performed and a distinguishably different mechanism from that of natural enzymes is found. A combination of Fourier transform infrared spectroscopy, nuclear magnetic resonance, electrospray ionization mass spectrometry, and electron microscopic studies provides compelling evidence that polymerization of OPD occurs on the surface of several different nanozymes. The unexpected polymerization causes a dense coating layer of poly(o-phenylenediamine) (POPD) on nanozymes renders the intrinsic properties of nanozymes. Therefore, this fundamental discovery raise serious concerns using OPD-based colorimetric method for determining nanozyme activities. Without examining the surface change of nanozymes after catalytic reactions, the use of OPD-based colorimetric method for determining nanozyme activities is strongly discouraged. Furthermore, POPD is discovered as a new oxidase mimic, and this new mechanism also provides a general and robust method to coat nanomaterials with POPD polymers of enzyme-mimicking properties.

9.
Biotechnol Biofuels ; 14(1): 194, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34598725

RESUMO

BACKGROUND: Sunflower stalk pith, residue from the processing of sunflower, is rich in pectin and cellulose, thereby acting as an economic raw material for the acquisition of these compounds. In order to increase the commercial value of sunflower processing industry, a two-step dilute sulfuric acid treatment process was conducted on spent sunflower stalk pith to obtain the value-added products, pectin and glucose. RESULTS: In this study, pectin was firstly extracted under mild acid condition to avoid pectin degradation, which was conducted at 90 °C with a pH of 2.0 for 2 h, and ~0.14 g/g of pectin could be recovered. Then the remaining solids after pectin extraction were subjected to the reinforced treatment process with 0.75% H2SO4 at 150 °C for 30 min to further improve enzymatic hydrolysis efficiency. Moreover, by combining a fed-batch enzymatic hydrolysis strategy, a solid loading content of 16% was successfully achieved and the glucose titer reached 103.1 g/L with a yield of 83.6%. CONCLUSION: Finally, ~140 g pectin and 260 g glucose were produced from 1 kg of raw sunflower stalk pith using the integrated biorefinery process. This work puts forward a two-step dilute acid pretreatment combined with enzymatic hydrolysis method to produce pectin and glucose from sunflower spent waste.

10.
J Formos Med Assoc ; 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34686412

RESUMO

BACKGROUND/PURPOSE: Gastroparesis is a common but easily overlooked disease. Gastric peroral endoscopic myotomy (G-POEM) is one of the third-space endoscopy techniques to treat gastroparesis. In this study, we aimed to evaluate the efficacy and safety of G-POEM for patients with refractory gastroparesis. METHODS: Between December 2017 and 2020, we consecutively enrolled patients with gastroparesis who failed after the administration of several kinds of medication and repeated admission for nutritional support. All patients underwent gastric emptying scintigraphy and answered a questionnaire on Gastroparesis Cardinal Symptom Index (GCSI). Demographic data, endoscopic procedure, and post procedural outcome were analyzed. RESULTS: A total of 11 (9 women and 2 men) patients with refractory gastroparesis (nine with diabetes mellitus, one systemic lupus erythematosus, and one idiopathic) were enrolled. The mean (±standard deviation (SD)) procedure time was 61.82 (±18.99) min with technical and clinical success rates of 100% and 81.82%, respectively. A statistically significant improvement was observed in the clinical severity (mean GCSI score 36.00 vs. 14.73, p < 0.0001) and gastric emptying time (mean T1/2 341.92 vs. 65.92 min, p = 0.016) after G-POEM. Hospital stay was 7.18 (±4.49) days without mortality. Complications included 4 (36.36%) patients with self-limited postprocedural abdominal pain and 3 (27.27%) patients with intra-procedural pneumoperitoneum. During the mean follow-up period of 554.36 days, one (9.09%) patient had relapsed clinical symptoms after 6 months. CONCLUSIONS: G-POEM is an efficient and safe pylorus-directed endoscopic therapy for refractory gastroparesis with promising results.

11.
Age Ageing ; 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34673897

RESUMO

BACKGROUND: Multiple myeloma is a disease of the older people, whose prognoses are highly heterogeneous. The International Myeloma Working Group (IMWG) proposed a geriatric assessment (GA) based on age, functional status and comorbidities to discriminate between fit and frail patients. Given the multidimensional nature of frailty and the relatively recent exploration of frailty in the field of MM, reaching a consensus on the measurement of frailty in MM patients remains challenging. OBJECTIVE: We sought to assess the feasibility of performing a comprehensive GA (CGA) in older MM patients in a real-world and multicentre setting and to evaluate their baseline CGA profiles. RESULTS: We studied 349 older patients with newly diagnosed MM (age range, 65-86 years). Our results showed that a CGA is feasible for older MM patients. Using the IMWG-GA criteria, we identified significantly more frail patients in our cohort comparing to in the IMWG cohort (43% vs 30%, P = 0.002). In the IMWG-GA 'fit' group, risk of malnutrition, depression and cognitive impairment remains. The median follow-up time was 26 months (range 1-38). The median overall survival (OS) was 34.7 months, and the estimated 3-year OS rate was 50%. A high MNA-SF score (MNA-SF ≥ 12), low GDS score (GDS ≤ 5) and high CCI score (CCI ≥ 2) can be used to predict the OS of older patients with newly diagnosed MM. This study is registered at www.clinicaltrials.gov (NCT03122327). CONCLUSIONS: Our study justifies the need for a CGA in older patients with newly diagnosed MM.

12.
Bioengineered ; 12(1): 7033-7045, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34587869

RESUMO

To investigate the EMD's capacity in BMSCs osteogenic differentiation. In vivo and in vitro, BMSCs were treated with EMD, scanning electron microscopy, and Alizarin Red staining were used to detect the changes in the osteogenic ability of BMSCs, and the proliferation ability of BMSCs was evaluated by CCK8. In addition, by adding xav939, a typical inhibitor of Wnt/ß-catenin signaling pathway, the regulatory function of Wnt/ß-catenin signaling was clarified. The results showed that EMD promote cell proliferation and 25 µg/ml EMD had the most significant effect. Cells inducing osteogenesis for 2 and 3 even 4 weeks, the cell staining is deeper in EMD treated group than that of the control (P < 0.05) by alizarin Red staining, suggesting more mineralization of BMSCs. In vivo implanting the titanium plate wrapped with 25 µg/ml EMD treated-BMSC film into nude mice for 8 weeks, more nodules were formed on the surface of the titanium plate than that the control (P < 0.05). HE showed that there is a little blue-violet immature bone-like tissue block. Besides, the expression of RUNX Family Transcription Factor 2 (Runx2), Osterix, Osteocalcin (OCN), collagen I (COLI), alkaline phosphatase (ALP) and ß-catenin were inhibited in xav939 group (P < 0.05); Inversely, all were activated in EMD group (P < 0.05). In conclusion, EMD promoted the proliferation and osteogenic differentiation of BMSCs. EMD's function on BMSCs might be associated with the Wnt/ß-catenin signaling pathway.

13.
J Mol Model ; 27(10): 307, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34591190

RESUMO

Due to the diversity of solid nitrogen structure, its phase transition has been a hot topic for many scientists. Herein, we first studied the structural softening of rhombohedral solid nitrogen under pressure using first-principles calculations. Then, a new criterion, Egret criterion, was proposed to predict the whole process from beginning to end of structural phase transition of solid nitrogen. Based on the discussion of acoustic phonons, we concluded that the phase transition of rhombohedral solid nitrogen starts from k-point F along the [- 1, - 1, 0] direction in a-axis, and the structural phase transition velocity is slow. Also, we use the Egret criterion proposed by us to predict the emergence of ξ-N2 and the stability of ξ-N2 at 17 GPa and 22 GPa, respectively, and this result is in good agreement with the phase diagram of nitrogen.

14.
Science ; 374(6563): 77-81, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34591631

RESUMO

[Figure: see text].

16.
Eur J Pharm Sci ; 167: 106009, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34537373

RESUMO

Pulmonary fibrosis is a chronic progressive lung disease that lacks effective treatments in clinic. It is characterized by repair disorder of epithelial cells, formation of fibroblast foci as well as destruction of alveolar structure. Previously we first determined that parent peptide DR8 (DHNNPQIR-NH2) has anti-fibrotic activity in bleomycin-induced mice. In order to further improve the druggability of DR8, including anti-fibrotic activity, stability and security, the structure-activity relationship was investigated using a series of D-amino acid and alanine scanning analogs of DR8. The results indicated that peptides DR8-3D and DR8-8A exhibited potent anti-fibrotic activity and better stability. Further mechanism research revealed that DR8-3D and DR8-8A ameliorated lung fibrosis by inhibiting TGF-ß1 mediated epithelial-mesenchymal transition process and ERK1/2 signaling pathway in vitro and in vivo. Moreover, we found that anti-fibrotic activity of DR8 was closely related to the residues aspartic acid (Asp)1, histidine (His)2, proline (Pro)5 and glutamine (Gln)6, which suggested that the position of residues asparagine (Asn)3, asparagine (Asn)4, isoleucine (Ile)7 and arginine (Arg)8 could be further modified to optimized its anti-fibrotic effect. Therefore, we consider that DR8-3D and DR8-8A not only could be used as a potential leading compound for the treatment of bleomycin-induced lung fibrosis but also laid a foundation for the development of new anti-fibrotic drugs.


Assuntos
Fibrose Pulmonar , Fator de Crescimento Transformador beta1 , Animais , Bleomicina , Transição Epitelial-Mesenquimal , Pulmão/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fator de Crescimento Transformador beta1/metabolismo
18.
J Agric Food Chem ; 69(37): 10932-10942, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34505780

RESUMO

The intestinal flora serves a critical role in the development of hyperuricemia-induced chronic kidney disease (CKD). We previously found that natural flavonol fisetin exhibited nephroprotective effects in hyperuricemic mice. However, the mechanism remains largely unknown. To investigate the underlying mechanism of fisetin, mice were fed with potassium oxonate and adenine to introduce hyperuricemia-induced CKD. Fisetin improved kidney function, ameliorated renal fibrosis, and restored enteric dysbacteriosis in hyperuricemia-induced CKD mice. Meanwhile, gut microbiota-derived tryptophan metabolites, especially l-kynurenine, showed correlations with nephroprotective profiles of fisetin. Additionally, the kidney expression of the aryl hydrocarbon receptor (AHR), an endogenous receptor of l-kynurenine, was enhanced in hyperuricemic mice and further reduced in fisetin-treated mice. Finally, in vitro results showed that inhibition of AHR activation attenuated l-kynurenine-induced fibrosis. These results highlighted that fisetin protected against hyperuricemia-induced CKD via modulating gut microbiota-mediated tryptophan metabolism and AHR activation.


Assuntos
Microbioma Gastrointestinal , Hiperuricemia , Insuficiência Renal Crônica , Animais , Flavonóis , Hiperuricemia/tratamento farmacológico , Camundongos , Receptores de Hidrocarboneto Arílico/genética , Insuficiência Renal Crônica/tratamento farmacológico , Triptofano
19.
Lasers Med Sci ; 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34562156

RESUMO

The 755-nm Alexandrite Laser has a good clinical effect in treating resistant port wine stain, without causing thermal damage of normal tissue and side effects such as purpura. However, little is known about the mechanism of vascular damage induced by 755-nm laser irradiation, which restricts the optimization of laser parameters. In this work, the thermal damage model and the pressure damage model were used to study the damage mechanism of 755-nm laser irradiation on vessels, and the incident energy density and pulse width required for vascular damage were determined according to the damage mode. Under the irradiation of 755-nm laser, the vascular injury pattern was the co-occurrence of vessel rupture and vessel constriction, and the energy density required for the treatment of vessels with a diameter of 200 µm to reach the damage threshold was the lowest.

20.
Mol Biol Rep ; 48(8): 5955-5964, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34350550

RESUMO

BACKGROUND: Vitiligo is a complex disease in which patchy depigmentation is the result of an autoimmune-induced loss of melanocytes in affected regions. On the basis of a genome-wide linkage analysis of vitiligo in the Chinese Han population, we previously showed significant evidence of a linkage between 22q12 and vitiligo. Our aim in the current study was to identify vitiligo susceptibility variants within an expanded region of the 22q12 locus. METHODS AND RESULTS: An in-depth analysis of the expanded region of the 22q12 locus was performed by imputation using a large GWAS dataset consisting of 1117 cases and 1701 controls. Eight nominal SNPs were selected and genotyped in an independent cohort of Chinese Han individuals (2069 patients and 1370 control individuals) by using the Sequenom MassArray iPLEX1 system. The data were analyzed with PLINK 1.07 software. The C allele of rs730669 located in ZDHHC8/RTN4R showed a strong association with vitiligo (P = 3.25 × 10-8, OR = 0.81). The C allele of rs4820338 located in VPREB1 and the A allele of rs2051582 (a SNP reported in our previous study) located in IL2RB showed a suggestive association with vitiligo (P = 1.04 × 10-5, OR = 0.86; P = 1.78 × 10-6, OR = 1.27). The three identified SNPs showed independent associations with vitiligo in a conditional logistic regression analysis (all P < 1.0 × 10-5; all D' < 0.05 and r2 < 1.0 × 10-4). CONCLUSIONS: The study reveals that two novel variants rs730669 (ZDHHC8/RTN4R) and rs4820338 (VPREB1) on 22q11.2 might confer susceptibility to vitiligo and affect disease subphenotypes. The presence of multiple independent variants emphasizes their important roles in the genetic pathogenesis of disease.

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