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Aging hallmarks of the primate ovary revealed by spatiotemporal transcriptomics

PROTEIN & CELL 2024年第5期15卷 364-384页

作者： Lu, Huifen Jing, Ying Zhang, Chen Ma, Shuai Zhang, Weiqi Huang, Daoyuan Zhang, Bin Zuo, Yuesheng Qin, Yingying Liu, Guang-Hui Yu, Yang Qu, Jing Wang, Si Capital Med Univ Xuanwu Hosp Natl Clin Res Ctr Geriatr Disorders Adv Innovat Ctr Human Brain Protect Beijing 100053 Peoples R China Capital Med Univ Xuanwu Hosp Aging Translat Med Ctr Int Ctr Aging & Canc Beijing Municipal Geriatr Med Res Ctr Beijing 100053 Peoples R China Chinese Acad Sci Inst Zool State Key Lab Membrane Biol Beijing 100101 Peoples R China Univ Chinese Acad Sci Beijing 100049 Peoples R China Beijing Inst Stem Cell & Regenerat Med Beijing 100101 Peoples R China Chinese Acad Sci Inst Stem cell & Regenerat Beijing 100101 Peoples R China Chinese Acad Sci Inst Zool Key Lab Organ Regenerat & Reconstruct Beijing 100101 Peoples R China Aging Biomarker Consortium Beijing 100101 Peoples R China Fifth Peoples Hosp Chongqing Chongqing 400062 Peoples R China Chinese Acad Sci Inst Zool State Key Lab Stem Cell & Reprod Biol Beijing 100101 Peoples R China Chinese Acad Sci Beijing Inst Genom CAS Key Lab Genom & Precis Med Beijing 100101 Peoples R China China Natl Ctr Bioinformat Beijing 100101 Peoples R China Univ Chinese Acad Sci Sino Danish Coll Beijing 101408 Peoples R China Sino Danish Ctr Educ & Res Beijing 101408 Peoples R China Peking Univ Third Hosp Ctr Reprod Med Dept Obstet & Gynecol Beijing 100191 Peoples R China Peking Univ Third Hosp Clin Stem Cell Res Ctr Beijing 100191 Peoples R China Shandong Univ Cheeloo Coll Med Ctr Reprod Med Jinan 250012 Peoples R China Natl Res Ctr Assisted Reprod Technol & Reprod Gene Shandong Prov Clin Res Ctr Reprod Hlth Shandong Key Lab Reprod Med Key Lab Reprod EndocrinolMinist Educ Jinan 250012 Peoples R China

The ovary is indispensable for female reproduction, and its age-dependent functional decline is the primary cause of infertility. However, the molecular basis of ovarian aging in higher vertebrates remains poorly understood. Herein, we apply spatiotemporal transcriptomics to benchmark architecture organization as well as cellular and molecular determinants in young primate ovaries and compare these to aged primate ovaries. From a global view, somatic cells within the non-follicle region undergo more pronounced transcriptional fluctuation relative to those in the follicle region, likely constituting a hostile microenvironment that facilitates ovarian aging. Further, we uncovered that inflammation, the senescent-associated secretory phenotype, senescence, and fibrosis are the likely primary contributors to ovarian aging (PCOA). Of note, we identified spatial co-localization between a PCOA-featured spot and an unappreciated MT2 (Metallothionein 2) highly expressing spot (MT2high) characterized by high levels of inflammation, potentially serving as an aging hotspot in the primate ovary. Moreover, with advanced age, a subpopulation of MT2high accumulates, likely disseminating and amplifying the senescent signal outward. Our study establishes the first primate spatiotemporal transcriptomic atlas, advancing our understanding of mechanistic determinants underpinning primate ovarian aging and unraveling potential biomarkers and therapeutic targets for aging and age-associated human ovarian disorders.

关键词： spatial transcriptome primate ovary aging senescence inflammation ENDOCRINOLOGY SENESCENCE DYNAMICS CANCER ATLAS CELLS GENE

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Insulin Resistance in Polycystic ovary Syndrome Improved by Chinese Medicine Dingkun Pill(定坤丹):A Randomized Controlled Clinical Trial

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Chinese Journal of Integrative Medicine 2019年第4期25卷 246-251页

作者： DENG Yan XUE Wei WANG Yan-fang LIU Xiao-hui ZHU Shi-yang MA Xiao ZUO Hong-ling JIANG Jian-fa ZHENG Ting-ping SUN Ai-jun Department of Obstetrics and Gynecology Peking Union Medical College HospitalPeking Union Medical CollegeChinese Academy of Medical Sciences Technology Center for Protein Sciences School of Life SciencesTsinghua University Department of Obstetrics and Gynecology The Second Hospital of Hebei Medical University Department of Obstetrics and Gynecology Third Xiangya HospitalCentral South University Department of Obstetrics and Gynecology Beijing Chaoyang Hospital Affiliated of Capital Medical University

Objective: To assess the ef?cacy and safety of the Chinese medicine Dingkun Pill(定坤丹,DKP) on insulin resistance in women with polycystic ovary syndrome(PCOS).Methods: A total of 117 women with PCOS were randomly assigned to Group A(38 women),Group B(40 women),or Group C(39 women) in a randomization sequence with SAS software and a 1:1:1 allocation ratio using random block sizes of 6,and were given 7 g of oral DKP daily(Group A),1 tablet of Diane-35 orally daily(Group B),or 7 g of oral DKP daily plus 1 tablet of Diane-35 orally daily(Group C).Patients took all drugs cyclically for 21 consecutive days,followed by 7 drug-free days.The treatment course for the 3 groups was continued for 3 consecutive months.Oral glucose tolerance tests(OGTT)were performed before treatment and again after 2 and 3 months of therapy,respectively,and homeostasis model assessment for insulin resistance(HOMA-IR) and quantitative insulin sensitivity check index(QUICKI) were calculated.Results: Of 117 women with PCOS,110 completed the entire course of therapy: 35 in Group A,36 in Group B,and 39 in Group C.After treatment,all three groups showed signi?cant decreases in fasting glucose: at1 h glucose decreased signi?cantly in Group A(by 0.5±1.4 mmol/L,P=0.028) and Group C(by 0.5±1.2 mmol/L,P=0.045); while showing a tendency to increase in Group B(by 0.4±1.9 mmol/L,P=0.238).HOMA-IR decreased signi?cantly in Group C [by 0.5(–2.2 to 0.5) m IU mmol/L2,P=0.034].QUICKI was signi?cantly increased in Groups A and C(by 0.009±0.02,P=0.033 and by 0.009±0.027,P=0.049,respectively),while no change was observed in Group B.Repeated-measure ANOVA showed that the absolute changes in all parameters(except for glucose at1 h),including glucose and insulin levels at all time-points during OGTT and in HbA1 c,HOMA-IR,and QUICKI,were not signi?cantly different among the 3 groups after treatment(P>0.05).Conclusion: DKP or DKP combined with Diane-35 produce a slight improvement in insulin sensitivity compared with Diane-35 alone in PCOS patients(Trial Registration: Cli

关键词： Diane-35 Dingkun Pill Chinese medicine polycystic ovary syndrome oral glucose tolerance tests insulin resistance

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Community structure, dispersal ability and functional profiling of microbiome existing in fat body and ovary of the brown planthopper, Nilaparvata lugens

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Insect Science 2019年第4期26卷 683-694页

作者： Jian-Hua Zhang Na Yu Xi-Xia Xu Ze-Wen Liu Key laboratory of Integrated Management of Crop Diseases and Pests (Ministry of Education) College of Plant Protection Nanjing Agricultural University Nanjing China

The endosymbionts play vital roles in growth, development and reproduction in insects. Yeast-like endosymbionts (YLSs) have been well studied in Nilaparvata lugens (N. lugens), but little is known about the tissue-specific bacterial microbiomes, especially on the microbial intersection among internal tissues. Here, the correlation of microbial composition, structure, dispersal ability and functional profiling were illuminated in two tissues, the fat body and ovary in N. lugens. A total of 11 phyla and 105 genera were captured from all samples;Firmicutes and Proteobacteria were the most predominant and accounted for more than 99% in all samples. However, the relative abundance ofFirmicutes and Proteobacteria was significantly different in ovary and fat body through Fisher's Least Significant Difference test. Microbial diversity but not the richness index in the two tissues exhibited significant difference. Furthermore, the microbial community structure of the ovary and fat body were primarily determined by tissue quality. Firmicutes showed strong dispersal ability between ovary and fat body based on the quantitative null model assessing, indicating the frequent interaction of these microbiomes in the two tissues. In addition, the Kyoto Encyclopedia of Genes and Genomes pathways of microbial participation were delineated. The ten most abundant pathways counted for over 46% of the annotation and were shared between the two tissues, mainly containing Energy Metabolism and Amino Acid Metabolism/Biosynthesis. The results will provide insights into the correlation of microbial community structure between ovary and fat body of N. lugens.

关键词： dispersal ability fat body functional profiling microbial structure Nilaparvata lugens ovary

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Neuroendocrine characteristics of induced pluripotent stem cells from polycystic ovary syndrome women

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Protein & Cell 2019年第7期10卷 526-532页

作者： Zheying Min Yue Zhao Jing Hang Yun Ren Tao Tan Yong Fan Yang Yu Key Laboratory for Major Obstetric Diseases of Guangdong Province The Third Affiliated Hospital of Guangzhou Medical University Guangzhou 510150 China Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology and Key Laboratory of Assisted Reproduction Ministry of Education Center for Reproductive Medicine Department of Obstetrics and Gynecology Peking University Third Hospital Beijing 100191 China Peking-lsinghua Center for Life Sciences Academy for Advanced Interdisciplinery Studies Peking University Beijing 100871 China Yunnan Key Laboratory of Primate Biomedical Research Institute of Primate Translational Medicine Kunming University of Science and Technology Kunming 650500 China

Dear Editor, Polycystic ovary syn drome (PCOS) is a comm on female reproductive endocrinopathy that afflicts up to 10%-15% of women in reproductive age worldwide (Nestler, 2016). Women with PCOS exhibit hyperandrogenism, intermittent/ absent menstrual cycles, and polycystic ovaries on ultrasound (Rotterdam, 2004). The pathophysiology of PCOS extends beyond infertility and hirsutism to hypothalamic neuroendocrine dysfunotion (Goodarzi et al., 2011). Most wome n with PCOS exhibit in creased luteinizing horm one (LH) levels, resulting from high-frequency gonadotropin-releasing hormone (GnRH) secretion (Cimino et al., 2016). Pren ata I testostero ne (T) treatment in sheep results in disrupted steroid feedback on gonadotropin release, which in creases pituitary sen sitivity to GnRH and subseque ntly leads to LH hypersecretion (Sullivan and Moenter, 2004;Cardoso et al., 2016). A recent study shows that GnRHdependent LH pulsatility and secretion are elevated by anti- Mullerian hormone (AMH) in PCOS disease. The increased prenatal AMH reprograms fetus and induces PCOS in adults (Tata et al., 2018). Furthermore, the androgen receptor (AR) plays a role in hyperandrogenism and ovarian folliculoge esis in PCOS (Wang et al., 2015;Abbott, 2017). However, the disease mechanism behind PCOS remains unclear, and current management focuses on treating the symptoms but not the mechanism (Chen et al., 2016;Shi et al., 2018). A further understanding of this disease is necessary to uncover the pathology of PCOS and develop new potential therapeutic avenues and drugs.

关键词： Neuroendocrine characteristics induced pluripotent stem cells polycystic ovary

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Controversial conclusions from two randomized controlled trials for acupuncture’s effects on polycystic ovary syndrome or in vitro fertilization support

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Journal of Integrative Medicine 2020年第2期18卷 89-91页

作者： Sherman Gu Arthur Yin Fan Federation of Chinese Medicine&Acupuncture Societies of Australia Ltd(FCMA) MelbourneVictoria 3150Australia Knox Chinese Healing&Myotherapy Wantirna SouthVictoria 3152Australia American TCM Association ViennaVA 22182USA McLean Center for Complementary and Alternative Medicine PLCViennaVA 22182USA

Two reports of trials investigating the potential effect of acupuncture in increasing live birth rate(LBR) in women with polycystic ovary syndrome(PCOS) or those undergoing in vitro fertilization(IVF) were published by Journal of American Medical Association in 2017 and 2018 respectively. The trial investigators did not recommend acupuncture for the women with PCOS or IVF based on their findings. This paper raises the concern that the findings that acupuncture did not increase LBR for women with PCOS or undergoing IVF may be the result of methodological flaws in the studies and unintended bias such as use of an invalid control intervention and underestimation of the true acupuncture effect. Therefore, their findings may not be a valid reflection of acupuncture’s effect in improving LBR in women with these clinical conditions.

关键词： Acupuncture Randomized controlled trial Polycystic ovary syndrome Fertilization in vitro Traditional Chinese medicine

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Characterization and expression analysis of gonad specific igf3 in the medaka ovary

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Aquaculture and Fisheries 2022年第3期7卷 259-268页

作者： Jiale Xie Ying Zhong Yuli Zhao Wenjie Xie Jing Guo Lang Gui Mingyou Li International Research Center for Marine Biosciences Ministry of Science and TechnologyShanghai Ocean UniversityChina Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources Ministry of EducationShanghai Ocean UniversityShanghai201306China

The gonad specific expression of insulin-like growth factor 3(igf3)has suggested an important role of igf3 in fish reproduction.In this study,medaka igf3 was isolated and its expression patterns were compared with igf1,and germ cell gene vasa in adult medaka ovary.Molecular cloning and sequencing showed that the open reading frame(ORF)of medaka igf3 was comprised of 501 nucleotides and encoded 166 amino acid residues.Reverse transcription polymerase chain reaction(RT-PCR)analysis showed that igf3 RNA was specifically expressed in developing embryos and adult gonads of both sexes.Real time quantitative PCR(q-PCR)indicated that igf3 expression was gradually increased during oogenesis,and reached its highest level at stage V.Using Chromogenic and fluorescent in situ hybridization,igf3 was shown to be present in the germ cells of oogonia and in oocytes at stages I-III,as well as abundant in granulosa cells and theca cells of oocytes at stages IV-V.In addition,igf3 and igf1 were expressed mutually in the outer theca cells of stage V oocytes in ovary.Collectively,we demonstrated that gonad specific igf3 could mark medaka ovarian somatic cells and germ cells.These findings highlight the importance of igf3 during ovarian development.

关键词： igf3 igf1 Medaka ovary

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MIF May Participate in Pathogenesis of Polycystic ovary Syndrome in Rats through MAPK Signalling pathway

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Current Medical Science 2018年第5期38卷 853-860页

作者： Dan-ni ZHOU Sai-jiao LI Jin-li DING Tai-lang YIN Jing YANG Hong YE Chongqing Institute of Reproduction and Genetics Chongqing Health Center for Women and ChildrenChongqing 400010China Reproductive Medical Center Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic DevelopmentRenmin Hospital of Wuhan UniversityWuhan 430060China

The polycystic ovary syndrome (PCOS) model was established in fats and correlation between the expression of macrophage migration inhibitory factor (MIF) and cytokinesis with the MAPK signalling pathway in the rat ovary was measured. The PCOS model in rats was established by dehydroepiandrosterone (DHEA).Thirty sexually immature female Sprague-Dawley rats were randomly and equally assigned to three groups:control group,PCOS group,and PCOS with high-fat diet (HFD) group.Serum hormones were assayed by radioimmunoassay (RIA).The ovaries'were immunohistochemically stained with MIF,and the expression of MIF,p-JNK and p-p38 was detected by Western blotting in ovaries.The serum testosterone level,LH concentration,LH/FSH ratio,fasting insulin level and HOMA IR index in the PCOS group (6.077±0.478,13.809±1.701,1.820±0.404,10.83±1.123 and 1.8692±0.1096)and PCOS with HFD group (6.075±0.439,14.075±1.927,1.779±0.277,10.20±1.377 and 1.7736±0.6851)were significantly higher than those in the control group (4.949±0.337, 2.458±0.509,1.239±0.038,9.53±0.548 and 1.5329±0.7363),but there was no significant difference between the PCOS group and PCOS with HFD group.The expression levels of MIF,p-JNK,and p-p38 in the PCOS group (0.4048±0.013,0.6233±0.093 and 0.7987±0.061)and PCOS withHFD group (0.1929±0.012,0.3346±0.103 and 0.3468±0.031)were obviously higher than those in control group (0.2492±0.013, 0.3271±0.093 and 0.3393±0.061),but no Significant difference was observed between PCOS group and PCOS with HFD group.It was suggested that MIF may participate in the pathogenesis of PCOS through the MAPK signalling pathway in PCOS rats induced by DHEA.

关键词： polycystic ovary syndrome high-fat diet dehydroepiandrosterone migration inhibitory factor MAPK signalling pathway rats

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Identification of Sheep ovary Genes Potentially Associated with Off-season Reproduction

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Journal of Genetics and Genomics 2012年第4期39卷 181-190页

作者： Lei Chen Ka Liu Zongsheng Zhao Hugh T.Blair Peng Zhang Daquan Li Runlin Z.Ma College of Animal Science and Technology Shihezi UniversityXinjiang 832000China State Key Laboratory of Molecular Developmental Biology Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing 100101China Institute of Veterinary Animal and Biomedical Sciences Massey UniversityNew Zealand IGDB-Massey Joint Research Center for Sheep Breeding and Developmental Biology Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing 100101China

Off-season reproduction is a favorable economic trait for sheep industry. Hu sheep, an indigenous Chinese sheep breed, demonstrates a higher productivity of lambs and displays year-around oestrous behavior under proper nutrition and environment. The genetic basis behind these traits, however, is not well understood. In order to identify genes associated with the off-season reproduction, we constructed a suppression subtractive hybridization （SSH） cDNA library using pooled ovary mRNAs of 6 oestrous Hu females as a tester and the pooled ovary mRNAs of 6 non-oestrous Chinese Merino females as a driver. A total of 382 resulting positive clones were obtained after the SSH. We identified 114 differentially up-regulated genes in oestrous Hu sheep by using subsequent screening and DNA sequencing, of which 8 were previously known, 93 were reported for the first time in sheep, and 13 were novel with no significant homology to any sequence in the DNA databases. Functions of the genes identified are related to cell division, signal transduction, structure, metabolism, or cell defense. To validate the results of SSH, 6 genes （Ntrk2, Ppap2b, Htral, Nidl, Serpine2 and Foxola） were selected for conformational analysis using quantitative real-time PCR （qRT-PCR）, and two of them （Htral and Foxola） were verified by Northern blot. All of the 6 genes were differentially up-regulated in the ovary of oestrous Hu. It is obvious that off-season reproduction is a complex trait involving multiple genes in multiple organs. This study helps to provide a foundation for the final identification of functional genes involved in the sheep ovary.

关键词： Hu sheep Suppression subtractive hybridization Oestrous ovary cDNA library

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Primary sarcoma of the ovary： clinicopathological characteristics, prognostic factors and evaluation of therapy

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Chinese Medical Journal 2011年第9期124卷 1316-1321页

作者： DAI Yi SHEN Keng LANG Jing-he HUANG Hui-fang PAN Ling-ya WU Ming YANG Jia-xin ZHONG Ding-rong Department of Obstetrics and Gynecology Peking Union Medical College HospitalPeking Union Medical College & Chinese Academy of Medical Sciences Beijing 100730 China Department of Pathology Peking Union Medical College HospitalPeking Union Medical College & Chinese Academy of Medical Sciences Beijing 100730 China

Background The primary ovarian sarcoma is a very rare malignancy. The objective of this study was to further investigate the clinicopathologic features and outcome in patients with primary sarcoma of the ovary.Methods Between 1988 and 2007, 24 patients with primary ovarian sarcoma who underwent treatment at Peking Union Medical Hospital were reviewed retrospectively. Response to treatment, progression and overall survival were analyzed.Results Patients with ovarian sarcoma had a mean age of （54.3±10.3） years, and 16 of them were postmenopausal.The most common symptom was abdominal pain, present in 14 patients. Of the 24 patients, 16 patients were pathologically diagnosed as carcinosarcoma （known as malignant mixed mesodermal tumor （MMMT））, 2 as ovarian leiomyosarcoma （LS） and 6 patients as ovarian endometrial stromal sarcoma （ESS）. The patients in optimal debulking group had a median survival period of 28 months and 1-year survival rate of 71%. The patients in suboptimal debulking group had a significantly lower median survival of 6 months （P=-0.02） and 1-year survival rate of 29%. Among the patients,23 patients received chemotherapy and most of regimens were based on platinum, 3 patients received chemoradiation.The mean number of courses of combined chemotherapy was 6.6±5.0, and the response was unsatisfactory. The median survival for the entire group was 18.7 months. The one-year survival rate was 58%, and two-year survival rate only 29%.Conclusions Ovarian primary sarcoma has a poor overall prognosis. Optimal debulking surgery appears to be of prognostic significance. There is a clear need for further study to explore the role and the regimen of platinum-based chemotherapy in primary ovarian sarcoma.

关键词： ovary sarcoma chemotherapy

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Overexpression of tyrosine phosphorylated proteins in reproductive tissues of polycystic ovary syndrome rats induced by letrozole

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Asian pacific Journal of Reproduction 2020年第6期9卷 275-282页

作者： Sudtida Bunsueb Supatcharee Arun Arada Chaiyamoon Alexander Tsang-Hsien Wu Sitthichai Iamsaard Department of Anatomy Faculty of MedicineKhon Kaen UniversityKhon Kaen40002Thailand Research Institute for Human High Performance and Health Promotion Khon Kaen University40002Khon KaenThailand The PhD Program for Translational Medicine College of Medical Science and TechnologyTaipei Medical University and Academia SinicaTaipei Graduate Institute of Medical Sciences National Defense Medical CenterTaipei

Objective:To identify the alteration of tyrosine phosphorylated protein expression in rats with polycystic ovary syndrome(PCOS).Methods:Sixteen female Sprague-Dawley rats were divided into the control and letrozole-induced PCOS groups.The oestrus cycle of rats was performed by vaginal smear.Sex hormones and morphology of the ovary,oviduct,and uterus were observed.Expressions and intensity of androgen receptor and tyrosine phosphorylated proteins of reproductive organs were investigated by Western blot.Results:Various polycysts and increased androgen receptor expression were present in the ovary of the PCOS group.The levels of follicle-stimulating hormone and testosteone were significantly higher in the PCOS group while progesterone and estradiol levels were significantly decreased as compared with the control group(Povary(52,42,and 28 kDa),oviduct(72,56,42,and 28 kDa),and uterus(53 and 42 kDa)of the PCOS group compared to the control group.Conclusions:Presence of tyrosine phosphorylated proteins in the ovary,oviduct and uterus suggests that overexpression of tyrosine phosphorylated proteins may be involved in potential mechanism of female infertility especially in PCOS.

关键词： Polycystic ovary syndrome Overexpression Tyrosine phosphorylated proteins ovary Oviduct Uterus

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